Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study.

PubMed

Rice, Gillian I; Forte, Gabriella M A; Szynkiewicz, Marcin; Chase, Diana S; Aeby, Alec; Abdel-Hamid, Mohamed S; Ackroyd, Sam; Allcock, Rebecca; Bailey, Kathryn M; Balottin, Umberto; Barnerias, Christine; Bernard, Genevieve; Bodemer, Christine; Botella, Maria P; Cereda, Cristina; Chandler, Kate E; Dabydeen, Lyvia; Dale, Russell C; De Laet, Corinne; De Goede, Christian G E L; Del Toro, Mireia; Effat, Laila; Enamorado, Noemi Nunez; Fazzi, Elisa; Gener, Blanca; Haldre, Madli; Lin, Jean-Pierre S-M; Livingston, John H; Lourenco, Charles Marques; Marques, Wilson; Oades, Patrick; Peterson, Pärt; Rasmussen, Magnhild; Roubertie, Agathe; Schmidt, Johanna Loewenstein; Shalev, Stavit A; Simon, Rogelio; Spiegel, Ronen; Swoboda, Kathryn J; Temtamy, Samia A; Vassallo, Grace; Vilain, Catheline N; Vogt, Julie; Wermenbol, Vanessa; Whitehouse, William P; Soler, Doriette; Olivieri, Ivana; Orcesi, Simona; Aglan, Mona S; Zaki, Maha S; Abdel-Salam, Ghada M H; Vanderver, Adeline; Kisand, Kai; Rozenberg, Flore; Lebon, Pierre; Crow, Yanick J

2013-12-01

Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. 74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14-20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57-1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r=-0·604; serum, r=-0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials. European Union's Seventh Framework Programme; European Research Council. Copyright © 2013 Elsevier Ltd. All rights reserved.

Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study

PubMed Central

Rice, Gillian I; Forte, Gabriella M A; Szynkiewicz, Marcin; Chase, Diana S; Aeby, Alec; Abdel-Hamid, Mohamed S; Ackroyd, Sam; Allcock, Rebecca; Bailey, Kathryn M; Balottin, Umberto; Barnerias, Christine; Bernard, Genevieve; Bodemer, Christine; Botella, Maria P; Cereda, Cristina; Chandler, Kate E; Dabydeen, Lyvia; Dale, Russell C; De Laet, Corinne; De Goede, Christian G E L; del Toro, Mireia; Effat, Laila; Enamorado, Noemi Nunez; Fazzi, Elisa; Gener, Blanca; Haldre, Madli; Lin, Jean-Pierre S-M; Livingston, John H; Lourenco, Charles Marques; Marques, Wilson; Oades, Patrick; Peterson, Pärt; Rasmussen, Magnhild; Roubertie, Agathe; Schmidt, Johanna Loewenstein; Shalev, Stavit A; Simon, Rogelio; Spiegel, Ronen; Swoboda, Kathryn J; Temtamy, Samia A; Vassallo, Grace; Vilain, Catheline N; Vogt, Julie; Wermenbol, Vanessa; Whitehouse, William P; Soler, Doriette; Olivieri, Ivana; Orcesi, Simona; Aglan, Mona S; Zaki, Maha S; Abdel-Salam, Ghada M H; Vanderver, Adeline; Kisand, Kai; Rozenberg, Flore; Lebon, Pierre; Crow, Yanick J

2015-01-01

Summary Background Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. Methods In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. Findings 74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14–20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57–1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r=−0·604; serum, r=−0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. Interpretation AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials. Funding European Union’s Seventh Framework Programme; European Research Council. PMID:24183309

Interferon-γ Inhibits Ebola Virus Infection.

PubMed

Rhein, Bethany A; Powers, Linda S; Rogers, Kai; Anantpadma, Manu; Singh, Brajesh K; Sakurai, Yasuteru; Bair, Thomas; Miller-Hunt, Catherine; Sinn, Patrick; Davey, Robert A; Monick, Martha M; Maury, Wendy

2015-01-01

Ebola virus outbreaks, such as the 2014 Makona epidemic in West Africa, are episodic and deadly. Filovirus antivirals are currently not clinically available. Our findings suggest interferon gamma, an FDA-approved drug, may serve as a novel and effective prophylactic or treatment option. Using mouse-adapted Ebola virus, we found that murine interferon gamma administered 24 hours before or after infection robustly protects lethally-challenged mice and reduces morbidity and serum viral titers. Furthermore, we demonstrated that interferon gamma profoundly inhibits Ebola virus infection of macrophages, an early cellular target of infection. As early as six hours following in vitro infection, Ebola virus RNA levels in interferon gamma-treated macrophages were lower than in infected, untreated cells. Addition of the protein synthesis inhibitor, cycloheximide, to interferon gamma-treated macrophages did not further reduce viral RNA levels, suggesting that interferon gamma blocks life cycle events that require protein synthesis such as virus replication. Microarray studies with interferon gamma-treated human macrophages identified more than 160 interferon-stimulated genes. Ectopic expression of a select group of these genes inhibited Ebola virus infection. These studies provide new potential avenues for antiviral targeting as these genes that have not previously appreciated to inhibit negative strand RNA viruses and specifically Ebola virus infection. As treatment of interferon gamma robustly protects mice from lethal Ebola virus infection, we propose that interferon gamma should be further evaluated for its efficacy as a prophylactic and/or therapeutic strategy against filoviruses. Use of this FDA-approved drug could rapidly be deployed during future outbreaks.

Innate immunity during Equid herpesvirus 1 (EHV-1) infection.

PubMed Central

Bridges, C G; Edington, N

1986-01-01

Intrinsic phagocytosis and killing of C. albicans by equine monocytes and polymorphonuclear leucocytes (PMN) was examined during Equid Herpesvirus 1 (EHV-1) (subtypes 1 or 2) and Adenovirus infections. Monocyte function increased during EHV-1 subtype 2 and Adenovirus infection. Conversely, there was an impairment of monocyte ingestion during EHV-1 subtype 1 infection which was ascribed to virus replication in peripheral blood mononuclear cells. PMN phagocytosis was not decreased in any of the infections studied. The raised levels of haemolytic complement in animals which subsequently developed EHV-1 subtype 1 induced paresis suggested an abnormality of complement turnover. Increased levels of interferon were evident in the nasal secretions of both subtype 1 and subtype 2 infected animals but only subtype 1 virus induced measurable levels of serum interferon. No intrinsic abnormality of interferon production by monocytes or lymphocytes was found. PMID:2431815

Pancreatitis induced by pegylated interferon alfa-2b in a patient affected by chronic hepatitis C.

PubMed

Cecchi, Enrica; Forte, Paolo; Cini, Elisabetta; Banchelli, Grazia; Ferlito, Chiara; Mugelli, Alessandro

2004-01-01

A middle-aged man was admitted to the ED because of nausea and vomiting, abdominal distention and fainting. A blood analysis revealed high levels of serum amylase and lipase, confirming a diagnosis of acute pancreatitis. The history showed that the patient had self-administered a single dose of pegylated interferon alfa-2b and ribavirin daily for 7 days for chronic hepatitis C. The medications were stopped and his condition gradually improved. In agreement with the literature and the Naranjo algorythm result, pegylated interferon alfa-2b is associated with acute pancreatitis. Identification of a few signs and symptoms is the first 'signal' in preventing a serious drug-induced adverse event.

Randomized, controlled pharmacokinetic and pharmacodynamic evaluation of albinterferon in patients with chronic hepatitis B infection.

PubMed

Colvin, Richard A; Tanwandee, Tawesak; Piratvisuth, Teerha; Thongsawat, Satawat; Hui, Aric Josun; Zhang, Hongfei; Ren, Hong; Chen, Pei-Jer; Chuang, Wan-Long; Sobhonslidsuk, Abhasnee; Li, Ruobing; Qi, Yin; Praestgaard, Jens; Han, Yi; Xu, Junfang; Stein, Daniel S

2015-01-01

Albinterferon is a fusion of albumin and interferon-α2b developed to improve the pharmacokinetics, convenience, and potential efficacy of interferon-α for the treatment of chronic hepatitis infections. This open-label, randomized, active-controlled, multicenter study investigated the safety and efficacy of albinterferon in patients with chronic hepatitis B virus (HBV) infection who were e-antigen (HBeAg) positive. One hundred and forty-one patients received one of four albinterferon doses/regimens or pegylated-interferon-α2a. Primary efficacy outcomes were changes in serum HBeAg and antibody, HBV-DNA, and alanine aminotransferase. Principal safety outcomes were changes in laboratory values, pulmonary function, and adverse events. The study was prematurely terminated as phase III trials in hepatitis C infection indicated noninferior efficacy but inferior safety compared with pegylated-interferon-α2a. Here, all treatment groups had a significant reduction in HBV-DNA from baseline. Reductions in HBV-DNA were not significantly different, except the 1200 μg every 4 weeks albinterferon dose which was inferior compared with pegylated-interferon-α2a. The serum alanine aminotransferase levels decreased in all arms. The per-patient incidence of adverse events was not significantly different for albinterferon (96.4-100%) and pegylated-interferon-α2a (93.1%). Total adverse events, however, were higher for albinterferon and correlated to dose. Decreased lung function was found in all arms (∼93% of patients), and was more common in some albinterferon groups. Albinterferon doses with similar anti-HBV efficacy to pegylated-interferon-α2a had higher rates of certain adverse events, particularly changes in lung diffusion capacity (http://www.clinicaltrials.gov number NCT00964665). © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Genetic predisposition to parthenium dermatitis in an Indian cohort due to lower-producing genotypes of interleukin-10 (-) 1082 G>A and (-) 819 C>T loci but no association with interferon-γ (+) 874 A>T locus.

PubMed

Khatri, R; Mukhopadhyay, K; Verma, K K; Sethuraman, G; Sharma, A

2011-07-01

Parthenium dermatitis is an activated T cell-mediated type IV hypersensitivity. Its pathogenesis is well characterized, with interindividually varying serum levels of pro- and anti-inflammatory and regulatory T-cell cytokines and coherently perturbed cross-regulation between them. The functional single nucleotide polymorphisms (SNPs) in these cytokine genes might function as risk/susceptibility factors for the disease. We analysed the serum levels of interferon (IFN)-γ and interleukin (IL)-10 cytokines in cases vs. controls and investigated whether IFN-γ (+) 874 A>T and IL-10 (-) 1082 G > A and (-) 819 C>T are associated with serum levels and genetically predispose to the disease. The study included 60 patch test-confirmed patients and 60 age- and sex-matched controls. The serum levels of cytokines were estimated by high-sensitivity enzyme-linked immunosorbent assay kits. SNP genotyping was performed by amplification refractory mutational system-polymerase chain reaction. In patients, the serum level of IFN-γ was significantly increased and that of IL-10 was significantly decreased, with no difference in IgE concentration. Genetically no IFN-γ (+) 874 A>T alleles/genotypes were associated with the disease, but a strong predisposition was found due to lower-producing genotypes of IL-10 (-) 1082 G>A and (-) 819 C>T SNPs, with 2·1 and 3·5 times more risk, respectively, while intermediate IL-10-producing genotypes provided resistance. High serum IFN-γ might play a role in disease pathogenesis, but this is genetically not endowed by the IFN-γ SNP studied. In contrast, low serum IL-10 was very much connected, with the genetics of both studied IL-10 loci. These might be key managing factors concerning pathogenesis/susceptibility. © 2011 The Authors. BJD © 2011 British Association of Dermatologists 2011.

Serum adiponectin is increased in advancing liver fibrosis and declines with reduction in fibrosis in chronic hepatitis B.

PubMed

Hui, Chee-Kin; Zhang, Hai-Ying; Lee, Nikki P; Chan, Weng; Yueng, Yui-Hung; Leung, Kar-Wai; Lu, Lei; Leung, Nancy; Lo, Chung-Mau; Fan, Sheung-Tat; Luk, John M; Xu, Aimin; Lam, Karen S; Kwong, Yok-Lam; Lau, George K K

2007-08-01

Despite the possible role of adiponectin in the pathogenesis of liver cirrhosis, few data have been collected from patients in different stages of liver fibrosis. We studied the role of adiponectin in 2 chronic hepatitis B (CHB)-patient cohorts. Serum adiponectin was quantified by enzyme-linked immunosorbent assay. One-hundred liver biopsy specimens from CHB patients with different stages of fibrosis and 38 paired liver biopsies from hepatitis B e antigen-positive patients randomized to lamivudine (n=15), pegylated interferon alfa-2a (n=15) or pegylated interferon alfa-2a plus lamivudine (n=8) therapy for 48 weeks were assessed. Serum adiponectin was detected at levels ranging over fourfold magnitude with advancing fibrosis stage and correlated positively with fibrosis stage [r=0.45, p<0.001]. CHB patients with stage 0-1 fibrosis had higher composition of high molecular weight (HMW) form of adiponectin when compared with CHB patients with liver cirrhosis [mean+/-SEM 51.2+/-2.1% vs. 40.9+/-1.7%, respectively, p=0.001]. After antiviral therapy, patients with fibrosis reduction had marked decline in serum adiponectin level and increase in HMW form of adiponectin [mean+/-SEM 43.5+/-1.2% vs. 37.0+/-3.0%, respectively, p=0.04]. Serum adiponectin may have a role in fibrosis progression in CHB infection. A marked decline in serum adiponectin after antiviral therapy is associated with fibrosis reduction.

Minimal dose interferon suppository treatment suppresses viral replication with platelet counts and serum albumin levels increased in chronically hepatitis C virus-infected patients: a phase 1b, placebo-controlled, randomized study.

PubMed

Haruna, Yoshimichi; Inoue, Atsuo

2014-02-01

Animal studies have shown that rectally administrated interferon (IFN) is transferred into the lymphatic system via the rectal mucous membrane, suggesting that an IFN suppository could serve as another drug delivery method. We developed an IFN suppository and administered it to patients with chronic hepatitis C to evaluate its efficacy and safety. Twenty-eight patients with chronic hepatitis C participated in the study. The low-dose IFN suppository containing 1,000 international units (IU) of lymphoblastoid IFNα was administered to 14 patients daily for 24 weeks. Others had a placebo dosing. In 13 of the 14 IFN suppository-treated patients, viral load decreased at week 4. The serum hepatitis C virus (HCV) RNA levels (Log IU/mL, mean±standard error) were 5.65±0.18 before the treatment and 5.17±0.27 at week 4 (P=0.01). The 2'-5' oligoadenylate synthetase activity increased, while the CD4/CD8 ratio decreased significantly. Interestingly, platelet counts and serum albumin levels were significantly increased during and after the treatment. No serious adverse events were observed. The low-dose IFN suppository treatment suppressed HCV replication, modifying host immunity, with increased platelet counts and serum albumin levels. The IFN suppository could be considered a new drug delivery method to preserve the quality of life of patients.

Interferon-γ-inducible protein-10 in chronic hepatitis C: Correlations with insulin resistance, histological features & sustained virological response.

PubMed

Crisan, Dana; Grigorescu, Mircea Dan; Radu, Corina; Suciu, Alina; Grigorescu, Mircea

2017-04-01

One of the multiple factors contributing to virological response in chronic hepatitis C (CHC) is interferon-gamma-inducible protein-10 (IP-10). Its level reflects the status of interferon-stimulated genes, which in turn is associated with virological response to antiviral therapy. The aim of this study was to evaluate the role of serum IP-10 levels on sustained virological response (SVR) and the association of this parameter with insulin resistance (IR) and liver histology. Two hundred and three consecutive biopsy proven CHC patients were included in the study. Serum levels of IP-10 were determined using ELISA method. IR was evaluated by homeostasis model assessment-IR (HOMA-IR). Histological features were assessed invasively by liver biopsy and noninvasively using FibroTest, ActiTest and SteatoTest. Predictive factors for SVR and their interrelations were assessed. A cut-off value for IP-10 of 392 pg/ml was obtained to discriminate between responders and non-responders. SVR was obtained in 107 patients (52.70%). Area under the receiver operating characteristic curve for SVR was 0.875 with a sensitivity of 91.6 per cent, specificity 74.7 per cent, positive predictive value 80.3 per cent and negative predictive value 88.7 per cent. Higher values of IP-10 were associated with increasing stages of fibrosis (P<0.01) and higher grades of inflammation (P=0.02, P=0.07) assessed morphologically and noninvasively through FibroTest and ActiTest. Significant steatosis and IR were also associated with increased levels of IP-10 (P=0.01 and P=0.02). In multivariate analysis, IP-10 levels and fibrosis stages were independently associated with SVR. Our findings showed that the assessment of serum IP-10 level could be a predictive factor for SVR and it was associated with fibrosis, necroinflammatory activity, significant steatosis and IR in patients with chronic HCV infection.

Impact of interferon-free antivirus therapy on lipid profiles in patients with chronic hepatitis C genotype 1b

PubMed Central

Endo, Daisuke; Satoh, Kenichi; Shimada, Noritomo; Hokari, Atsushi; Aizawa, Yoshio

2017-01-01

AIM To investigate the influence of interferon-free antivirus therapy on lipid profiles in chronic hepatitis C virus genotype 1b (HCV1b) infection. METHODS Interferon-free antiviral agents were used to treat 276 patients with chronic HCV1b infection, and changes in serum lipids of those who achieved sustained virologic response (SVR) were examined. The treatment regimen included 24 wk of daclatasvir plus asunaprevir (DCV + ASV) or 12 wk of sofosbuvir plus ledipasvir (SOF + LDV). SVR was achieved in 121 (85.8%) of 141 patients treated with DCV + ASV and 132 (97.8%) of 135 patients treated with SOF + LDV. In the two patient groups (DCV + ASV-SVR and SOF + LDV-SVR), serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides were measured at baseline during treatment and at 4 and 12 wk after treatment. Then, longitudinal changes in lipid profiles were analyzed. RESULTS Serum levels of TC, LDL-C, and HDL-C were significantly increased throughout the observation period in both the DCV + ASV-SVR and SOF + LDV-SVR groups. During antivirus treatment, the increases in TC and LDL-C were significantly greater in the SOF + LDV-SVR group than in the DCV + ASV-SVR group (P < 0.001). At 4 and 12 wk after the therapy, serum levels of TC and LDL-C were similar between the two groups and were significantly greater than those at baseline. Approximately 75%-80% of the increase in TC was derived from an increased LDL-C. In multiple regression analysis, the difference in therapy protocol (DCA + ASV or SOF + LDV) was an independent predictor that was significantly associated with the increase in TC and LDL-C at 4 wk of therapy. CONCLUSION Serum cholesterol significantly increased during SOF + LDV treatment. After treatment, HCV elimination was associated with a similar increase in cholesterol regardless of the therapy protocol. PMID:28428715

The Impact of Physical Activity on Serum Inflammatory Markers in Overweight Pubertal Boys: 24-Month Follow-Up Study.

PubMed

Remmel, Liina; Tillmann, Vallo; Mengel, Eva; Kool, Pille; Purge, Priit; Lätt, Evelin; Jürimäe, Jaak

2018-05-01

To investigate the differences in the pattern of changes in serum inflammatory cytokines measured annually over a 24-month period, between less active and more active overweight boys. In total, 25 pubertal overweight boys were divided by their moderate to vigorous physical activity (MVPA) levels into 2 groups: less active group (LAG; n = 10; MVPA < 60 min/d) and more active group (MAG; n = 15; MVPA > 60 min/d). Physical activity was measured by 7-day accelerometry. Serum concentration of 13 inflammatory cytokines [interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, IL-1α, IL-1β, vascular endothelial growth factor, interferon-γ, tumor necrosis factor-α, monocyte chemotactic protein-1, epidermal growth factor, and C-reactive protein] was measured at baseline (T0), after 12 months (T1), and after 24 months (T2) from fasting blood samples. Serum IL-6 level was significantly higher [LAG: 1.27 (0.86, 1.98) pg/mL; MAG: 0.80 (0.52, 0.84) pg/mL] at T0 and IL-8 level [LAG: 10.26 (8.80, 11.64) pg/mL; MAG: 7.42 (6.10, 9.54) pg/mL] at T2 in LAG compared with MAG. The changes over the study period varied between different inflammatory markers. None of the slopes of any measured markers were statistically different between the LAG and MAG, although the slopes of interferon-γ and IL-10 tended to be different between the groups. The pattern of changes over the study period varied between different inflammatory markers, but these changes were not different between the MVPA groups. More longitudinal studies are needed to investigate whether IL-6, IL-8, IL-10, and interferon-γ would be the choice of inflammatory markers to study the associations between obesity and physical activity in future.

Serum apolipoprotein B-100 concentration predicts the virological response to pegylated interferon plus ribavirin combination therapy in patients infected with chronic hepatitis C virus genotype 1b.

PubMed

Yoshizawa, Kai; Abe, Hiroshi; Aida, Yuta; Ishiguro, Haruya; Ika, Makiko; Shimada, Noritomo; Tsubota, Akihito; Aizawa, Yoshio

2013-07-01

Host lipoprotein metabolism is associated closely with the life cycle of hepatitis C virus (HCV), and serum lipid profiles have been linked to the response to pegylated interferon (Peg-IFN) plus ribavirin (RBV) therapy. Polymorphisms in the human IL28B gene and amino acid substitutions in the core and interferon sensitivity-determining region (ISDR) in NS5A of HCV genotype 1b (G1b) were also shown to strongly affect the outcome of Peg-IFN plus RBV therapy. In this study, an observational cohort study was performed in 247 HCV G1b-infected patients to investigate whether the response to Peg-IFN and RBV combination therapy in these patients is independently associated with the level of lipid factors, especially apolipoprotein B-100 (apoB-100), an obligatory structural component of very low density lipoprotein and low density lipoprotein. The multivariate logistic analysis subsequently identified apoB-100 (odds ratio (OR), 1.602; 95% confidence interval (CI), 1.046-2.456), alpha-fetoprotein (OR, 0.764; 95% CI, 0.610-0.958), non-wild-type ISDR (OR, 5.617; 95% CI, 1.274-24.754), and the rs8099917 major genotype (OR, 34.188; 95% CI, 10.225-114.308) as independent factors affecting rapid initial virological response (decline in HCV RNA levels by ≥3-log10 at week 4). While lipid factors were not independent predictors of complete early or sustained virological response, the serum apoB-100 level was an independent factor for sustained virological response in patients carrying the rs8099917 hetero/minor genotype. Together, we conclude that serum apoB-100 concentrations could predict virological response to Peg-IFN plus RBV combination therapy in patients infected with HCV G1b, especially in those with the rs8099917 hetero/minor genotype. Copyright © 2013 Wiley Periodicals, Inc.

Inhibition of Interferon-beta Responses in Multiple Sclerosis Immune Cells Associated With High-Dose Statins

PubMed Central

Feng, Xuan; Han, Diana; Kilaru, Bharat K.; Franek, Beverly S.; Niewold, Timothy B.; Reder, Anthony T.

2014-01-01

Objective To determine whether statins affect type 1 interferon responses in relapsing-remitting multiple sclerosis (RRMS). Design Study effects of atorvastatin on type 1 interferon responses in Jurkat cells, mononuclear cells (MNCs) from therapy-naive patients with RRMS in vitro, and MNCs from interferon-treated RRMS patients in vivo in 4 conditions: no drug, statin only, interferon-beta only, and statin added on to interferon-beta therapy. Patients The study examined clinically stable patients with RRMS: 21 therapy-naive patients and 14 patients receiving interferon-beta with a statin. Interventions Statin effects on in vitro and in vivo interferon-beta–induced STAT1 transcription factor activation, expression of interferon-stimulated proteins in MNCs, and serum type 1 interferon activity. Results In vitro, atorvastatin dose dependently inhibited expression of interferon-stimulated P-Y-STAT1 by 44% (P< .001), interferon regulatory factor 1 protein by 30% (P= .006), and myxovirus resistance 1 protein by 32% (P=.004) compared with no-statin control in MNCs from therapy-naive RRMS patients. In vivo, 9 of 10 patients who received high-dose statins (80 mg) had a significant reduction in interferon-beta therapy–induced serum interferon-α/β activity, whereas only 2 of 4 patients who received medium-dose statins (40 mg) had reductions. High-dose add-on statin therapy significantly blocked interferon-beta function, with less P-Y-STAT1 transcription factor activation, and reduced myxovirus resistance 1 protein and viperin protein production. Medium doses of statins did not change STAT1 activation. Conclusions High-dose add-on statin therapy significantly reduces interferon-beta function and type 1 interferon responses in RRMS patients. These data provide a putative mechanism for how statins could counteract the beneficial effects of interferon-beta and worsen disease. PMID:22801747

Thyroid hormonal disturbances related to treatment of hepatitis C with interferon-alpha and ribavirin

PubMed Central

Danilovic, Debora Lucia Seguro; Mendes-Correa, Maria Cassia; Chammas, Maria Cristina; Zambrini, Heverton; Marui, Suemi

2011-01-01

OBJECTIVE: To characterize thyroid disturbances induced by interferon-alpha and ribavirin therapy in patients with chronic hepatitis C. INTRODUCTION: Interferon-alpha is used to treat chronic hepatitis C infections. This compound commonly induces both autoimmune and non-autoimmune thyroiditis. METHODS: We prospectively selected 26 patients with chronic hepatitis C infections. Clinical examinations, hormonal evaluations, and color-flow Doppler ultrasonography of the thyroid were performed before and during antiviral therapy. RESULTS: Of the patients in our study, 54% had no thyroid disorders associated with the interferon-alpha therapy but showed reduced levels of total T3 along with a decrease in serum alanine aminotransferase. Total T4 levels were also reduced at 3 and 12 months, but free T4 and thyroid stimulating hormone (TSH) levels remained stable. A total of 19% of the subjects had autoimmune interferon-induced thyroiditis, which is characterized by an emerge of antithyroid antibodies or overt hypothyroidism. Additionally, 16% had non-autoimmune thyroiditis, which presents as destructive thyroiditis or subclinical hypothyroidism, and 11% remained in a state of euthyroidism despite the prior existence of antithyroidal antibodies. Thyrotoxicosis with destructive thyroiditis was diagnosed within three months of therapy, and ultrasonography of these patients revealed thyroid shrinkage and discordant change in the vascular patterns. DISCUSSION: Decreases in the total T3 and total T4 levels may be related to improvements in the hepatocellular lesions or inflammatory changes similar to those associated with nonthyroidal illnesses. The immune mechanisms and direct effects of interferon-alpha can be associated with thyroiditis. CONCLUSION: Interferon-alpha and ribavirin induce autoimmune and non-autoimmune thyroiditis and hormonal changes (such as decreased total T3 and total T4 levels), which occur despite stable free T4 and TSH levels. A thyroid hormonal evaluation, including the analysis of the free T4, TSH, and antithyroid antibody levels, should be mandatory before therapy, and an early re-evaluation within three months of treatment is necessary as an appropriate follow-up. PMID:22012048

Thyroid hormonal disturbances related to treatment of hepatitis C with interferon-alpha and ribavirin.

PubMed

Danilovic, Debora Lucia Seguro; Mendes-Correa, Maria Cassia; Chammas, Maria Cristina; Zambrini, Heverton; Marui, Suemi

2011-01-01

To characterize thyroid disturbances induced by interferon-alpha and ribavirin therapy in patients with chronic hepatitis C. Interferon-alpha is used to treat chronic hepatitis C infections. This compound commonly induces both autoimmune and non-autoimmune thyroiditis. We prospectively selected 26 patients with chronic hepatitis C infections. Clinical examinations, hormonal evaluations, and color-flow Doppler ultrasonography of the thyroid were performed before and during antiviral therapy. Of the patients in our study, 54% had no thyroid disorders associated with the interferon-alpha therapy but showed reduced levels of total T3 along with a decrease in serum alanine aminotransferase. Total T4 levels were also reduced at 3 and 12 months, but free T4 and thyroid stimulating hormone (TSH) levels remained stable. A total of 19% of the subjects had autoimmune interferon-induced thyroiditis, which is characterized by an emerge of antithyroid antibodies or overt hypothyroidism. Additionally, 16% had non-autoimmune thyroiditis, which presents as destructive thyroiditis or subclinical hypothyroidism, and 11% remained in a state of euthyroidism despite the prior existence of antithyroidal antibodies. Thyrotoxicosis with destructive thyroiditis was diagnosed within three months of therapy, and ultrasonography of these patients revealed thyroid shrinkage and discordant change in the vascular patterns. Decreases in the total T3 and total T4 levels may be related to improvements in the hepatocellular lesions or inflammatory changes similar to those associated with nonthyroidal illnesses. The immune mechanisms and direct effects of interferon-alpha can be associated with thyroiditis. Interferon-alpha and ribavirin induce autoimmune and non-autoimmune thyroiditis and hormonal changes (such as decreased total T3 and total T4 levels), which occur despite stable free T4 and TSH levels. A thyroid hormonal evaluation, including the analysis of the free T4, TSH, and antithyroid antibody levels, should be mandatory before therapy, and an early re-evaluation within three months of treatment is necessary as an appropriate follow-up.

[Allergic asthma and interleukins 2, 4, 5, 6 and 12 and gamma interferon levels].

PubMed

Bastida Segura, Diana Lyzbeth; López Velásquez, Benjamin; Castrejón Vázquez, María Isabel; Galicia Tapía, Jorge; Cano Altamirano, Silvia; Miranda Feria, Alfonso Javier

2004-01-01

Asthma is an inflammatory chronic illness, in which mastocyt cells, basophils, T lymphocytes, eosinophils and cytokines play a role. Its association with the production of TH2 cytokines is not well known, but it is considered an aberrant immune response, yielding the activation and recruitment of a number of effector cells (mastocyts/eosinophils) and the appearance of clinical symptoms. To determine the serum values of the interleukins 2, 4, 5, 6 and 12 and gamma interferon in relation to the severity degree of asthma and the time of immunotherapy in patients with stable chronic allergic bronchial asthma. Clinical records of allergic asthmatic patients from the external consultation at Servicio de Alergia e Immunología Clínica were reviewed in a period of 12 months (1st January 2002 to 1st January 2003) and those of healthy volunteers, forming three groups: Group 1, allergic asthmatics with immunotherapy less than 24 months; Group 2, allergic asthmatics with more than 24 months of immunotherapy, and Group 3, healthy volunteers (control group). Previous informed consent, a serum sample was taken of all subjects. Ninety-two subjects were included: 41 (45%) allergic asthmatics and 51 (55%) healthy volunteers. Significant differences were found in interleukins 2, 4, 5, 6 and 12 levels between healthy volunteers and asthmatics without relating the immunotherapy time. In the total group gamma interferon levels were not found. A relation of interleukins Th2 levels with the severity degree of asthma was not found. Differences of serum interleukins Th1 and Th2 in allergic patients related to immunotherapy time were not significant; even though, irrespective of immunotherapy time, IgG levels were always high. Patients with allergic asthma have a predominance of serum interleukins Th2 and, despite of the immunotherapy, in the maintaining phase, these continue high, which may be due to an immune system dysregulation maybe including other factors. Immunotherapy continues being one of the most useful specific treatments in allergic diseases, demonstrated by its satisfactory clinical response, reduced drugs' use and modification in severity and evolution of the disease.

Prolactin, dendritic cells, and systemic lupus erythematosus.

PubMed

Jara, Luis J; Benitez, Gamaliel; Medina, Gabriela

2008-01-01

Dendritic cells (DC) play a central role in the induction of autoimmunity in T and B cells. DC express a high level of the major histocompatibility complex that interact with the receptors on T cells. Immature DC present antigens efficiently. Prolactin (PRL) participates in DC maturation. Systemic lupus erythematosus (SLE) is characterized by a loss of tolerance to self-antigens and persistent production of autoantibodies. Serum from SLE patients induces normal monocytes to differentiate into DC in correlation with disease activity depending on the actions of interferon-alpha, immune complexes, PRL, etc. High serum PRL levels have been found in a subset of SLE patients associated with active disease and organ involvement. It is possible that PRL interacts with DC, skewing its function from antigen presentation to a proinflammatory phenotype with high interferon-alpha production. Therefore, SLE is characterized by deficiency of DC functions and abnormal PRL secretion. The relationships between PRL and DC may have a role in the pathogenesis of SLE.

Serum free light chains, interferon-alpha, and interleukins in systemic lupus erythematosus.

PubMed

Jolly, M; Francis, S; Aggarwal, R; Mikolaitis, R A; Niewold, T B; Chubinskaya, S; Block, J A; Scanzello, C; Sequeira, W

2014-08-01

Interleukin-6 (IL-6), interleukin-10 (IL-10), interferon-alpha (IFN-α), and free light chains (FLCs: lambda, kappa) have all been noted to be of importance in systemic lupus erythematosus (SLE). Herein, we quantified and explored the relationship between these inflammatory mediators and disease activity in SLE; and stratified by their current anti-dsDNA antibody status. Seventy-seven SLE patients underwent assessment of disease activity using the SLE disease activity index (SLEDAI). Serum FLC (lambda, kappa, and total), IL-6, IL-10, and IFN-α were quantified. Demographics of disease characteristics were determined by chart reviews. Statistical analyses included Mann-Whitney test, chi square, and linear regression analyses. Mean (SD) age of the patients was 44.9 ± 12.7 years; SLEDAI (mean ± SD) was 3.4 ± 4.0. Serum lambda FLC levels had a moderate correlation (r = 0.46 with physician global assessment, 0.44 with SLEDAI) and the strongest correlation with disease activity as compared with other inflammatory mediators including current dsDNA antibody status. After adjusting for prednisone use, the correlation of lambda FLC with PGA (r = 0.48) and SLEDAI (r = 0.52) was better than of current dsDNA antibody status with PGA (r = 0.33) and adjusted SLEDAI (r = 0.24), respectively. IL-10 and IFN-α activity did not correlate with disease activity. Serum FLC and IL-6 levels could differentiate between active and inactive SLE patients. Serum lambda FLC and IL-6 levels differed significantly among patients with and without current dsDNA antibodies. Serum lambda FLC levels accounted for 31% of variance in SLEDAI scores. Serum FLC and IL-6 are potentially useful biomarkers of disease activity in SLE. Further studies, with larger study sample and longitudinal design, are indicated. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Effect of Silymarin (Milk Thistle) on Liver Disease in Patients With Chronic Hepatitis C Unsuccessfully Treated With Interferon Therapy

PubMed Central

Fried, Michael W.; Navarro, Victor J.; Afdhal, Nezam; Belle, Steven H.; Wahed, Abdus S.; Hawke, Roy L.; Doo, Edward; Meyers, Catherine M.; Reddy, K. Rajender

2013-01-01

Context The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease, despite scant and conflicting evidence of its efficacy. Objective To determine the effect of silymarin on liver disease activity in patients with chronic hepatitis C virus (HCV) infection unsuccessfully treated with interferon-based therapy. Design, Setting, and Participants Multicenter, double-blind, placebo-controlled trial conducted at 4 medical centers in the United States. Participants included 154 persons with chronic HCV infection and serum alanine aminotransferase (ALT) levels of 65 U/L or greater who were previously unsuccessfully treated with interferon-based therapy. Enrollment began in May 2008 and was completed in May 2010, with the last follow-up visit completed in March 2011. Intervention Participants were randomly assigned to receive 420-mg silymarin, 700-mg silymarin, or matching placebo administered 3 times per day for 24 weeks. Main Outcome Measures The primary outcome measure was serum ALT level of 45 U/L or less (considered within the normal range) or less than 65 U/L, provided this was at least a 50% decline from baseline values. Secondary outcomes included changes in ALT levels, HCV RNA levels, and quality-of-life measures. Results After 24 weeks of treatment, only 2 participants in each treatment group (P≥.99) met the primary outcome measure (3.8% [95% CI, 0.5% to 13.2%] for placebo, 4.0% [95% CI, 0.5% to 13.7%] for 420-mg silymarin, and 3.8% [95% CI, 0.5% to 13.2%] for 700-mg silymarin). The mean decline in serum ALT activity at the end of treatment did not differ significantly (P=.75) across the 3 treatment groups (mean decline, −4.3 [95% CI, −17.3 to 8.7] U/L for placebo, −14.4 [95% CI, −41.6 to 12.7] U/L for 420-mg silymarin, −11.3 [95% CI, −27.9 to 5.4] U/L for 700-mg silymarin); there likewise were no significant differences in HCV RNA levels (mean change, 0.07 [95% CI, −0.05 to 0.18] log10 IU/mL for placebo, −0.03 [95% CI, −0.18 to 0.12] log10 IU/mL for 420-mg silymarin, 0.04 [95% CI, −0.08 to 0.16] log10 IU/mL for 700-mg silymarin; P=.54) or quality-of-life measures. The adverse event profile of silymarin was comparable with that of placebo. Conclusion Higher than customary doses of silymarin did not significantly reduce serum ALT levels more than placebo in participants with chronic HCV infection unsuccessfully treated with interferon-based therapy. PMID:22797645

Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial.

PubMed

Fried, Michael W; Navarro, Victor J; Afdhal, Nezam; Belle, Steven H; Wahed, Abdus S; Hawke, Roy L; Doo, Edward; Meyers, Catherine M; Reddy, K Rajender

2012-07-18

The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease, despite scant and conflicting evidence of its efficacy. To determine the effect of silymarin on liver disease activity in patients with chronic hepatitis C virus (HCV) infection unsuccessfully treated with interferon-based therapy. Multicenter, double-blind, placebo-controlled trial conducted at 4 medical centers in the United States. Participants included 154 persons with chronic HCV infection and serum alanine aminotransferase (ALT) levels of 65 U/L or greater who were previously unsuccessfully treated with interferon-based therapy. Enrollment began in May 2008 and was completed in May 2010, with the last follow-up visit completed in March 2011. Participants were randomly assigned to receive 420-mg silymarin, 700-mg silymarin, or matching placebo administered 3 times per day for 24 weeks. The primary outcome measure was serum ALT level of 45 U/L or less (considered within the normal range) or less than 65 U/L, provided this was at least a 50% decline from baseline values. Secondary outcomes included changes in ALT levels, HCV RNA levels, and quality-of-life measures. After 24 weeks of treatment, only 2 participants in each treatment group (P ≥ .99) met the primary outcome measure (3.8% [95% CI, 0.5% to 13.2%] for placebo, 4.0% [95% CI, 0.5% to 13.7%] for 420-mg silymarin, and 3.8% [95% CI, 0.5% to 13.2%] for 700-mg silymarin). The mean decline in serum ALT activity at the end of treatment did not differ significantly (P = .75) across the 3 treatment groups (mean decline, -4.3 [95% CI, -17.3 to 8.7] U/L for placebo, -14.4 [95% CI, -41.6 to 12.7] U/L for 420-mg silymarin, -11.3 [95% CI, -27.9 to 5.4] U/L for 700-mg silymarin); there likewise were no significant differences in HCV RNA levels (mean change, 0.07 [95% CI, -0.05 to 0.18] log10 IU/mL for placebo, -0.03 [95% CI, -0.18 to 0.12] log10 IU/mL for 420-mg silymarin, 0.04 [95% CI, -0.08 to 0.16] log10 IU/mL for 700-mg silymarin; P = .54) or quality-of-life measures. The adverse event profile of silymarin was comparable with that of placebo. Higher than customary doses of silymarin did not significantly reduce serum ALT levels more than placebo in participants with chronic HCV infection unsuccessfully treated with interferon-based therapy. clinicaltrials.gov Identifier: NCT00680342.

Increased serum APRIL differentially correlates with distinct cytokine profiles and disease activity in systemic lupus erythematosus patients.

PubMed

Boghdadi, Ghada; Elewa, Enass A

2014-09-01

Cytokines play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Among the cytokines that regulate B cell homeostasis is a proliferation-inducing ligand (APRIL). This study aimed to determine whether serum levels of APRIL are raised in patients with SLE and correlate with disease activity or proinflammatory cytokines production, or both. Serum APRIL, interleukin-17 (IL-17), IL-4 and interferon gamma (IFN-γ) levels were measured in forty patients with SLE and 30 healthy controls. Disease activity was assessed by SLE disease activity index (SLEDAI), and results were correlated with serum APRIL levels. Serum APRIL levels were significantly higher in patients with SLE than in healthy controls. Positive correlation was found between serum APRIL levels and total SLEDAI score and anti-dsDNA antibody titers. Moreover, serum APRIL levels was significantly higher in patients with arthritis, mucocutaneous manifestations and proteinuria. APRIL is increased in patients with active SLE accompanying the increase of IL-17 and IFN-γ. Significant positive correlations between serum levels of APRIL and IL-17 and IFN-γ and a negative correlation between serum levels of APRIL and IL-4 were found. The results suggest that APRIL may be an important marker of disease activity in patients with SLE. We provide the analyses of APRIL levels in patients with SLE, suggesting new tools for the diagnosis, prognosis and possible therapeutic management of SLE.

Interferon-alpha receptor 1 mRNA expression in peripheral blood mononuclear cells is associated with response to interferon-alpha therapy of patients with chronic hepatitis C.

PubMed

Massirer, K B; Hirata, M H; Silva, A E B; Ferraz, M L G; Nguyen, N Y; Hirata, R D C

2004-05-01

Interferon (IFN)-alpha receptor mRNA expression in liver of patients with chronic hepatitis C has been shown to be a response to IFN-alpha therapy. The objective of the present study was to determine whether the expression of mRNA for subunit 1 of the IFN-alpha receptor (IFNAR1) in peripheral blood mononuclear cells (PBMC) is associated with the response to IFN-alpha in patients with chronic hepatitis C. Thirty patients with positive anti-HCV and HCV-RNA, and abnormal levels of alanine aminotransferase in serum were selected and treated with IFN-alpha 2b for one year. Those with HBV or HIV infection, or using alcohol were not included. Thirteen discontinued the treatment and were not evaluated. The IFN-alpha response was monitored on the basis of alanine aminotransferase level and positivity for HCV-RNA in serum. IFNAR1-mRNA expression in PBMC was measured by reverse transcription-polymerase chain reaction before and during the first three months of therapy. The results are reported as IFNAR1-mRNA/beta-actin-mRNA ratio (mean +/- SD). Before treatment, responder patients had significantly higher IFNAR1-mRNA expression in PBMC (0.67 +/- 0.15; N = 5; P < 0.05) compared to non-responders (0.35 +/- 0.17; N = 12) and controls (0.30 +/- 0.16; N = 9). Moreover, IFNAR1-mRNA levels were significantly reduced after 3 months of treatment in responders, whereas there were no differences in IFNAR1 expression in non-responders during IFN-alpha therapy. Basal IFNAR1-mRNA expression was not correlated with the serum level of alanine and aspartate aminotransferases or the presence of cirrhosis. The present results suggest that IFNAR1-mRNA expression in PBMC is associated with IFN-alpha response to hepatitis C and may be useful for monitoring therapy in patients with chronic hepatitis C.

Dietary Selenium Levels Affect Selenoprotein Expression and Support the Interferon-γ and IL-6 Immune Response Pathways in Mice

PubMed Central

Tsuji, Petra A.; Carlson, Bradley A.; Anderson, Christine B.; Seifried, Harold E.; Hatfield, Dolph L.; Howard, Michael T.

2015-01-01

Selenium is an essential element that is required to support a number of cellular functions and biochemical pathways. The objective of this study was to examine the effects of reduced dietary selenium levels on gene expression to assess changes in expression of non-selenoprotein genes that may contribute to the physiological consequences of selenium deficiency. Mice were fed diets that were either deficient in selenium or supplemented with selenium in the form of sodium selenite for six weeks. Differences in liver mRNA expression and translation were measured using a combination of ribosome profiling, RNA-Seq, microarrays, and qPCR. Expression levels and translation of mRNAs encoding stress-related selenoproteins were shown to be up-regulated by increased selenium status, as were genes involved in inflammation and response to interferon-γ. Changes in serum cytokine levels were measured which confirmed that interferon-γ, as well as IL-6, were increased in selenium adequate mice. Finally, microarray and qPCR analysis of lung tissue demonstrated that the selenium effects on immune function are not limited to liver. These data are consistent with previous reports indicating that adequate selenium levels can support beneficial immune responses, and further identify the IL-6 and interferon-γ pathways as being responsive to dietary selenium intake. PMID:26258789

Predictive impact of polymorphism of PNPLA3 on HCC development after interferon therapy in Japanese patients with chronic hepatitis C.

PubMed

Moritou, Yuki; Ikeda, Fusao; Iwasaki, Yoshiaki; Baba, Nobuyuki; Takaguchi, Kouichi; Senoh, Tomonori; Nagano, Takuya; Takeuchi, Yasuto; Yasunaka, Tetsuya; Ohnishi, Hideki; Miyake, Yasuhiro; Takaki, Akinobu; Nouso, Kazuhiro; Yamamoto, Kazuhide

2013-12-01

The impact of single-nucleotide polymorphisms (SNP) of patatin-like phospholipase domain-containing protein 3 (PNPLA3) on development of hepatocellular carcinoma (HCC) is not clarified for Japanese patients with chronic hepatitis C. The present study investigated the associations of rs738409 PNPLA3 with HCC development after the antiviral therapy with peg-interferon and ribavirin for Japanese patients with hepatitis C virus serotype 1 and high viral load. Of the 271 patients enrolled in the study, 20 patients developed HCC, during a median follow-up period of 4.6 years. Multivariate analysis in the proportional hazards models revealed that sex, body mass index, platelet counts, and alpha feroprotein (AFP) had significant associations with HCC development (p = 0.011, 0.029, 0.0002, and 0.046, respectively). Multivariate regression analysis revealed that PNPLA3 148 M was significantly associated with serum AFP level (p = 0.032), other than body mass index, platelet count, and alanine aminotransferase (p = 0.0006, 0.0002, and 0.037, respectively), and that serum AFP level was significantly associated with PNPLA3 148 M (p = 0.017). Serum AFP level is an important factor in predicting HCC development after the antiviral therapy for Japanese patients with chronic hepatitis C, the mechanism of which might involve its significant associations with the SNP genotype of PNPLA3.

Effects of interferon-tau on cattle persistently infected with bovine viral diarrhea virus.

PubMed

Kohara, Junko; Nishikura, Yumiko; Konnai, Satoru; Tajima, Motoshi; Onuma, Misao

2012-08-01

In this study, the antiviral effects of bovine interferon-tau (boIFN-tau) on bovine viral diarrhea virus (BVDV) were examined in vitro and in vivo. In the in vitro experiments, the replication of cytopathic and non-cytopathic BVDV was inhibited in the bovine cells treated with boIFN-tau. The replication of BVDV was completely suppressed by boIFN-tau at a concentration higher than 10(2) U/ml. In order to examine the effect of boIFN-tau on virus propagation in cattle persistently infected (PI) with non-cytopathic BVDV, boIFN-tau was subcutaneously administered to PI cattle at 10(5) U/kg or 10(6) U/kg body weight 5 times per week for 2 weeks. No physical abnormality such as depression was observed in the cattle during the experiment. The mean BVDV titers in the serum of the PI cattle decreased slightly during the boIFN-tau administration period with the dose of 10(6) U/kg. However, the BVDV titers in the serum returned to the pre-administration level after the final boIFN-tau administration. These results suggest that boIFN-tau demonstrates an anti-BVDV effect, reducing the BVDV level in serum transiently when injected into PI cattle.

Treatment of three patients with systemic mastocytosis with interferon alpha-2b.

PubMed

Worobec, A S; Kirshenbaum, A S; Schwartz, L B; Metcalfe, D D

1996-08-01

It has been reported that the administration of interferon alpha-2b is of potential benefit in the treatment of mastocytosis based on a single patient study (NEJM, Feb 27, 1992, 326(9):619-623). Following this report, we administered interferon alpha-2b at a dose of 4 to 5 million units per square meter of body surface area for at least 12 months to one patient with mastocytosis with an associated hematologic disorder (patient 1), one patient with aggressive systemic mastocytosis (patient 2), and one patient with indolent mastocytosis (patient 3). Patients were monitored with the following clinical and laboratory parameters: serial bone marrow biopsies and aspirates, patient log of histamine release attacks, medication dependency, plasma tryptase levels, serum lactate dehydrogenase (LDH) levels, white blood cell counts and differentials, extent of urticaria pigmentosa lesions, bony involvement, and extent of gastrointestinal involvement and hepatomegaly. We also examined the ability of interferon alpha-2b to inhibit recombinant human stem cell factor (rhSCF)-dependent mast cell proliferation from CD34+ bone marrow-derived cells. All patients demonstrated continued progression of disease in one or more clinical criteria at one year of therapy. Similarly, interferon alpha-2b did not inhibit the culture of mast cells from CD34+ bone marrow-derived cells in the presence of SCF. Thus, in our study of three patients with systemic mastocytosis, treatment with interferon alpha-2b was found to be ineffective in controlling progression of disease.

Monoclonal antibody against interferon gamma can prevent experimental cerebral malaria and its associated overproduction of tumor necrosis factor.

PubMed Central

Grau, G E; Heremans, H; Piguet, P F; Pointaire, P; Lambert, P H; Billiau, A; Vassalli, P

1989-01-01

Experimental cerebral malaria (ECM), a lethal hyperacute neurological syndrome associated with high blood levels of tumor necrosis factor, develops in genetically susceptible (CBA/Ca) mice 7 days after infection with Plasmodium berghei ANKA strain. Injections of neutralizing monoclonal antibody against recombinant murine interferon gamma, not later than 4 days after infection, markedly reduced the incidence of ECM and the elevation in serum levels of tumor necrosis factor. This treatment prevented the cerebral lesions (plugging of brain vessels by monocytes, lymphocytes, and parasitized erythrocytes). In contrast, the extent of macrophage infiltration in lymphoid organs (which is a characteristic feature of mice developing ECM), as well as the course of infection, remained unaffected by the antibody treatment. Protected mice died at a later time of severe anemia and overwhelming parasitemia, the usual outcome of P. berghei infection in mice that are not susceptible to ECM. The present data indicate that interferon gamma constitutes an important link in the cytokine network that leads to brain vessel inflammation in experimental malaria. It is proposed that interferon gamma released by activated CD4+ T cells acts by augmenting both production and action of tumor necrosis factor. PMID:2501793

Clearance of HCV RNA following acute hepatitis A superinfection.

PubMed

Cacopardo, B; Nunnari, G; Nigro, L

2009-05-01

A transient reduction of hepatitis C virus replication during the course of acute hepatitis A virus infection has already been reported in the literature. The present study reports the case study of a subject with chronic hepatitis due to hepatitis C virus who went on to develop an acute hepatitis A. From the early onset of acute disease, hepatitis C virus ribonucleic acid became undetectable. Following recovery from acute hepatitis, alanine amino-transferase levels became persistently normal and liver biopsy revealed a reduction in the Knodell histological activity index score. Hepatitis C virus ribonucleic acid clearance was maintained up to 4 years after the onset of acute hepatitis A. During the course of the acute disease, a sharp increase in interferon gamma levels was detected in serum and in the supernatant of both unstimulated and phytoemagglutinin/lipopolysaccharide-stimulated peripheral blood mononuclear cells. Interferon gamma levels were still high 3 months later. We hypothesize that acute hepatitis A virus superinfection during the course of chronic hepatitis C may lead to hepatitis C virus ribonucleic acid clearance through an immunological mechanism related to interferon gamma production.

A strong interferon response correlates with a milder dengue clinical condition.

PubMed

De La Cruz Hernández, Sergio Isaac; Puerta-Guardo, Henry; Flores-Aguilar, Hilario; González-Mateos, Silvia; López-Martinez, Irma; Ortiz-Navarrete, Vianney; Ludert, Juan E; Del Angel, Rosa María

2014-07-01

Type 1 interferon (IFNα/β) has a significant role in establishing protection against virus infections. It has been well documented by in vitro studies that dengue virus (DENV) activates a robust IFNα/β response. However, DENV also induces a down-regulation of the JAK/STAT pathway, inhibiting the induction of interferon regulated genes. As a consequence, the role played by the IFN type 1 response in the protection of dengue patients is not fully understood. To compare IFN-α levels in dengue patients with dengue fever (DF) or dengue hemorrhagic fever (DHF) undergoing primary or secondary infections. Two hundred and four serum samples were analyzed for IFN-α level by cytometric bead array. Patients' clinical condition was assigned following the WHO 1997 criteria and specific IgG and IgM antibodies were measured using commercial assays to determine primary and secondary infections. The infecting serotype was determined by qRT-PCR. The IFN-α levels were found significantly higher in DF than DHF patients irrespective of the infecting serotype (DENV1 or 2), and were found to decline rapidly at day 3 after fever onset. For DENV2 infections, higher IFN-α level was found during primary than secondary infections. These results suggest that an early strong interferon response correlates with a better clinical condition. Copyright © 2014 Elsevier B.V. All rights reserved.

Effect of vitamin D replacement on immunological biomarkers in patients with multiple sclerosis.

PubMed

Mrad, May F; El Ayoubi, Nabil K; Esmerian, Maria O; Kazan, Jalal M; Khoury, Samia J

2017-08-01

We aimed to investigate the immunologic effects of vitamin D replacement in RRMS patients. In a controlled single center study, patients deficient in 25-hydroxyvitamin D (serum level<25ng/ml) received 10,000IU/week cholecalciferol for 3months. Sufficient vitamin D patients (serum level>35ng/ml) were followed for the same period. Assessments were performed at baseline and at 3months. 25-hydroxyvitamin D levels increased significantly from baseline to month-3 in the deficient group after treatment and remained stable in the sufficient group. We observed a decreased interferon-γ (IFNγ) secretion by CD4 + T cells in vitamin D deficient group but not in the sufficient group, and a negative correlation between baseline serum vitamin D and IFNγ production. There was no change in the frequency of T helper or regulatory T cell subsets in either group. Increasing serum levels of 25-hydroxyvitamin D are associated with decreased production of IFNγ by CD4 + T cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Onset of Type 1 Diabetes Mellitus During Pegylated-interferon Alfa and Ribavirin Therapy for Chronic Hepatitis C Virus Infection

PubMed Central

Ranganathan, Raghini; Janarthanan, Krishnaveni; Rajasekaran, Senthilkumar

2012-01-01

A 16-year-old female was treated with pegylated-interferon (PEG-IFN) alfa (a)-2b and ribavirin combination therapy for chronic hepatitis C virus (HCV) infection. She attained rapid virological response. She presented with diabetic ketoacidosis after 41 weeks of therapy. Anti-glutamic acid decarboxylase antibodies and islet cell antibodies were negative. Her fasting serum C-peptide level was <0.1 ng/mL, and the treatment course was completed. This case underlines the importance of periodic plasma glucose monitoring in patients during and after PEG-IFN and ribavirin therapy. PMID:25755410

Underlying pathways for interferon risk to type II diabetes mellitus.

PubMed

Abdel-Hamid, Nabil; Jubori, Taghreed Al; Farhan, Amaal; Mahrous, Mariam; Gouri, Adel; Awad, Ezzat; Breuss, Johannes

2013-11-01

It has been known that chronic liver treatments interfere with blood glucose metabolism. It was recognized that diabetes mellitus among chronic hepatitis C was greater in other types of chronic liver diseases. Hepatitis C directly promotes insulin resistance through the proteosomal degradation of insulin resistance substrate. It suppressed hepatocyte glucose uptake through down-regulation of surface expression of glucose transporter. Long-term exposure to cytokine over expression seems to be cytotoxic to both beta cells of the pancreas and to hepatocytes. Elevated tumor necrosis factor-a, or its neutralization, increased insulin sensitivity. Interferon-a may also elevate the serum level of interleukin-1 which is cytotoxic to pancreatic islet cells. Both diabetes mellitus and resistance to interferon-a therapy are abnormally mediated by over-expression of suppressor of cytokine signaling-1 in hepatocytes of chronic hepatitis C patients. These data suggest that interferon-a therapy should be administered with caution in patients showing any predisposition to Diabetes mellitus. Anti inflammatory therapy is critically recommended as a protector against disease development due to cytokine mediated Diabetes mellitus during hepatitis C therapy, since inflammation seems to be a main candidate to interferon suspected diabetogenesis.

Effect of postcalving serum nonesterified fatty acids concentration on the functionality of bovine immune cells.

PubMed

Ster, C; Loiselle, M-C; Lacasse, P

2012-02-01

The periparturient period is marked by metabolic, hormonal, and immunological changes, which have an effect on the incidence of infectious and metabolic diseases. In a previous study, a slower increase in milk production was induced by milking cows once daily during the first week of lactation, leading to an improvement in levels of several metabolites, including nonesterified fatty acids (NEFA) and β-hydroxybutyrate (BHBA). The aim was to determine the influence of serum collected on d 2, 5, and 61 postpartum from cows milked once or twice daily on immune cell functions and to determine which of the constituents were responsible for these effects. Peripheral blood mononuclear cells (PBMC) and polymorphonuclear leukocytes were collected from healthy midlactation cows and their immune functions (i.e., proliferation and interferon-γ production and chemotaxis, phagocytosis, and oxidative burst, respectively), were evaluated in presence of serum, NEFA, and BHBA. Proliferation of PBMC was greater with d-61 (65.1±1.6%) serum than with d-2 (37.3±2.4%) or d-5 (48.4±1.6%) serum and greater with d-2 and -5 serum from cows milked once (42.2±3.7 and 54.0±2.5) compared with cows milked twice daily (32.4±3.0 and 42.9±2.1). Proliferation was inversely correlated with the concentration of NEFA and BHBA in the serum (r=-0.86). Adding NEFA to d-61 serum to reach the level present in d-5 serum decreased proliferation to the level observed with d-5 serum. No effect of BHBA addition was observed. The release of interferon-γ by PBMC was lower in d-5 serum (766±63 pg/mL) than in d-61 serum (1,187±90 pg/mL) and by NEFA. Milking frequency did not affect chemotaxis, phagocytosis, or oxidative burst of polymorphonuclear leukocytes. Phagocytosis decreased over time in serum from d 2 to 61. Similarly, oxidative burst was greater with d-5 serum (12.7×10(8) ± 1.6×10(8) relative light units) than with d-61 serum (9.0×10(8) ± 1.6×10(8) relative light units). The NEFA had a negative effect on oxidative burst, but BHBA did not. In conclusion, several immune cell functions appear affected by the NEFA concentration. Therefore, strategies that prevent increases in blood NEFA during the transition period may limit postpartum immunosuppression. Copyright © 2012 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Monitoring acute phase proteins in retrovirus infected cats undergoing feline interferon-ω therapy.

PubMed

Leal, R O; Gil, S; Sepúlveda, N; McGahie, D; Duarte, A; Niza, M M R E; Tavares, L

2014-01-01

Recombinant feline interferon-ω therapy is an immunomodulator currently used in the treatment of different retroviral diseases including feline immune deficiency virus and feline leukaemia virus. Although its mechanism of action remains unclear, this drug appears to potentiate the innate response. Acute phase proteins are one of the key components of innate immunity and studies describing their use as a monitoring tool for the immune system in animals undergoing interferon-ω therapy are lacking. This study aimed to determine whether interferon-ω therapy influences acute phase protein concentrations namely serum amyloid-A, α-1-glycoprotein and C-reactive protein. A single-arm study was performed using 16 cats, living in an animal shelter, naturally infected with retroviruses and subjected to the interferon-ω therapy licensed protocol. Samples were collected before (D0), during (D10 and D30) and after therapy (D65). Serum amyloid-A and C-reactive protein were measured by specific enzyme-linked immunosorbent assay kits and α-1-glycoprotein by single radial immunodiffusion. All the acute phase proteins significantly increased in cats undergoing interferon-ω therapy (D0/D65: P<0·05) CLINICAL SIGNIFICANCE: Acute phase proteins appear to be reasonable predictors of innate-immune stimulation and may be useful in the individual monitoring of naturally retroviral infected cats undergoing interferon-ω therapy. © 2013 British Small Animal Veterinary Association.

Direct-acting antiviral agents against hepatitis C virus and lipid metabolism.

PubMed

Kanda, Tatsuo; Moriyama, Mitsuhiko

2017-08-21

Hepatitis C virus (HCV) infection induces steatosis and is accompanied by multiple metabolic alterations including hyperuricemia, reversible hypocholesterolemia and insulin resistance. Total cholesterol, low-density lipoprotein-cholesterol and triglyceride levels are increased by peginterferon and ribavirin combination therapy when a sustained virologic response (SVR) is achieved in patients with HCV. Steatosis is significantly more common in patients with HCV genotype 3 but interferon-free regimens are not always effective for treating HCV genotype 3 infections. HCV infection increases fatty acid synthase levels, resulting in the accumulation of fatty acids in hepatocytes. Of note, low-density lipoprotein receptor, scavenger receptor class B type I and Niemann-Pick C1-like 1 proteins are candidate receptors that may be involved in HCV. They are also required for the uptake of cholesterol from the external environment of hepatocytes. Among HCV-infected patients with or without human immunodeficiency virus infection, changes in serum lipid profiles are observed during interferon-free treatment and after the achievement of an SVR. It is evident that HCV affects cholesterol metabolism during interferon-free regimens. Although higher SVR rates were achieved with interferon-free treatment of HCV, special attention must also be paid to unexpected adverse events based on host metabolic changes including hyperlipidemia.

Interleukin-28B polymorphisms and interferon gamma inducible protein-10 serum levels in seronegative occult hepatitis C virus infection.

PubMed

Bartolomé, Javier; Castillo, Inmaculada; Quiroga, Juan Antonio; Carreño, Vicente

2016-02-01

Polymorphisms upstream interleukin (IL)-28B gene and serum levels of interferon gamma inducible protein-10 (IP-10) are associated with spontaneous and treatment-induced hepatitis C virus (HCV) clearance. Patients with seronegative occult HCV infection are anti-HCV and serum HCV-RNA negative but have viral RNA in liver and abnormal values of liver enzymes. We examined if the rs12979860 polymorphism of IL-28B and serum IP-10 levels differ between chronic and seronegative occult CV infection. IL-28B polymorphism was determined with allele specific TaqMan probes in total DNA isolated from peripheral blood mononuclear cells and IP-10 by an enzyme-linked immunosorbent assay in serum from 99 patients with seronegative occult HCV infection and 130 untreated patients with chronic hepatitis C. IL-28B genotypes were also determined in 54 healthy volunteers. Prevalence of the IL-28B CC genotype was significantly higher in seronegative occult HCV infection (52/99; 52.5%) than in chronic hepatitis C (32/130; 24.6%, P < 0.0001) or healthy controls (19/54: 32.5%, P = 0.039). Among patients with seronegative occult HCV infection, HCV-RNA load in liver was significantly lower in those with the IL-28B CC genotype than in those with CT + TT genotypes (2.8 × 10(5)  ± 5.8 × 10(4) vs. 4.1 × 10(5)  ± 5.9 × 10(4)  copies/μg of total RNA respectively; P = 0.023). Mean serum IP-10 levels were significantly lower in patients with seronegative occult HCV infection than in patients with chronic hepatitis C (160.8 ± 17.9 vs. 288.7 ± 13.3 pg/ml respectively; P < 0.0001). These findings suggest that the host immune response plays an important role in seronegative occult HCV infection in comparison with chronic hepatitis C. © 2015 Wiley Periodicals, Inc.

[Autoimmunity in children with chronic hepatitis C treated with interferon alpha and ribavirin].

PubMed

Gora-Gebka, Magdalena; Liberek, Anna; Bako, Wanda; Raczkowska-Kozak, Janina; Sikorska-Wisniewska, Grazyna; Korzon, Maria

2004-01-01

The role of interferon alpha or the virus itself in the pathogenesis and the risk of autoimmunological disorders in patients infected with HCV, still remain unknown, especially in children. The aim of the study was to evaluate the incidence of autoantibodies and the risk of autoimmunological disorders in children with chronic hepatitis C, treated with interferon alpha and ribavirin in the Department of Paediatrics, Paediatric Gastroenterology and Oncology in Gdansk. In the studied group of 12 patients, in 4 cases autoantibodies were present in low titers prior to the treatment and they had no prognostic value for the response to the therapy or the risk of autoimmunological disorders. Positive response for the treatment was achieved in 4 cases; in 3 cases indications for discontinuation of the therapy were established. During the therapy with interferon alpha and ribavirin, in 2 children elevation of serum titers of antibodies to liver-kidney microsome type 1 (anti-LKM1) (> 1:640) with normal gammaglobulin levels was noted. In none of the children autoimmunological disorders were observed.

Features of Postoperative Immune Suppression Are Reversible With Interferon Gamma and Independent of Interleukin-6 Pathways.

PubMed

Longbottom, E Rebecca; Torrance, Hew D T; Owen, Helen C; Fragkou, Paraskevi C; Hinds, Charles J; Pearse, Rupert M; O'Dwyer, Michael J

2016-08-01

The aim of this study was to evaluate the role of interleukin (IL)-6 pathways in postoperative immune suppression and to assess the reversibility of this phenomenon. The postoperative period is characterized by increased IL-6 production and features of immune suppression. In vitro, IL-6 mediates anti-inflammatory effects through inhibition of interferon gamma (IFN-γ) pathways. The significance of the immunomodulatory effects of IL-6 in the clinical setting of postoperative immune suppression remains unclear. Patients over 45 years old undergoing elective surgery, involving the gastrointestinal tract, were recruited. IL-6 levels were assayed using an enzyme linked immunosorbent assay preoperatively, and at 24 and 48 hours. Peripheral blood mononuclear cells from healthy volunteers were cultured in perioperative serum and CD14Human Leukocyte Antigen-DR (HLA-DR) [monocyte HLA-DR (mHLA-DR)] geometric mean florescent intensity was measured in the presence and absence of IL-6 neutralizing antibody and recombinant IFN-γ. Of the 108 patients, 41 developed a postoperative infection. The IL-6 levels increased 19-fold from the preoperative sample to 24 hours postoperatively (P < 0.0001). Higher IL-6 levels at 24 (P = 0.0002) and 48 hours (P = 0.003) were associated with subsequent postoperative infectious complications. mHLA-DR mean florescent intensity fell when healthy peripheral blood mononuclear cells were cultured with postoperative serum compared with preoperative serum (P = 0.008). This decrease was prevented by the presence of IFN-γ in the culture media, but not by the presence of IL-6-neutralizing antibody. IL-6 levels increase after a major surgery and are associated with an increased susceptibility to postoperative infections. Serum obtained from postoperative patients induces an immunosuppressive response, reflected in reduced mHLA-DR levels, mediated through IL-6 independent pathways and is reversible with IFN-γ. These data may have therapeutic implications for the prevention of infection in patients undergoing major surgery.

Vitamin C attenuation of the development of type I diabetes mellitus by interferon-alpha.

PubMed

al-Zuhair, H; Mohamed, H E

1998-07-01

Interferon alpha (IFN-alpha) inhibits insulin release and may be cytotoxic to pancreatic islets. Increased free radical activity may be implicated in the cytotoxic action of IFN-alpha and development of diabetes mellitus. Therefore we measured markers of free radical activity (lipid peroxides and the non-peroxide-conjugated diene isomer of linoleic acid [PL-9,11-LA']) along with some pancreatic variables in male albino rats treated with IFN-alpha, as well as the possible protective effect of two antioxidants, vitamin C and mannitol. Compared to untreated rats, it was shown that IFN-alpha induced an increase in plasma glucose. Pancreatic and serum insulin, as well as serum C-peptide, were increased after 1 week, then their levels were reduced after 2 weeks. Plasma lipids peroxides and (PL-9,11-LA') were markedly elevated, while linoleic acid was reduced. These changes in the studied parameters were attributed, in part, to the superoxide and free radical generation during IFN-alpha treatment. Plasma glucagon was increased after 2 weeks. Administration of vitamin C along with IFN-alpha succeeded in modulating most of the altered parameters affected during IFN-alpha. The hyperglycaemic effect of IFN-alpha was greatly ameliorated and the negative effect on pancreatic and serum insulin and serum C-peptide were nearly abolished. The elevated levels of lipid peroxide and (PL-9,11-LA') and the reduction in linoleic acid being normalised. The only persistent effect was the increase in plasma glucagon. Concurrent administration of mannitol with IFN-alpha caused no changes in the parameters studied compared to that induced by treatment with IFN-alpha alone.

Is serum neopterin level a marker of responsiveness to interferon beta-1a therapy in multiple sclerosis?

PubMed

Casoni, F; Merelli, E; Bedin, R; Sola, P; Bertolotto, A; Faglioni, P

2004-01-01

Interferon beta (INFbeta) may induce the expression of several proteins, including neopterin, considered a biological marker of INFbeta activity. The aim of this study was to determine the serum neopterin concentration at the beginning of, and during, IFNbeta-1a therapy in relapsing-remitting multiple sclerosis (r-r MS) patients, and to look for a possible correlation between protein synthesis and the clinical course of the disease. Thirteen r-r MS patients were treated with INFbeta-1a (i.m. 6 MIU/week) for 2 years. Blood samples for neopterin determinations were taken daily over a period of 1 week at the end of each 6 months of therapy, and tested for neutralizing antibodies (NABs). Neopterin levels peaked 24-48 h post-injection and returned to baseline after 120 h. After 1 year of therapy, four patients dropped out of the study because of progression of the disease: in these subjects a significant decrement of neopterin was observed. Neopterin baseline values were not found to decrease over the 2 years of therapy, and neopterin may be considered to be a useful marker of responsiveness to IFNbeta.

Treatment of yellow fever virus with an adenovirus-vectored interferon, DEF201, in a hamster model.

PubMed

Julander, Justin G; Ennis, Jane; Turner, Jeffrey; Morrey, John D

2011-05-01

Interferon (IFN) is an innate immune response protein that is involved in the antiviral response during viral infection. Treatment of acute viral infections with exogenous interferon may be effective but is generally not feasible for clinical use due to many factors, including cost, stability, and availability. To overcome these limitations, an adenovirus type 5-vectored consensus alpha IFN, termed DEF201, was constructed as a potential way to deliver sustained therapeutic levels of systemic IFN. To demonstrate the efficacy of DEF201 against acute flaviviral disease, various concentrations of the construct were administered as a single intranasal dose prior to virus infection, which resulted in a dose-responsive, protective effect in a hamster model of yellow fever virus (YFV) disease. A DEF201 dose of 5×10(7) PFU/animal administered intranasally just prior to YFV challenge protected 100% of the animals, while a 10-fold lower DEF201 dose exhibited lower, although significant, levels of protection. Virus titers in the liver and serum and levels of serum alanine aminotransferase were all significantly reduced as a result of DEF201 administration at all doses tested. No toxicity, as indicated by weight loss or gross morbidity, was observed in non-YFV-infected animals treated with DEF201. Protection of YFV-infected animals was observed when DEF201 was delivered as early as 7 days prior to virus challenge and as late as 2 days after virus challenge, demonstrating effective prophylaxis and therapy in a hamster model of disease. Overall, it appears that DEF201 is effective in the treatment of YFV in a hamster model.

Early development of de novo hepatocellular carcinoma after direct-acting agent therapy: Comparison with pegylated interferon-based therapy in chronic hepatitis C patients.

PubMed

Yoo, S H; Kwon, J H; Nam, S W; Kim, H Y; Kim, C W; You, C R; Choi, S W; Cho, S H; Han, J-Y; Song, D S; Chang, U I; Yang, J M; Lee, H L; Lee, S W; Han, N I; Kim, S-H; Song, M J; Hwang, S; Sung, P S; Jang, J W; Bae, S H; Choi, J Y; Yoon, S K

2018-04-16

Patients with chronic hepatitis C who achieve a sustained viral response after pegylated interferon therapy have a reduced risk of hepatocellular carcinoma, but the risk after treatment with direct-acting antivirals is unclear. We compared the rates of early development of hepatocellular carcinoma after direct-acting antivirals and after pegylated interferon therapy. We retrospectively analysed 785 patients with chronic hepatitis C who had no history of hepatocellular carcinoma (211 treated with pegylated interferon, 574 with direct-acting antivirals) and were followed up for at least 24 weeks after antiviral treatment. De novo hepatocellular carcinoma developed in 6 of 574 patients receiving direct-acting antivirals and in 1 of 211 patients receiving pegylated interferon. The cumulative incidence of early hepatocellular carcinoma development did not differ between the treatment groups either for the whole cohort (1.05% vs 0.47%, P = .298) or for those patients with Child-Pugh Class A cirrhosis (3.73% vs 2.94%, P = .827). Multivariate analysis indicated that alpha-fetoprotein level >9.5 ng/mL at the time of end-of-treatment response was the only independent risk factor for early development of hepatocellular carcinoma in all patients (P < .0001, hazard ratio 176.174, 95% confidence interval 10.768-2882.473) and in patients treated with direct-acting agents (P < .0001, hazard ratio 128.402, 95% confidence interval 8.417-1958.680). In conclusion, the rate of early development of hepatocellular carcinoma did not differ between patients treated with pegylated interferon and those treated with direct-acting antivirals and was associated with the serum alpha-fetoprotein level at the time of end-of-treatment response. © 2018 John Wiley & Sons Ltd.

Poly (lactide-co-glycolide)-polymethacrylate nanoparticles for intramuscular delivery of plasmid encoding interleukin-10 to prevent autoimmune diabetes in mice.

PubMed

Basarkar, Ashwin; Singh, Jagdish

2009-01-01

Determine the efficiency of cationic nanoparticles prepared by blending poly (lactide-co-glycolide; PLGA) and methacrylate copolymer (Eudragit(R) E100) to deliver a therapeutic gene encoding mouse interleukin-10, in vitro and in vivo. Nanoparticles prepared with PLGA and E100 were evaluated for delivery of plasmid DNA encoding mouse interleukin-10 in vitro and in vivo in mice upon intramuscular injection. Blood-glucose, serum interferon-gamma levels and histology of pancreas were studied to determine therapeutic efficacy. Histological evaluation of skeletal muscle from the injection site was performed to assess the biocompatibility of nanoparticles. PLGA/E100 nanoparticles showed endosomal escape evidenced by confocal microscopy and buffering ability. Transfecting HEK293 cells with plasmid-loaded PLGA/E100 nanoparticles resulted in significantly (p < 0.05) greater expression of interleukin-10 compared to PLGA nanoparticles. Mice treated with PLGA/E100 nanoparticles displayed higher serum levels of interleukin-10 and lower blood glucose levels compared to those treated with interleukin-10 plasmid alone or PLGA nanoparticles. High expression of interleukin-10 facilitated suppression of interferon-gamma levels and reduced islet infiltration. Histology of muscle showed that nanoparticles were biocompatible and did not cause chronic inflammatory response. Nanoparticles prepared by blending PLGA with methacrylate can efficiently and safely deliver plasmid DNA encoding mouse interleukin-10 leading to prevention of autoimmune diabetes.

Genetic and environmental determinants of interferon-tau secretion by in vivo- and in vitro-derived bovine blastocysts.

PubMed

Kubisch, H M; Larson, M A; Ealy, A D; Murphy, C N; Roberts, R M

2001-04-30

Several experiments were conducted to assess the effects of genotype and various culture media on interferon-tau secretion by in vitro-derived bovine blastocysts and to compare these values with interferon released by blastocysts flushed from superovulated cows. In experiment 1, oocytes were inseminated with semen from three different bulls. While paternal genotype had no effect on cleavage rate, the size or hatching ability of blastocysts, it was a significant determinant of the embryo's ability to develop to the blastocyst stage and of subsequent interferon-tau secretion. In the second experiment, embryos were cultured in synthetic oviductal fluid containing either polyvinyl alcohol, bovine serum albumin or fetal bovine serum. While there was no effect of supplement on the percentage of embryos developing to the blastocyst stage, blastocysts which formed in medium with polyvinyl alcohol had significantly fewer cells, were older at blastocyst formation and produced significantly more interferon-tau. In the third experiment, embryos were cultured to the blastocyst stage in either TCM199 alone or in co-culture with buffalo rat liver, bovine oviductal or bovine uterine epithelial cells. Culture with oviductal or buffalo rat liver cells increased blastocyst cell number, although secretion of interferon-tau was not affected. In the final experiment, bovine blastocysts were flushed from superovulated cows on Day 7 following insemination. Overall, secretion of interferon-tau by in vivo-produced blastocysts did not differ from that of age-matched blastocysts produced in vitro.

Current issues in the management of paediatric viral hepatitis.

PubMed

Yeung, Latifa T F; Roberts, Eve A

2010-01-01

Viral hepatitis poses important problems for children. In preschoolers, hepatitis A virus (HAV) infection frequently causes acute liver failure. Vaccinating toddlers against HAV in countries with high endemicity is expected to decrease mortality. HAV vaccine demonstrates efficacy (comparable to immunoglobulin) as post-exposure prophylaxis. A recently developed vaccine against hepatitis E virus (HEV) may benefit fetal health, because pregnant women are most prone to acute liver failure as a result of HEV. Hepatitis B vaccine continues to demonstrate value and versatility for preventing serious liver disease. With chronic infection, undetectable levels of serum HBV DNA complement e-seroconversion as the preferred outcome measure; suppressed viral load correlates with long-term complications better than HBeAg status. Among Taiwanese children, low pretreatment HBV DNA (<2 x 10(8) copies/ml) strongly predicted response to interferon-alpha. Future paediatric studies must incorporate HBV DNA levels. The rationale for routine treatment of immunotolerant hepatitis B during childhood remains uncertain. Any treatment of chronic hepatitis B in childhood requires consideration of the risks and benefits. Childhood hepatitis C virus (HCV) infection results mainly from mother-to-infant transmission. Babies of HCV-infected women should be tested for serum HCV RNA at 1 month of age. If negative, confirmatory anti-HCV antibody testing may be performed between 12 and 15 months of age. Children with chronic hepatitis C may develop progressive fibrosis/cirrhosis, particularly in the setting of obesity and insulin resistance. Treatment of children chronically infected with genotype 2 or 3 is highly successful: combination therapy of pegylated interferon-alpha and ribavirin is well tolerated and superior to pegylated interferon-alpha alone.

Serum IFN neutralizing antibodies and neopterin levels in a cross-section of MS patients.

PubMed

Cook, S D; Quinless, J R; Jotkowitz, A; Beaton, P

2001-09-25

To determine levels of serum interferon beta (IFNbeta) neutralizing antibody (NAb) and neopterin-an IFN biologic response marker-in patients with MS treated with Betaseron or Avonex. Controversy exists over the relative immunogenicity of IFNbeta-1a and IFNbeta-1b and the reasons for any such difference. To determine the role of patient profile and test methodology in IFNbeta, NAb levels need to be measured blindly and simultaneously in a predefined closely matched MS patient cohort. Serum NAb and neopterin levels were measured in closely matched patients on Avonex (n = 98) or Betaseron (n = 64). NAb were determined by Athena Diagnostics and serum neopterin levels by Covance Laboratories using a competitive binding radioimmunoassay. More patients taking Betaseron (22%) than Avonex (7%) had elevated titers of NAb (p = 0.008). Mean serum neopterin levels were lower in patients with high as compared to low NAb titers (p = 0.0002). No difference in mean neopterin levels was found comparing the total Betaseron group to the Avonex group; however, in the subset of patients with low NAb titers, mean neopterin levels were higher in the Betaseron than in the Avonex group (p = 0.027). A random cross-sectional sampling of patients on Avonex showed a decrease in neopterin levels over time between weekly doses. NAb are more commonly found with Betaseron than Avonex. More studies are needed to determine the correlation among serum neopterin levels, other biologic response markers, NAb, and disease activity in patients with MS being treated with IFNbeta.

Large-scale analysis of tumor necrosis factor α levels in systemic lupus erythematosus.

PubMed

Weckerle, Corinna E; Mangale, Dorothy; Franek, Beverly S; Kelly, Jennifer A; Kumabe, Marissa; James, Judith A; Moser, Kathy L; Harley, John B; Niewold, Timothy B

2012-09-01

Systemic lupus erythematosus (SLE) disease manifestations are highly variable among patients, and the prevalence of individual clinical features differs significantly by ancestry. Serum tumor necrosis factor α (TNFα) levels are elevated in some SLE patients and may play a role in disease pathogenesis. The aim of this study was to look for associations between serum TNFα levels, clinical manifestations of SLE, autoantibodies, and serum interferon-α (IFNα) levels in a large multiancestral SLE cohort. We studied serum TNFα levels in 653 SLE patients (214 African Americans, 298 European Americans, and 141 Hispanic Americans). TNFα was measured using an enzyme-linked immunosorbent assay, and IFNα was measured with a functional reporter cell assay. Stratified and multivariate analyses were used to detect associations in each ancestral background separately, with meta-analysis when appropriate. Serum TNFα levels were significantly higher in SLE patients than in non-autoimmune disease controls (P < 5.0 × 10(-3) for each ancestral background). High serum TNFα levels were positively correlated with high serum IFNα levels when tested in the same sample across all ancestral backgrounds (odds ratio range 1.76-1.86, P = 4.8 × 10(-3) by Fisher's combined probability test). While serum TNFα levels alone did not differ significantly among SLE patients of different ancestral backgrounds, the proportion of patients with concurrently high levels of TNFα and IFNα was highest in African Americans and lowest in European Americans (P = 5.0 × 10(-3) ). Serum TNFα levels were not associated with autoantibodies, clinical criteria for the diagnosis of SLE, or age at the time of sampling. Serum TNFα levels are high in many SLE patients, and we observed a positive correlation between serum TNFα and IFNα levels. These data support a role for TNFα in the pathogenesis of SLE across all ancestral backgrounds and suggest important cytokine subgroups within the disease. Copyright © 2012 by the American College of Rheumatology.

Serum profile of cytokines interferon gamma and interleukin-10 in ewes subjected to artificial insemination by cervical retraction.

PubMed

Alvares, C T G; Cruz, J F; Romano, C C; Brandão, F Z

2016-04-15

This study evaluated the influence of artificial insemination (AI) by cervical retraction (CRI) on serum levels of interferon gamma (IFNγ) and interleukin-10 (IL-10) in ewes. Synchronized pluriparous Santa Inês ewes were subjected to natural mating (NM, n = 8) and AI, which was performed for a fixed time (55 ± 1 hour) by CRI (n = 8) or laparoscopy (n = 8). Ewes were classified as pregnant, with return to estrus (RE) or with embryonic loss (EL). Blood samples were collected on Day 0, Day 3, Day 5, Day 12, and Day 17 (Day 0 = AI/NM) for progesterone dosage and cytokines were quantified from Day 0 to Day 12. Progesterone levels were constant, except for a decrease in ewes with RE at Day 17 (P < 0.05). Regardless of the reproductive method used, there was no difference in the IFNγ and IL-10 levels at any time, with averages of 642.1, 713.2, and 741.2 pg/mL for IFNγ and 667.1, 616.8, and 721.1 pg/mL for IL-10 when using CRI, laproscopy, and NM, respectively. Regarding the physiological status, ewes with EL had lower serum levels of IFNγ and IL-10 than pregnant ewes and ewes with RE, regardless of the reproductive method used, with averages of 769.1, 714.9, and 555.7 pg/mL for IFNγ and 713.8, 699.3, and 578.7 pg/mL for IL-10 in pregnant ewes, ewes with RE and EL, respectively (P < 0.01). In conclusion, AI by CRI in Santa Inês ewes does not alter the profile of serum cytokines IFNγ and IL-10 and does not induce an inflammatory reaction that can compromise pregnancy. Copyright © 2016 Elsevier Inc. All rights reserved.

Catecholamine plasma levels, IFN-γ serum levels and antibodies production induced by rabies vaccine in dogs selected for their paw preference.

PubMed

Siniscalchi, Marcello; Cirone, Francesco; Guaricci, Antonio Ciro; Quaranta, Angelo

2014-01-01

To explore the possible role of the sympathetic nervous activity in the asymmetrical crosstalk between the brain and immune system, catecholamine (E, NE) plasma levels, Interferon-γ (IFN-γ) serum levels and production of antibodies induced by rabies vaccine in dogs selected for their paw preference were measured. The results showed that the direction of behavioural lateralization influenced both epinephrine levels and immune response in dogs. A different kinetic of epinephrine levels after immunization was observed in left-pawed dogs compared to both right-pawed and ambidextrous dogs. The titers of antirabies antibodies were lower in left-pawed dogs than in right-pawed and ambidextrous dogs. Similarly, the IFN-γ serum levels were lower in left-pawed dogs than in the other two groups. Taken together, these findings showed that the left-pawed group appeared to be consistently the different group stressing the fundamental role played by the sympathetic nervous system as a mechanistic basis for the crosstalk between the brain and the immune system.

The role of autosuggestion in geriatric patients' quality of life: a study on psycho-neuro-endocrine-immunology pathway.

PubMed

Sari, Nina Kemala; Setiati, Siti; Taher, Akmal; Wiwie, Martina; Djauzi, Samsuridjal; Pandelaki, Jacub; Purba, Jan Sudir; Sadikin, Mohamad

2017-10-01

There has been no study conducted about the effect of autosuggestion on quality of life for geriatric patients. Our aim was to evaluate the efficacy of autosuggestion for geriatric patients' quality of life and its impact on psycho-neuro-endocrine-immune pathway. Sixty geriatric patients aged ≥60 years in a ward were randomly assigned to either receive autosuggestion or not. Autosuggestion was recorded in a tape to be heard daily for 30 days. Both groups received the standard medical therapy. Primary outcome was quality of life by COOP chart. Secondary outcomes were serum cortisol level, interleukin-2, interleukin-6, interferon-γ, and N-acetylaspartate/creatine ratio in limbic/paralimbic system by magnetic resonance spectroscopy. The study was single blinded due to the nature of the intervention studied. Out of 60 subjects, 51 finished the study. The autosuggestion group reported better scores than the control one for quality of life, COOP chart 1.95 vs. 2.22 (95% CI, p = 0.02). There were increments of serum cortisol (p = 0.03) and interleukin-6 in the autosuggestion group (p = 0.04). Interleukin-2, interferon-γ, and N-acetylaspartate/creatine ratio in prefrontal cortex showed a tendency to increase in the autosuggestion groups. Autosuggestion is associated with improvement of geriatrics' quality of life, serum cortisol level, and adaptive immunity. There is a better trend for neuroplasticity in prefrontal cortex in the autosuggestion group.

The mechanism of Cordyceps sinensis and strontium in prevention of osteoporosis in rats.

PubMed

Qi, Wei; Wang, Pu-jie; Guo, Wen-jun; Yan, Ya-bo; Zhang, Yang; Lei, Wei

2011-10-01

The effects of Cordyceps sinensis (Caterpillar fungus) and strontium ranelate on ovariectomized osteopenic rats was studied in this paper. After the rats were treated orally with C. sinensis, strontium, and C. sinensis rich in strontium ranelate (CSS) respectively, serum alkaline phosphatase (ALP), tartarate-resistant acid phosphatase (TRAP), serum osteocalcin (OC), homocysteine, C-terminal crosslinked telopeptides of collagen type I (CTX), estradiol, and interferon-gamma (IFN-γ) level were examined. The beneficial effects of CSS on improvement of osteoporosis in rats were attributable mainly to decrease ALP activity, TRAP activity, CTX level, and IFN-γ level. At the same time, CSS also increase the OC and estradiol level in ovariectomized osteopenic rats. This study demonstrates the value of C. sinensis rich in strontium ranelate in the management of postmenopausal osteoporosis in humans.

Differential screening-selected gene aberrative in neuroblastoma (DAN) is increased in the CSF of patients with MS and may be induced by therapy with interferon-β.

PubMed

Mausner-Fainberg, Karin; Kolb, Hadar; Penn, Moran; Regev, Keren; Vaknin-Dembinsky, Adi; Gadoth, Avi; Kestenbaum, Meir; Karni, Arnon

2016-03-15

Bone morphogenic proteins (BMPs) signaling blockade induce neurogenesis and oligodendrogenesis. Differential screening-selected gene aberrative in neuroblastoma (DAN) is a glycoprotein that antagonizes BMPs. We found that DAN levels were higher in CSF compared to serum in all participants. CSF-DAN levels were elevated in RR-and progresssive MS patients compared to controls. Moreover, serum-DAN levels were reduced in those patients, but elevated in IFN-β1a treated patients. The main source of DAN is apparently CNS- resident cells. The enhanced levels of CSF-DAN in MS patients suggest a tendency to induce neurogenesis/oligodendrogenesis in the patients CNS. Our results suggest an unreported mode of action of IFN-β1a. Copyright © 2016 Elsevier B.V. All rights reserved.

Do cytokines have any role in Wilson's disease?

PubMed Central

Goyal, M K; Sinha, S; Patil, S A; Jayalekshmy, V; Taly, A B

2008-01-01

The aim of this study was to determine the serum cytokine levels in patients with Wilson's disease (WD) and correlate with phenotype, therapeutic status and laboratory data. In this cross-sectional study, the serum levels of cytokines were estimated in 34 patients (M : F, 23 : 11; drug-naive, 11) with WD (mean age: 13·8 ± 8·6 and 19·6 ± 9·03 years) and compared with 30 controls. The following serum cytokines were analysed using enzyme-linked immunosorbent assay: (i) tumour necrosis factor (TNF)-α, (ii) interferon (IFN)-γ, (iii) interleukin (IL)-2, (iv) IL-6 and (v) IL-4. Serum TNF-α (P < 0·001), IFN-γ (P = 0·005) and IL-6 (P < 0·001) were detectable in WD compared with controls. However, serum level elevation of IL-4 (P = 0·49) and IL-2 (P = 0·11), although detectable compared with controls, was statistically insignificant. The disease severity and therapeutic status did not affect the cytokines. Presence of anaemia, leucopenia, thrombocytopenia, pancytopenia and hepatic dysfunction did not influence cytokine levels. There was a significant negative correlation between IL-6 and ceruloplasmin (P = 0·04) and anti-inflammatory cytokines (IL-4) and copper level (P = 0·01). Serum cytokines, both proinflammatory and anti-inflammatory subtypes, were elevated significantly in patients with WD. Further studies would establish their role in its pathogenesis. PMID:18821941

Role of T Cells and Gamma Interferon during Induction of Hypersensitivity to Lipopolysaccharide by Toxic Shock Syndrome Toxin 1 in Mice

PubMed Central

Dinges, Martin M.; Schlievert, Patrick M.

2001-01-01

The superantigenic function of toxic shock syndrome toxin 1 (TSST-1) is generally regarded as an important determinant of its lethal effects in humans or experimental animals. This study examined the role of superantigenicity in a BALB/c mouse model of lethal TSST-1-induced hypersensitivity to lipopolysaccharide (LPS). In this model, TSST-1 greatly potentiated both LPS-induced lethality, as well as LPS-induced serum tumor necrosis factor alpha (TNF-α) activity. Although BALB/c-SCID mice were resistant to these LPS enhancement effects of TSST-1, BALB/c-SCID mice reconstituted with T cells were completely susceptible to the enhancement effect of TSST-1 on LPS-induced serum TNF-α. Mice pretreated with cyclosporine (Cs) or neutralizing antibodies against gamma interferon (IFN-γ) did not develop lethal LPS hypersensitivity when injected with TSST-1, and these agents reduced the enhancement effect of TSST-1 on LPS-induced serum TNF-α by 99 and 85%, respectively. Cs pretreatment also completely inhibited the known capacity of TSST-1 to amplify LPS-induced levels of IFN-γ in serum. In contrast, mice given Cs after a priming injection of TSST-1, but before LPS, still exhibited lethal hypersensitivity to LPS. Cs given after TSST-1 also did not inhibit enhancement of LPS-induced serum TNF-α by TSST-1 but inhibited the enhancement effect of TSST-1 on LPS-induced serum IFN-γ by 50%. These experiments support the theory that TSST-1-induced hypersensitivity to LPS is mediated primarily by IFN-γ derived from superantigen-activated T cells. PMID:11179286

Correlation of Immunomodulatory and Therapeutic Activities of Interferon and Interferon Inducers in Metastatic Disease

DTIC Science & Technology

1988-01-01

Eagle’s minimum essential medium with Earle’s salts, supplemented with 5% fetal bovine serum, L-glutamine, sodium pyruvate, nonessential amino acids...LC (iv., tiw) was initiated 1 day lacer . The statistical significance of the differences in survival was analyzed with the Kruskal-Wallis test

MHC2TA mRNA levels and human herpesvirus 6 in multiple sclerosis patients treated with interferon beta along two-year follow-up

PubMed Central

2012-01-01

Background In previous studies we found that MHC2TA +1614 genotype frequency was very different when MS patients with and without human herpesvirus 6 (HHV-6) in serum samples were compared; a different clinical behavior was also described. The purpose of the study was: 1. To evaluate if MHC2TA expression in MS patients was influenced by interferon beta (IFN-beta) treatment. 2. To study MHC2TA expression in MS patients with and without minor allele C. 3. To analyze the relation between MHC2TA mRNA levels and HHV-6 active infection in MS patients. Methods Blood and serum samples of 154 MS patients were collected in five programmed visits: basal (prior to beginning IFN-beta treatment), six, twelve, eighteen and twenty-four months later. HHV-6 in serum and MHC2TA mRNA levels were evaluated by PCR and RT-PCR, respectively. Neutralizing antibodies (NAbs) against IFN-beta were analyzed by the cytopathic effect assay. Results We found that MHC2TA mRNA levels were significantly lower among MS patients with HHV-6 active infection at the basal visit (without treatment) than in those MS patients without HHV-6 active infection at the basal visit (p = 0.012); in all the positive samples we only found variant A. Furthermore, 58/99 (58.6%) MS patients without HHV-6 along the five programmed visits and an increase of MHC2TA expression after two-years of IFN-beta treatment were clinical responders vs. 5/21 (23.8%) among those MS patients with HHV-6 and a decrease of MHC2TA mRNA levels along the two-years with IFN-beta treatment (p = 0.004); no differences were found between patients with and without NAbs. Conclusions MHC2TA mRNA levels could be decreased by the active replication of HHV-6; the absence of HHV-6 in serum and the increase of MHC2TA expression could be further studied as markers of good clinical response to IFN-beta treatment. PMID:23009575

Cytokine profile after oral food challenge in infants with food protein-induced enterocolitis syndrome.

PubMed

Kimura, Mitsuaki; Ito, Yasunori; Shimomura, Masaki; Morishita, Hideaki; Meguro, Takaaki; Adachi, Yuichi; Seto, Shiro

2017-07-01

Although food protein-induced enterocolitis syndrome (FPIES) is supposed to be caused by inflammation, the role of cytokines has not yet been clarified. To elucidate the role of cytokines in the development of symptoms and abnormal laboratory findings at an oral food challenge (OFC), changes in serum cytokine levels were analyzed for 6 OFCs in 4 patients with FPIES. The result of OFC was judged positive if any gastrointestinal (GI) symptoms (vomiting, diarrhea, or bloody stool) were induced. Among 11 cytokines profiled, serum levels of interleukin (IL)-2, IL-5, and IL-8 were clearly increased in all 4 positive OFCs in which elevations of the serum level of C-reactive protein (CRP) and peripheral blood neutrophilia were also seen. The level of serum IL-10 also rose in 2 positive OFCs. Remarkable increases in the serum level of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), IL-6, and IL-12 were observed in a positive OFC where the serum level of CRP rose markedly (6.75 mg/dL). The serum levels of IL-5 were also elevated in 2 negative OFCs. No apparent specific correlations were found between cytokines and GI symptoms. These results suggest that IL-2 and IL-8 are involved in the antigen-specific immune responses in most patients with FPIES. Further studies are needed to elucidate the significance of these cytokine in the pathogenesis of FPIES. Copyright © 2016 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

Fatigue in primary Sjögren's syndrome is associated with lower levels of proinflammatory cytokines.

PubMed

Howard Tripp, Nadia; Tarn, Jessica; Natasari, Andini; Gillespie, Colin; Mitchell, Sheryl; Hackett, Katie L; Bowman, Simon J; Price, Elizabeth; Pease, Colin T; Emery, Paul; Lanyon, Peter; Hunter, John; Gupta, Monica; Bombardieri, Michele; Sutcliffe, Nurhan; Pitzalis, Costantino; McLaren, John; Cooper, Annie; Regan, Marian; Giles, Ian; Isenberg, David A; Saravanan, Vadivelu; Coady, David; Dasgupta, Bhaskar; McHugh, Neil; Young-Min, Steven; Moots, Robert; Gendi, Nagui; Akil, Mohammed; Griffiths, Bridget; Lendrem, Dennis W; Ng, Wan-Fai

2016-01-01

This article reports relationships between serum cytokine levels and patient-reported levels of fatigue, in the chronic immunological condition primary Sjögren's syndrome (pSS). Blood levels of 24 cytokines were measured in 159 patients with pSS from the United Kingdom Primary Sjögren's Syndrome Registry and 28 healthy non-fatigued controls. Differences between cytokines in cases and controls were evaluated using Wilcoxon test. Patient-reported scores for fatigue were evaluated, classified according to severity and compared with cytokine levels using analysis of variance. Logistic regression was used to determine the most important predictors of fatigue levels. 14 cytokines were significantly higher in patients with pSS (n=159) compared to non-fatigued healthy controls (n=28). While serum levels were elevated in patients with pSS compared to healthy controls, unexpectedly, the levels of 4 proinflammatory cytokines-interferon-γ-induced protein-10 (IP-10) (p=0.019), tumour necrosis factor-α (p=0.046), lymphotoxin-α (p=0.034) and interferon-γ (IFN-γ) (p=0.022)-were inversely related to patient-reported levels of fatigue. A regression model predicting fatigue levels in pSS based on cytokine levels, disease-specific and clinical parameters, as well as anxiety, pain and depression, revealed IP-10, IFN-γ (both inversely), pain and depression (both positively) as the most important predictors of fatigue. This model correctly predicts fatigue levels with reasonable (67%) accuracy. Cytokines, pain and depression appear to be the most powerful predictors of fatigue in pSS. Our data challenge the notion that proinflammatory cytokines directly mediate fatigue in chronic immunological conditions. Instead, we hypothesise that mechanisms regulating inflammatory responses may be important.

Fatigue in primary Sjögren's syndrome is associated with lower levels of proinflammatory cytokines

PubMed Central

Howard Tripp, Nadia; Tarn, Jessica; Natasari, Andini; Gillespie, Colin; Mitchell, Sheryl; Hackett, Katie L; Bowman, Simon J; Price, Elizabeth; Pease, Colin T; Emery, Paul; Lanyon, Peter; Hunter, John; Gupta, Monica; Bombardieri, Michele; Sutcliffe, Nurhan; Pitzalis, Costantino; McLaren, John; Cooper, Annie; Regan, Marian; Giles, Ian; Isenberg, David A; Saravanan, Vadivelu; Coady, David; Dasgupta, Bhaskar; McHugh, Neil; Young-Min, Steven; Moots, Robert; Gendi, Nagui; Akil, Mohammed; Griffiths, Bridget; Lendrem, Dennis W; Ng, Wan-Fai

2016-01-01

Objectives This article reports relationships between serum cytokine levels and patient-reported levels of fatigue, in the chronic immunological condition primary Sjögren's syndrome (pSS). Methods Blood levels of 24 cytokines were measured in 159 patients with pSS from the United Kingdom Primary Sjögren's Syndrome Registry and 28 healthy non-fatigued controls. Differences between cytokines in cases and controls were evaluated using Wilcoxon test. Patient-reported scores for fatigue were evaluated, classified according to severity and compared with cytokine levels using analysis of variance. Logistic regression was used to determine the most important predictors of fatigue levels. Results 14 cytokines were significantly higher in patients with pSS (n=159) compared to non-fatigued healthy controls (n=28). While serum levels were elevated in patients with pSS compared to healthy controls, unexpectedly, the levels of 4 proinflammatory cytokines—interferon-γ-induced protein-10 (IP-10) (p=0.019), tumour necrosis factor-α (p=0.046), lymphotoxin-α (p=0.034) and interferon-γ (IFN-γ) (p=0.022)—were inversely related to patient-reported levels of fatigue. A regression model predicting fatigue levels in pSS based on cytokine levels, disease-specific and clinical parameters, as well as anxiety, pain and depression, revealed IP-10, IFN-γ (both inversely), pain and depression (both positively) as the most important predictors of fatigue. This model correctly predicts fatigue levels with reasonable (67%) accuracy. Conclusions Cytokines, pain and depression appear to be the most powerful predictors of fatigue in pSS. Our data challenge the notion that proinflammatory cytokines directly mediate fatigue in chronic immunological conditions. Instead, we hypothesise that mechanisms regulating inflammatory responses may be important. PMID:27493792

Whole blood transcriptome comparison of pigs with extreme production of in vivo dsRNA-induced serum IFN-a.

PubMed

Liu, Xiangdong; Huang, Jing; Yang, Songbai; Zhao, Yunxia; Xiang, Anjing; Cao, Jianhua; Fan, Bin; Wu, Zhenfang; Zhao, Junlong; Zhao, Shuhong; Zhu, Mengjin

2014-05-01

Interferon (IFN) is one of the major regulators of innate immunity, it also mediates the adaptive immune responses to a broad spectrum of pathogens. This study aims in identifying differences between high vs. low INF-a responders which were chosen based on serum INF-a levels at 4 h post poly I:C treatment. A transcriptomic analysis was designed to describe the whole blood differential transcriptomal response to poly I:C by pigs with high vs. low IFN alpha levels. The capability of producing dsRNA (poly I:C)-induced serum IFN-a is highly variable in pig population. The high INF-a responders had 328 unique differentially expressed genes, suggesting that the HIGH pigs have greater responsiveness upon the dsRNA simulation. Based on the results, the interferon-dependent antiviral responsiveness through the IFN-stimulated genes (ISGs) is likely more effective in HIGH pigs. Inferring from the known organization of IFN pathways, the reason for the more IFN-a production in the HIGH pigs was likely due to the enhanced expression of IRF-7 in TLR or RIG- I/MDA5 signaling pathways. Furthermore, the larger number of the altered genes in the HIGH pigs after simulation is also possibly because of the greater number of the altered transcription factors. To our knowledge, this is the first report of comparative transcriptomic analysis to advance our understanding of whole blood immune response in pigs with different in vivo poly I:C-inducted IFN-a levels. The paper significantly expands our knowledge of how pigs respond to poly I:C which is highly relevant for understanding resistance to viral infections and also for vaccine development. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effects of salinomycin and Bacillus subtilis on growth performance and immune responses in broiler chickens.

PubMed

Lee, Kyung-Woo; Lillehoj, Hyun S; Jang, Seung I; Lee, Sung-Hyen

2014-10-01

The present study was undertaken to compare the effect of salinomycin and Bacillus subtilis on growth performance, serum antibody levels against Clostridium spp. and Eimeria spp., and cytokine mRNA expression levels in broiler chickens raised in the used litter. Broiler chickens fed a diet containing salinomycin showed lower (P < 0.05) body weights compared with the control diet-fed counterparts. Serum nitric oxide levels were significantly (P < 0.05) elevated in chickens fed the B. subtilis-enriched diet compared with those on either the salinomycin-fed or control diet-fed chickens. None of the dietary treatments affected (P > 0.05) serum antibody levels against Clostridium perfringens toxins. Both salinomycin and B.subtilis significantly lowered (P < 0.05) the serum levels of Eimeria-specific antibodies compared with the control group. Salinomycin, but not B. subtilis, significantly modulated (P < 0.05) the expression of cytokines encoding interferon-γ (IFN-γ), interleukin10 (IL-10) and tumor necrosis factor superfamily 15 (TNFSF15) compared with the control group. In conclusion, dietary salinomycin and B. subtilis affected serum anticoccidial antibody and intestinal cytokine expression, but failed to improve growth performance in broiler chickens. Further study is warranted to investigate the mode of action of salinomycin on host immune response and growth performance in broiler chickens. Copyright © 2014 Elsevier Ltd. All rights reserved.

Haemolytic anaemia to the alpha-interferon treatment: a proposed mechanism.

PubMed

Barbolla, L; Paniagua, C; Outeiriño, J; Prieto, E; Sánchez Fayos, J

1993-01-01

Auto-immune haemolytic anaemia (AIHA) has been found in a case of alpha-interferon treatment. Serum antibody and eluate were positive in the absence of the drug. Although the patient recovered after the treatment was stopped, DAGT remained positive for at least 8 months. The mechanism proposed to explain why this drug induced AIHA is similar to that proposed for alpha-methyl-dopa. Drugs could alter the red cell membrane and impair the immune system. Such changes have been observed with alpha-interferon and were related with increased autoimmunity.

Severe Disseminated Mycobacterium avium Infection in a Patient with a Positive Serum Autoantibody to Interferon-γ

PubMed Central

Ikeda, Hiroshi; Nakamura, Kiwamu; Ikenori, Mei; Saito, Takahiro; Nagamine, Keisuke; Inoue, Minoru; Sakagami, Takuro; Suzuki, Hiroko; Usui, Mariko; Kanemitsu, Keiji; Matsumoto, Akinori; Shinbo, Takuro

2016-01-01

We herein report a case of disseminated Mycobacterium avium infection that involved both optic nerves, the conjunctiva, the right lower lung, and multiple skin lesions, including a thoracic nodule. The patient was a 65-year-old man without any significant medical history. The pathogen was detected in the patient's eye discharge, sputum, bronchial lavage fluid, and thoracic nodule. Anti-mycobacterial chemotherapy, including clarithromycin, rifampicin, and ethambutol, was administered, and the thoracic nodule was resected. An autoantibody to interferon-γ was detected in the patient's serum. Bilateral swelling of his optic nerves and facial dermatitis improved after initiating anti-mycobacterial chemotherapy. PMID:27746449

Interferon-induced 2'-5' adenylate synthetase in vivo and interferon production in vitro by lymphocytes from systemic lupus erythematosus patients with and without circulating interferon

DOE Office of Scientific and Technical Information (OSTI.GOV)

Preble, O.T.; Rothko, K.; Klippel, J.H.

1983-06-01

The interferon (IFN)-induced enzyme 2-5A synthetase was elevated in mononuclear cells from both serum IFN-positive and -negative systemic lupus erythematosus (SLE) patients. This suggests that a much higher percentage of patients than previously thought produce endogenous IFN. These results may partly explain findings that mononuclear cells from SLE patients are deficient in IFN production in vitro in response to certain IFN inducers. Although normal lymphocytes can produce an acid-labile alpha IFN after stimulation with C. parvum in vitro, the reason for endogenous production of this unusual alpha IFN by SLE patients remains unknown.

Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

PubMed Central

Lotrich, Francis E; Albusaysi, Salwa; Ferrell, Robert E

2013-01-01

Depression has been associated with inflammation, and inflammation may both influence and interact with growth factors such as brain-derived neurotrophic factor (BDNF). Both the functional Val66Met BDNF polymorphism (rs6265) and BDNF levels have been associated with depression. It is thus plausible that decreased BDNF could mediate and/or moderate cytokine-induced depression. We therefore prospectively employed the Beck Depression Inventory-II (BDI-II), the Hospital Anxiety and Depression Scale (HADS), and the Montgomery–Asberg Depression Rating Scale (MADRS) in 124 initially euthymic patients during treatment with interferon-alpha (IFN-α), assessing serum BDNF and rs6265. Using mixed-effect repeated measures, lower pretreatment BDNF was associated with higher depression symptoms during IFN-α treatment (F144,17.2=6.8; P<0.0001). However, although the Met allele was associated with lower BDNF levels (F1,83.0=5.0; P=0.03), it was only associated with increased MADRS scores (F4,8.9=20.3; P<0.001), and not the BDI-II or HADS. An exploratory comparison of individual BDI-II items indicated that the Met allele was associated with suicidal ideation, sadness, and worthlessness, but not neurovegetative symptoms. Conversely, the serotonin transporter promoter polymorphism (5-HTTLPR) short allele was associated with neurovegetative symptoms such as insomnia, poor appetite and fatigue, but not sadness, worthlessness, or suicidal ideation. IFN-α therapy further lowered BDNF serum levels (F4,37.7=5.0; P=0.003), but this decrease occurred regardless of depression development. The findings thus do not support the hypothesis that decreasing BDNF is the primary pathway by which IFN-α worsens depression. Nonetheless, the results support the hypothesis that BDNF levels influence resiliency against developing inflammatory cytokine-associated depression, and specifically to a subset of symptoms distinct from those influenced by 5-HTTLPR. PMID:23303061

Regulatory T cell frequency in patients with melanoma with different disease stage and course, and modulating effects of high-dose interferon-alpha 2b treatment.

PubMed

Ascierto, Paolo A; Napolitano, Maria; Celentano, Egidio; Simeone, Ester; Gentilcore, Giusy; Daponte, Antonio; Capone, Mariaelena; Caracò, Corrado; Calemma, Rosa; Beneduce, Gerardo; Cerrone, Margherita; De Rosa, Vincenzo; Palmieri, Giuseppe; Castello, Giuseppe; Kirkwood, John M; Marincola, Francesco M; Mozzillo, Nicola

2010-08-16

High-dose interferon-alpha 2b (IFN-alpha 2b) is the only approved systemic therapy in the United States for the adjuvant treatment of melanoma. The study objective was to explore the immunomodulatory mechanism of action for IFN-alpha 2b by measuring serum regulatory T cell (Treg), serum transforming growth factor-beta (TGF-beta), interleukin (IL)-10, and autoantibody levels in patients with melanoma treated with the induction phase of the high-dose IFN-alpha 2b regimen. Patients with melanoma received IFN-alpha 2b administered intravenously (20 MU/m2 each day from day 1 to day 5 for 4 consecutive weeks). Serum Treg levels were measured as whole lymphocytes in CD4+ cells using flow cytometry while TGF-beta, IL-10, and autoantibody levels were measured using enzyme-linked immunosorbent assays. Twenty-two patients with melanoma received IFN-alpha 2b treatment and were evaluated for Treg levels. Before treatment, Treg levels were significantly higher in patients with melanoma when compared with data from 20 healthy subjects (P = 0.001; Mann-Whitney test). Although a trend for reduction of Treg levels following IFN-α 2b treatment was observed (average decrease 0.29% per week), statistical significance was not achieved. Subgroup analyses indicated higher baseline Treg levels for stage III versus IV disease (P = 0.082), early recurrence versus no recurrence (P = 0.017), deceased versus surviving patients (P = 0.021), and preoperative neoadjuvant versus postoperative adjuvant treatment groups (not significant). No significant effects were observed on the levels of TGF-beta, IL-10, and autoantibodies in patients with melanoma treated with IFN-alpha 2b. Patients with melanoma in this study showed increased basal levels of Treg that may be relevant to their disease and its progression. Treg levels shifted in patients with melanoma treated with IFN-alpha 2b, although no firm conclusions regarding the role of Tregs as a marker of treatment response or outcome can be made at present.

Network Analysis of Associations between Serum Interferon Alpha Activity, Autoantibodies, and Clinical Features in Systemic Lupus Erythematosus

PubMed Central

Weckerle, Corinna E.; Franek, Beverly S.; Kelly, Jennifer A.; Kumabe, Marissa; Mikolaitis, Rachel A.; Green, Stephanie L.; Utset, Tammy O.; Jolly, Meenakshi; James, Judith A.; Harley, John B.; Niewold, Timothy B.

2010-01-01

Background Interferon-alpha (IFN-α) is a primary pathogenic factor in systemic lupus erythematosus (SLE), and high IFN-α levels may be associated with particular clinical manifestations. The prevalence of individual clinical and serologic features differs significantly by ancestry. We used multivariate and network analyses to detect associations between clinical and serologic disease manifestations and serum IFN-α activity in a large diverse SLE cohort. Methods 1089 SLE patients were studied (387 African-American, 186 Hispanic-American, and 516 European-American). Presence or absence of ACR clinical criteria for SLE, autoantibodies, and serum IFN-α activity data were analyzed in univariate and multivariate models. Iterative multivariate logistic regression was performed in each background separately to establish the network of associations between variables that were independently significant following Bonferroni correction. Results In all ancestral backgrounds, high IFN-α activity was associated with anti-Ro and anti-dsDNA antibodies (p-values 4.6×10−18 and 2.9 × 10−16 respectively). Younger age, non-European ancestry, and anti-RNP were also independently associated with increased serum IFN-α activity (p≤6.7×10−4). We found 14 unique associations between variables in network analysis, and only 7 of these associations were shared by more than one ancestral background. Associations between clinical criteria were different in different ancestral backgrounds, while autoantibody-IFN-α relationships were similar across backgrounds. IFN-α activity and autoantibodies were not associated with ACR clinical features in multivariate models. Conclusions Serum IFN-α activity was strongly and consistently associated with autoantibodies, and not independently associated with clinical features in SLE. IFN-α may be more relevant to humoral tolerance and initial pathogenesis than later clinical disease manifestations. PMID:21162028

Decreased serum levels of sCD40L and IL-31 correlate in treated patients with Relapsing-Remitting Multiple Sclerosis.

PubMed

de J Guerrero-García, José; Rojas-Mayorquín, Argelia E; Valle, Yeminia; Padilla-Gutiérrez, Jorge R; Castañeda-Moreno, Víctor A; Mireles-Ramírez, Mario A; Muñoz-Valle, José F; Ortuño-Sahagún, Daniel

2018-01-01

The CD40/CD40L system is a binding key for co-stimulation of immune cells. Soluble form of CD40L has been widely studied as marker of inflammatory and autoimmune diseases. Here we analyze serum concentrations of sCD40L, as well as 14 cytokines, in patients with Multiple Sclerosis (MS) treated with Glatiramer acetate or Interferon beta. In the healthy control group, we found in serum a highly positive correlation between sCD40L and Interleukin (IL)-31, an anti-inflammatory Th2 cytokine. Additionally, an important reduction in IL-31 and sCD40L serum levels, as well as a significant reduction in CD40 mRNA expression and complete depletion of CD40L mRNA, detected from peripheral blood cells, was found in treated patients with MS. Therefore, sCD40L and IL-31 must be taken into account as possible prognostic markers when analyzing the disease progress of MS in order to provide more personalized treatment. Copyright © 2017 Elsevier GmbH. All rights reserved.

Current report on the interferon program at Roswell Park Memorial Institute.

PubMed

Murphy, G P

1981-01-01

An overview of the interferon program at Roswell Park Memorial Institute (RPMI), is presented. This program encompasses three interrelated areas of research and new drug development: (a) basic research on purification and characterization of animal and human interferons (leukocyte, fibroblast, and immune); (b) large scale manufacture and preclinical testing of human fibroblast interferon (HFIF); and (c) clinical trials with HFIF to determine its safety of administration as well as antiviral, antitumor, and immunomodulatory activities in patients with neoplastic or viral disease. The antitumor effect of HFIF produced at RPMI as assessed by intralesional injection of various metastatic nodules resulted in an overall 71% local response. Phase I studies in 13 patients demonstrated that HFIF can be administered safely by the subcutaneous, intramuscular, and intravenous routes in doses up to 25 million units per day without any serious untoward effects. Intrathecal administration of HFIF into patients with CNS leukemia was also well tolerated. Pharmacokinetic studies indicated significant levels of HFIF in serum and cerebrospinal fluid after intravenous and intrathecal administration, respectively. Coincidental with the HFIF systemic administration during the Phase I trials, favorable responses in several laboratory, immune, and clinical parameters were observed. These results provide the rationale for conducting phase II and phase III clinical trials with HFIF produced at RPMI.

Patients with depression display cytokine levels in serum and cerebrospinal fluid similar to patients with diffuse neurological symptoms without a defined diagnosis.

PubMed

Hestad, Knut A; Engedal, Knut; Whist, Jon Elling; Aukrust, Pål; Farup, Per G; Mollnes, Tom Eirik; Ueland, Thor

2016-01-01

Several reports indicate that inflammation may play a role in depression and demonstrate enhanced systemic levels of inflammatory mediators. We hypothesized that 44 patients with a diagnosis of depression would present with a specific and different serum and cerebrospinal fluid (CSF) cytokine profile compared to 21 patients with diffuse neurological symptoms, of whom 15 had fatigue as a major symptom, but no change in emotional state. The diagnoses of the patients with depression were according to the International Classification of Diseases, tenth edition (F32-34 spectra). Cytokine profiles in serum and CSF were determined by multiplex analysis, including 27 cytokines, chemokines, and growth factors. No differences could be found between the two groups studied regarding cytokine levels in serum or CSF except for serum interleukin (IL)-1 receptor antagonist that was lower in the depression group. There were only four high correlations (>0.4) between serum and CSF levels of the cytokines, reflecting independent synthesis and turnover in these two compartments. In the control group, fatigue was associated with increased IL-1 receptor antagonist, IL-10, granulocyte-colony stimulating factor, and interferon-γ (all P<0.01). Patients with depression had a similar cytokine profile as nondepressive patients, both systemically and in CSF. Fatigue was associated with higher levels of some inflammatory markers in the control group. It is possible that the presence of fatigue in a large proportion of patients and controls could contribute to the lack of difference in cytokine levels between these two groups.

Association of Tumor Growth Factor-β and Interferon-γ Serum Levels With Insulin Resistance in Normal Pregnancy.

PubMed

Sotoodeh Jahromi, Abdolreza; Sanie, Mohammad Sadegh; Yusefi, Alireza; Zabetian, Hassan; Zareian, Parvin; Hakimelahi, Hossein; Madani, Abdolhossien; Hojjat-Farsangi, Mohammad

2015-09-28

Pregnancy is related to change in glucose metabolism and insulin production. The aim of our study was to determine the association of serum IFN-γ and TGF- β levels with insulin resistance during normal pregnancy. This cross sectional study was carried out on 97 healthy pregnant (in different trimesters) and 28 healthy non-pregnant women. Serum TGF-β and IFN- γ level were measured by ELISA method. Pregnant women had high level TGF-β and low level IFN-γ as compared non-pregnant women. Maternal serum TGF-β concentration significantly increased in third trimester as compared first and second trimester of pregnancy. Maternal serum IFN-γ concentration significantly decreased in third trimester as compared first and second trimester of pregnancy. Pregnant women exhibited higher score of HOMA IR as compared non-pregnant women. There were association between gestational age with body mass index (r=0.28, P=0.005), TGF-β (r=0.45, P<0.001) and IFN-γ (r=-0.50, P<0.001). There was significant association between Insulin resistance and TGF-β (r=0.17, p=0.05). Our findings suggest that changes in maternal cytokine level in healthy pregnant women were anti-inflammatory. Furthermore, Tumor Growth Factor-β appears has a role in induction insulin resistance in healthy pregnant women. However, further studies needed to evaluate role of different cytokines on insulin resistance in normal pregnancy.

Role of the IL-12/IL-35 balance in patients with Sjögren syndrome.

PubMed

Fogel, Olivier; Rivière, Elodie; Seror, Raphaèle; Nocturne, Gaetane; Boudaoud, Saida; Ly, Bineta; Gottenberg, Jacques-Eric; Le Guern, Véronique; Dubost, Jean-Jacques; Nititham, Joanne; Taylor, Kimberly E; Chanson, Philippe; Dieudé, Philippe; Criswell, Lindsey A; Jagla, Bernd; Thai, Alice; Mingueneau, Michael; Mariette, Xavier; Miceli-Richard, Corinne

2017-09-12

An interferon signature is involved in the pathogenesis of primary Sjögren syndrome (pSS), but whether the signature is type 1 or type 2 remains controversial. Mouse models and genetic studies suggest the involvement of T H 1 and type 2 interferon pathways. Likewise, polymorphisms of the IL-12A gene (IL12A), which encodes for IL-12p35, have been associated with pSS. The IL-12p35 subunit is shared by 2 heterodimers: IL-12 and IL-35. We sought to confirm genetic association of the IL12A polymorphism and pSS and elucidate involvement of the IL-12/IL-35 balance in patients with pSS by using functional studies. The genetic study involved 673 patients with pSS from 2 French pSS cohorts and 585 healthy French control subjects. Functional studies were performed on sorted monocytes, irrespective of whether they were stimulated. IL12A mRNA expression and IL-12 and IL-35 protein levels were assessed by using quantitative RT-PCR and ELISA and a multiplex kit for IL-35 and IL-12, respectively. We confirmed association of the IL12A rs485497 polymorphism and pSS and found an increased serum protein level of IL-12p70 in patients with pSS carrying the risk allele (P = .016). Serum levels of IL-12p70 were greater in patients than control subjects (P = .0001), especially in patients with more active disease (P = .05); conversely, IL-35 levels were decreased in patients (P = .0001), especially in patients with more active disease (P = .05). In blood cellular subsets both IL12p35 and EBV-induced gene protein 3 (EBI3) mRNAs were detected only in B cells, with a trend toward a lower level among patients with pSS. Our findings emphasize involvement of the IL-12/IL-35 balance in the pathogenesis of pSS. Serum IL-35 levels were associated with low disease activity, in contrast with serum IL-12p70 levels, which were associated with more active disease. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Tula and Puumala hantavirus NSs ORFs are functional and the products inhibit activation of the interferon-beta promoter.

PubMed

Jääskeläinen, Kirsi M; Kaukinen, Pasi; Minskaya, Ekaterina S; Plyusnina, Angelina; Vapalahti, Olli; Elliott, Richard M; Weber, Friedemann; Vaheri, Antti; Plyusnin, Alexander

2007-10-01

The S RNA genome segment of hantaviruses carried by Arvicolinae and Sigmodontinae rodents encodes the nucleocapsid (N) protein and has an overlapping (+1) open reading frame (ORF) for a putative nonstructural protein (NSs). The aim of this study was to determine whether the ORF is functional. A protein corresponding to the predicted size of Tula virus (TULV) NSs was detected using coupled in vitro transcription and translation from a cloned S segment cDNA, and a protein corresponding to the predicted size of Puumala virus (PUUV) NSs was detected in infected cells by Western blotting with an anti-peptide serum. The activities of the interferon beta (IFN-beta) promoter, and nuclear factor kappa B (NF-kappaB)- and interferon regulatory factor-3 (IRF-3) responsive promoters, were inhibited in COS-7 cells transiently expressing TULV or PUUV NSs. Also IFN-beta mRNA levels in IFN-competent MRC5 cells either infected with TULV or transiently expressing NSs were decreased. These data demonstrate that Tula and Puumala hantaviruses have a functional NSs ORF. The findings may explain why the NSs ORF has been preserved in the genome of most hantaviruses during their long evolution and why hantavirus-infected cells secrete relatively low levels of IFNs. (c) 2007 Wiley-Liss, Inc.

Dual specific oral tolerance induction using interferon gamma for IgE-mediated anaphylactic food allergy and the dissociation of local skin allergy and systemic oral allergy: tolerance or desensitization?

PubMed

Noh, G; Jang, E H

2014-01-01

Specific oral tolerance induction (SOTI) for IgE-mediated food allergy (IFA) can be successfully achieved using interfero gamma (classic SOTI). In this study, a tolerable dose was introduced during tolerance induction with interferon gamma (dual SOTI), and its effectiveness was evaluated. The study population comprised 25 IFA patients. Blood samples were taken for analysis, including complete blood count with differential counts of eosinophils, serum total IgE levels, and specific IgE for allergenic foods. Skin prick tests were conducted with the allergens. Oral food challenges were performed to diagnose IFA. Ten patients received dual SOTI, 5 received classic SOTI, 5 received SOTI without interferon gamma (original SOTI), and 5 were not treated (controls). Patients treated with dual SOTI and classic SOTI using interferon gamma became tolerant to the allergenic food. The tolerable dose was introduced successfully in dual SOTI. It was difficult to proceed with the same dosing protocol used for classic SOTI in cases treated with original SOTI. Following dual SOTI, the systemic reaction to oral intake subsided, but the local skin reaction to contact with the allergenic food persisted. Dual SOTI is an improved protocol for SOTI using interferon gamma for IFA.The local skin reaction and systemic reaction to oral intake were dissociated following dual SOTI. In cases of food allergy, tolerance appears to result from desensitization to allergens.

Low 25-OH vitamin D serum levels correlate with severe fibrosis in HIV-HCV co-infected patients with chronic hepatitis.

PubMed

Terrier, Benjamin; Carrat, Fabrice; Geri, Guillaume; Pol, Stanislas; Piroth, Lionel; Halfon, Philippe; Poynard, Thierry; Souberbielle, Jean-Claude; Cacoub, Patrice

2011-10-01

Recent findings in hepatitis C virus (HCV)-monoinfected patients have shown a correlation between low serum levels of 25-OH vitamin D3 [25(OH)D3] and severe liver fibrosis and low sustained virologic response to therapy. Data are lacking in HIV-HCV coinfected patients. One hundred and eighty nine HIV-HCV coinfected patients, who received ≥80% of interferon (IFN) plus ribavirin therapy, were analyzed for baseline serum 25(OH)D3 levels. Correlations between serum 25(OH)D3 levels, chronic hepatitis C features, HCV virologic response to antiviral therapy, and HIV infection characteristics were analyzed. Mean serum 25(OH)D3 level was 18.5 ± 9.8 ng/ml, including 162 (85%) patients with level ≤30 ng/ml. Serum 25(OH)D3 levels were significantly correlated with the histological Metavir fibrosis score (r = -0.16; p = 0.027). Patients with severe fibrosis (Metavir F3/F4) had lower serum 25(OH)D3 levels compared to F2 and F1 patients (16.2 ± 10.0 vs. 18.9 ± 8.5 and 20.9 ± 11.1 ng/ml, respectively; p = 0.06). In multivariate analysis, low serum 25(OH)D levels were independently associated with severe liver fibrosis (p = 0.04) and cold season (p = 0.0002). Serum levels of 25(OH)D3 were also significantly correlated with liver fibrosis as assessed by FibroTest® (r = -0.22; p = 0.008) and serum α2-macroglobulin levels (r = -0.23; p = 0.006). In contrast, no correlation was found between 25(OH)D3 levels and HCV sustained virologic response to IFN-based therapy [OR 0.98 (0.95-1.01); p = 0.22]. No association was found between 25(OH)D3 levels and markers of HIV-related immunodeficiency. In HIV-HCV coinfected patients, low serum 25(OH)D3 levels correlate with severe liver fibrosis. In contrast, serum 25(OH)D3 levels are not linked to HCV virologic response to therapy or severity of immunodeficiency. Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Quantitative hepatitis B core antibody levels in the natural history of hepatitis B virus infection.

PubMed

Song, L-W; Liu, P-G; Liu, C-J; Zhang, T-Y; Cheng, X-D; Wu, H-L; Yang, H-C; Hao, X-K; Yuan, Q; Zhang, J; Kao, J-H; Chen, D-S; Chen, P-J; Xia, N-S

2015-02-01

We previously demonstrated that pretreatment quantitative anti-hepatitis B core protein (qAnti-HBc) levels can predict the treatment response for both interferon and nucleoside analogue therapy, but the characteristics of qAnti-HBc during chronic hepatitis B virus (HBV) infection remain poorly understood. To understand this issue, the qAnti-HBc levels were evaluated in individuals with past HBV infection, occult HBV infection and chronic HBV infection in the immune tolerance phase, immune clearance phase, low-replicative phase and hepatitis B e antigen (HBeAg)-negative hepatitis phase. Individuals with hepatitis B surface antigen (n = 598, 3.74 ± 0.90 log10 IU/mL) had significantly higher (p < 0.001, approximately 1000-fold) serum qAnti-HBc levels than those who had occult HBV, and serum qAnti-HBc levels were significantly higher in the occult HBV group than in the past HBV infection group (p < 0.001). qAnti-HBc levels were positively correlated with alanine aminotransferase levels (R = 0.663, p < 0.001), and subjects with an abnormal alanine aminotransferase level had a higher qAnti-HBc level (p < 0.001). Serum qAnti-HBc level varied in different phases of HBV infection, as determined by host immune status. Serum qAnti-HBc level is strongly associated with hepatitis activity in subjects with chronic HBV infection. Copyright © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Serum microRNA-122 level correlates with virologic responses to pegylated interferon therapy in chronic hepatitis C.

PubMed

Su, Tung-Hung; Liu, Chen-Hua; Liu, Chun-Jen; Chen, Chi-Ling; Ting, Te-Tien; Tseng, Tai-Chung; Chen, Pei-Jer; Kao, Jia-Horng; Chen, Ding-Shinn

2013-05-07

MicroRNA-122 (miR-122) facilitates hepatitis C virus replication in vitro. Serum miR-122 has been implicated as a biomarker for various liver diseases; however, its role in chronic hepatitis C remains unclear. To address this issue, 126 patients with chronic hepatitis C who completed pegylated IFN plus ribavirin therapy with sustained virologic response (SVR) or nonresponse (NR) were retrospectively included, and their pretreatment clinical profiles and treatment responses were collected. Serum miR-122 was quantified before and during treatment. Another 51 patients in SVR and NR groups were prospectively enrolled for validation. Serum miR-122 was found to be a surrogate for hepatic miR-122 and positively correlated with hepatic necroinflammation. Patients who showed complete early virologic response and SVR had significantly higher pretreatment serum miR-122 levels than those with NR (P = 0.001 and P = 0.008, respectively), especially in subgroups of patients with hepatitis C virus genotype 2 and IL-28B rs8099917 TT genotype. Patients with IL-28B TT genotype had significantly better treatment responses and higher pretreatment serum miR-122 level than those with GT or GG genotypes. Univariate analysis showed that pretreatment body mass index, γ-glutamyl transpeptidase, triglyceride, IL-28B TT genotype, and serum miR-122 are predictors for SVR. Multivariate analysis specifically in IL-28B TT genotype demonstrated that pretreatment serum miR-122 independently predicted SVR. The validation cohort confirmed a significantly greater pretreatment serum miR-122 level in patients with SVR compared with NR (P = 0.025). In conclusion, serum miR-122 may serve as a surrogate of hepatic miR-122, and a higher pretreatment serum miR-122 level can help predict virologic responses to pegylated IFN plus ribavirin therapy.

Anti-Yo Antibodies in Children With ADHD: First Results About Serum Cytokines.

PubMed

Donfrancesco, Renato; Nativio, Paola; Di Benedetto, Angela; Villa, Maria Pia; Andriola, Elda; Melegari, Maria Grazia; Cipriano, Enrica; Di Trani, Michela

2016-04-19

We investigated whether ADHD children who are positive to Purkinje cell antibodies display pro-inflammatory activity associated with high cytokine serum levels. Fifty-eight ADHD outpatients were compared with 36 healthy, age- and sex-matched children. Forty-five of the ADHD children were positive to anti-Yo antibodies, whereas 34 of the control children were negative. Interleukin 4 (IL-4), IL-6, IL-10, IL-17, tumor necrosis factor alpha (TNFα), and interferon gamma (IFNγ) cytokine serum levels were tested in ADHD children who were positive to anti-Yo antibodies and in the control children who were negative. Anti-Yo antibodies were present to a greater extent in the ADHD group: 77.58% versus 22.42%. Significant differences emerged between the two groups in IL-6 and IL-10, with higher cytokine levels being detected in ADHD children than in controls. Immune processes in ADHD are likely to be associated with mediators of inflammation, such as cytokines. These results contribute to our understanding of action of neural antibodies and cytokines in ADHD. © The Author(s) 2016.

Expression of interferon-inducible chemokines and sleep/wake changes during early encephalitis in experimental African trypanosomiasis.

PubMed

Laperchia, Claudia; Tesoriero, Chiara; Seke-Etet, Paul F; La Verde, Valentina; Colavito, Valeria; Grassi-Zucconi, Gigliola; Rodgers, Jean; Montague, Paul; Kennedy, Peter G E; Bentivoglio, Marina

2017-08-01

Human African trypanosomiasis or sleeping sickness, caused by the parasite Trypanosoma brucei, leads to neuroinflammation and characteristic sleep/wake alterations. The relationship between the onset of these alterations and the development of neuroinflammation is of high translational relevance, but remains unclear. This study investigates the expression of interferon (IFN)-γ and IFN-inducible chemokine genes in the brain, and the levels of CXCL10 in the serum and cerebrospinal fluid prior to and during the encephalitic stage of trypanosome infection, and correlates these with sleep/wake changes in a rat model of the disease. The expression of genes encoding IFN-γ, CXCL9, CXCL10, and CXCL11 was assessed in the brain of rats infected with Trypanosoma brucei brucei and matched controls using semi-quantitative end-point RT-PCR. Levels of CXCL10 in the serum and cerebrospinal fluid were determined using ELISA. Sleep/wake states were monitored by telemetric recording. Using immunohistochemistry, parasites were found in the brain parenchyma at 14 days post-infection (dpi), but not at 6 dpi. Ifn-γ, Cxcl9, Cxcl10 and Cxcl11 mRNA levels showed moderate upregulation by 14 dpi followed by further increase between 14 and 21 dpi. CXCL10 concentration in the cerebrospinal fluid increased between 14 and 21 dpi, preceded by a rise in the serum CXCL10 level between 6 and 14 dpi. Sleep/wake pattern fragmentation was evident at 14 dpi, especially in the phase of wake predominance, with intrusion of sleep episodes into wakefulness. The results show a modest increase in Cxcl9 and Cxcl11 transcripts in the brain and the emergence of sleep/wake cycle fragmentation in the initial encephalitic stage, followed by increases in Ifn-γ and IFN-dependent chemokine transcripts in the brain and of CXCL10 in the cerebrospinal fluid. The latter parameter and sleep/wake alterations could provide combined humoral and functional biomarkers of the early encephalitic stage in African trypanosomiasis.

Investigational drugs in development for Hepatitis D.

PubMed

Rizzetto, Mario

2017-09-01

Treatment of chronic hepatitis D still relies on Interferon. To improve efficacy, new therapeutic strategies are in development which aim to deprive the Hepatitis D Virus (HDV) of functions of the Hepatitis B Virus and of the host required for its life-cycle. Areas covered: The therapeutic options are; 1) The inhibition of the farnesylation of the large HD-protein permissive of virion assembly with Lonafarnib, 2) The blocking of HBsAg entry into cells with Myrcludex B via the inhibition of the Sodium Taurocholate Cotransporting Receptor, to prevent the spreading of HDV to uninfected hepatocytes, 3) The reduction of subviral HBsAg particles by REP 2139, leading to diminished virion morphogenesis . Expert opinion: Lonafarnib and Myrcludex reduced serum HVD-RNA; neither diminished serum HBsAg. NAP REP-2139 diminished both HDV-RNA and HBsAg in serum; a full report is awaited. In combination with Peg-Interferon, these new drugs may provide additional efficacy.

Impact of oral silymarin on virus- and non-virus-specific T-cells responses in chronic hepatitis C infection

PubMed Central

Adeyemo, Oluwasayo; Doi, Hiroyoshi; Reddy, K. Rajender; Kaplan, David E.

2013-01-01

Silymarin displays anti-inflammatory effects on T-lymphocytes in vitro. The immunomodulatory properties of oral silymarin in vivo in humans with chronic hepatitis C have not previously been characterized. We hypothesized that silymarin would suppress T-cell proliferation and pro-inflammatory cytokine production of virus- and non-virus-specific T-cells while increasing anti-inflammatory IL-10 production in vivo. Patients from one site of the SyNCH-HCV double-masked, placebo-controlled study of oral silymarin in prior interferon non-responders with chronic hepatitis C provided blood samples at baseline and treatment week 20. Mononuclear cells were stimulated with recombinant HCV proteins and controls in 3H-thymidine proliferation assays, IFNγ Elispot and IL-10 Elispot. The frequency of CD4+CD25hi and CD4+foxp3+ regulatory T-cells, serum cytokine levels, serum IP-10 and lymphocyte interferon-stimulated gene expression were also quantified at baseline and week 20. Thirty-two patients were recruited (10; placebo, 11; 420mg three times a day, 11; 700mg three times a day). Serum ALT and HCV RNA titers did not change in any group. HCV-specific CD4+ T-cell proliferation and the frequency of IFNγ– and IL-10-producing T-cells were not significantly changed in silymarin-treated subjects. However, C. albicans-induced T-cell IFNγ and phytohemagglutinin-induced T-cell proliferation were suppressed by silymarin therapy. A trend towards augmentation of interferon-induced ISG15 expression was present in the high-dose silymarin group. While no effect on HCV-specific T-cells was identified, these data confirm that high-dose oral silymarin exerts modest non-specific immunomodulatory effects in vivo. The impact of this anti-inflammatory effect on long-term liver health in chronic hepatitis C merits future clinical investigation. PMID:23730838

Efficacy of Fish Oil on Serum of TNFα, IL-1β, and IL-6 Oxidative Stress Markers in Multiple Sclerosis Treated with Interferon Beta-1b

PubMed Central

Ramirez-Ramirez, V.; Macias-Islas, M. A.; Ortiz, G. G.; Pacheco-Moises, F.; Torres-Sanchez, E. D.; Sorto-Gomez, T. E.; Cruz-Ramos, J. A.; Orozco-Aviña, G.; Celis de la Rosa, A. J.

2013-01-01

Multiple sclerosis (MS) is a chronic inflammatory disease, which leads to focal plaques of demyelination and tissue injury in the central nervous system. Oxidative stress is also thought to promote tissue damage in multiple sclerosis. Current research findings suggest that omega-3 polyunsaturated fatty acids (PUFAs) such as eicosapenta-enoic acid (EPA) and docosahexaenoic acid (DHA) contained in fish oil may have anti-inflammatory, antioxidant, and neuroprotective effects. The aim of the present work was to evaluate the efficacy of fish oil supplementation on serum proinflammatory cytokine levels, oxidative stress markers, and disease progression in MS. 50 patients with relapsing-remitting MS were enrolled. The experimental group received orally 4 g/day of fish oil for 12 months. The primary outcome was serum TNFα levels; secondary outcomes were IL-1β 1b, IL-6, nitric oxide catabolites, lipoperoxides, progression on the expanded disability status scale (EDSS), and annualized relapses rate (ARR). Fish oil treatment decreased the serum levels of TNFα, IL-1β, IL-6, and nitric oxide metabolites compared with placebo group (P ≤ 0.001). There was no significant difference in serum lipoperoxide levels during the study. No differences in EDSS and ARR were found. Conclusion. Fish oil supplementation is highly effective in reducing the levels of cytokines and nitric oxide catabolites in patients with relapsing-remitting MS. PMID:23861993

Immunogenicity of an interferon-beta1a product.

PubMed

Kauffman, M A; Sterin-Prync, A; Papouchado, M; González, E; Vidal, A J; Grossberg, S E; Chuppa, S; Odoriz, B; Vrech, C; Diez, R A; Ferro, H H

2011-01-01

In order to determine whether Blastoferon®, a biosimilar interferon (IFN)- beta 1a formulation, shares epitopes with other known IFN-beta products, a series of neutralization bioassays were performed with a set of well-characterized anti-IFN- beta monoclonal antibodies and human sera (World Health Organization Reference Reagents). The bioassay was the interferon-induced inhibition of virus cytopathic effect on human cells in culture (EMC virus and A-549 cells). Computer-calculated results were reported as Tenfold Reduction Units (TRU)/ml. To further assess Blastoferon® immunogenicity, in vivo production of anti-IFN beta antibodies was determined in sera of patients included in the pharmacovigilance plan of Blastoferon® by the level of IFN- beta 1a binding antibodies (by enzyme immunoassay -EIA) and neutralizing antibodies (in the Wish-VSV system). The highly characterized neutralizing monoclonal antibodies A1 and A5 that bind to specific regions of the IFN- beta molecule reacted positively with the three beta 1a IFNs: Blastoferon®, Rebif®, and the IFN- beta WHO Second International Standard 00/572. As expected, the non-neutralizing monoclonal antibodies B4 and B7 did not neutralize any of the IFN- beta preparations. The commercially available monoclonal antibody B-02 reacted essentially equally with Rebif® and Blastoferon®. The WHO Reference Reagent human serum anti-IFN- beta polyclonal antibody neutralized all the IFN- beta products, whereas the WHO Reference Reagent human serum anti-IFN-alpha polyclonal antibody G037-501-572 appropriately failed to react with any of the IFN- beta products. On the basis of in vitro reactivity with known, well-characterized monoclonal and polyclonal antibody preparations, Blastoferon® shares immunological determinants with other human interferon- beta products, especially IFN- beta 1a. In vivo antibodies were detected by EIA in 72.9% of 37 chronically treated multiple sclerosis patients, whereas neutralizing antibodies were found in 8.1% of them. Blastoferon® appears to have immunological characteristics comparable to other IFN- beta 1a products.

Natural killer cells promote tissue injury and systemic inflammatory responses during fatal Ehrlichia-induced toxic shock-like syndrome.

PubMed

Stevenson, Heather L; Estes, Mark D; Thirumalapura, Nagaraja R; Walker, David H; Ismail, Nahed

2010-08-01

Human monocytotropic ehrlichiosis is caused by Ehrlichia chaffeensis, a Gram-negative bacterium lacking lipopolysaccharide. We have shown that fatal murine ehrlichiosis is associated with CD8(+)T cell-mediated tissue damage, tumor necrosis factor-alpha, and interleukin (IL)-10 overproduction, and CD4(+)Th1 hyporesponsiveness. In this study, we examined the relative contributions of natural killer (NK) and NKT cells in Ehrlichia-induced toxic shock. Lethal ehrlichial infection in wild-type mice induced a decline in NKT cell numbers, and late expansion and migration of activated NK cells to the liver, a main infection site that coincided with development of hepatic injury. The spatial and temporal changes in NK and NKT cells in lethally infected mice correlated with higher NK cell cytotoxic activity, higher expression of cytotoxic molecules such as granzyme B, higher production of interferon-gamma and tumor necrosis factor-alpha, increased hepatic infiltration with CD8alphaCD11c(+) dendritic cells and CD8(+)T cells, decreased splenic CD4(+)T cells, increased serum concentrations of IL-12p40, IL-18, RANTES, and monocyte chemotactic protein-1, and elevated production of IL-18 by liver mononuclear cells compared with nonlethally infected mice. Depletion of NK cells prevented development of severe liver injury, decreased serum levels of interferon-gamma, tumor necrosis factor-alpha, and IL-10, and enhanced bacterial elimination. These data indicate that NK cells promote immunopathology and defective anti-ehrlichial immunity, possibly via decreasing the protective immune response mediated by interferon-gamma producing CD4(+)Th1 and NKT cells.

Impact of cytokine in type 1 narcolepsy: Role of pandemic H1N1 vaccination ?

PubMed

Lecendreux, Michel; Libri, Valentina; Jaussent, Isabelle; Mottez, Estelle; Lopez, Régis; Lavault, Sophie; Regnault, Armelle; Arnulf, Isabelle; Dauvilliers, Yves

2015-06-01

Recent advances in the identification of susceptibility genes and environmental exposures (pandemic influenza 2009 vaccination) provide strong support that narcolepsy type 1 is an immune-mediated disease. Considering the limited knowledge regarding the immune mechanisms involved in narcolepsy whether related to flu vaccination or not and the recent progresses in cytokine measurement technology, we assessed 30 cytokines, chemokines and growth factors using the Luminex technology in either peripheral (serum) or central (CSF) compartments in a large population of 90 children and adult patients with narcolepsy type 1 in comparison to 58 non-hypocretin deficient hypersomniacs and 41 healthy controls. Furthermore, we compared their levels in patients with narcolepsy whether exposed to pandemic flu vaccine or not, and analyzed the effect of age, duration of disease and symptom severity. Comparison for sera biomarkers between narcolepsy (n = 84, 54 males, median age: 15.5 years old) and healthy controls (n = 41, 13 males, median age: 20 years old) revealed an increased stimulation of the immune system with high release of several pro- and anti-inflammatory serum cytokines and growth factors with interferon-γ, CCL11, epidermal growth factor, and interleukin-2 receptor being independently associated with narcolepsy. Increased levels of interferon-γ, CCL11, and interleukin-12 were found when close to narcolepsy onset. After several adjustments, only one CSF biomarker differed between narcolepsy (n = 44, 26 males, median age: 15 years old) and non-hypocretin deficient hypersomnias (n = 57, 24 males, median age: 36 years old) with higher CCL 3 levels found in narcolepsy. Comparison for sera biomarkers between patients with narcolepsy who developed the disease post-pandemic flu vaccination (n = 36) to those without vaccination (n = 48) revealed an increased stimulation of the immune system with high release of three cytokines, regulated upon activation normal T-cell expressed and secreted, CXCL10, and CXCL9, being independently and significantly increased in the group exposed to the vaccine. No significant differences were found between narcoleptics whether exposed to flu vaccination or not for CSF biomarkers except for a lower CXCL10 level found in the exposed group. To conclude, we highlighted the role of sera cytokine with pro-inflammatory properties and especially interferon-γ being independently associated with narcolepsy close to disease onset. The activity of the interferon-γ network was also increased in the context of narcolepsy after the pandemic flu vaccination being a potential key player in the immune mechanism that triggers narcolepsy and that coordinates the immune response necessary for resolving vaccination assaults. Copyright © 2015 Elsevier Ltd. All rights reserved.

Increased levels of nitrite in the sera of children infected with human immunodeficiency virus type 1.

PubMed

Torre, D; Ferrario, G; Speranza, F; Martegani, R; Zeroli, C

1996-04-01

Nitric oxide (NO) is a newly discovered gas that plays an important role in cell communication and host resistance to infection. The production of NO was examined in the sera of seven children infected with human immunodeficiency virus type 1 (HIV-1) and in the sera of 14 children who became seronegative for HIV-1 during the first year of life. In addition, we determined serum levels of various cytokines, such as interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, and gamma interferon (IFN-gamma), inasmuch as these cytokines are potent inducers of NO production. Production of NO, detected as circulating serum levels of nitrite, was measured with use of the Griess reagent. Serum levels of cytokines were determined by enzyme immunoassay. Increased serum levels of nitrite were observed in children with HIV-1 infection (0.4 +/- 0.2 mumol/L; P = .013), and in those who became seronegative for HIV-1 during the first year of life (0.5 +/- 0.3 mumol/L; P = .04). Furthermore, serum levels of IL-1 beta and TNF-alpha were significantly elevated in children with HIV-1 infection (37.5 +/- 23.6 pg/mL and 91.2 +/- 45.1 pg/mL, respectively). Prophylactic administration of intravenous immune globulin provoked a significant decrease of circulating levels of nitrite in children with HIV-1 infection. In conclusion, NO may play a role as a cytostatic or cytotoxic factor for invading microorganisms, and thus it is probably involved in limiting and/or eradicating infection.

Inhibition of Choroidal Neovascularization by Intravenous Injection of Adenoviral Vectors Expressing Secretable Endostatin

PubMed Central

Mori, Keisuke; Ando, Akira; Gehlbach, Peter; Nesbitt, David; Takahashi, Kyoichi; Goldsteen, Donna; Penn, Michael; Chen, Cheauyan T.; Mori, Keiko; Melia, Michele; Phipps, Sandrina; Moffat, Diana; Brazzell, Kim; Liau, Gene; Dixon, Katharine H.; Campochiaro, Peter A.

2001-01-01

Endostatin is a cleavage product of collagen XVIII that inhibits tumor angiogenesis and growth. Interferon α2a blocks tumor angiogenesis and causes regression of hemangiomas, but has no effect on choroidal neovascularization (CNV). Therefore, inhibitors of tumor angiogenesis do not necessarily inhibit ocular neovascularization. In this study, we used an intravenous injection of adenoviral vectors containing a sig-mEndo transgene consisting of murine immunoglobulin κ-chain leader sequence coupled to sequence coding for murine endostatin to investigate the effect of high serum levels of endostatin on CNV in mice. Mice injected with a construct in which sig-mEndo expression was driven by the Rous sarcoma virus promoter had moderately high serum levels of endostatin and significantly smaller CNV lesions at sites of laser-induced rupture of Bruch’s membrane than mice injected with null vector. Mice injected with a construct in which sig-mEndo was driven by the simian cytomegalovirus promoter had ∼10-fold higher endostatin serum levels and had nearly complete prevention of CNV. There was a strong inverse correlation between endostatin serum level and area of CNV. This study provides proof of principle that gene therapy to increase levels of endostatin can prevent the development of CNV and may provide a new treatment for the leading cause of severe loss of vision in patients with age-related macular degeneration. PMID:11438478

Effect of hydroxychloroquine treatment on pro-inflammatory cytokines and disease activity in SLE patients: data from LUMINA (LXXV), a multiethnic US cohort

PubMed Central

Willis, R; Seif, AM; McGwin, G; Martinez-Martinez, LA; González, EB; Dang, N; Papalardo, E; Liu, J; Vilá, LM; Reveille, JD; Alarcón, GS; Pierangeli, SS

2013-01-01

Objective We sought to determine the effect of hydroxychloroquine therapy on the levels proinflammatory/prothrombotic markers and disease activity scores in patients with systemic lupus erythematosus (SLE) in a multiethnic, multi-center cohort (LUMINA). Methods Plasma/serum samples from SLE patients (n=35) were evaluated at baseline and after hydroxychloroquine treatment. Disease activity was assessed using SLAM-R scores. Interferon (IFN)-α2, interleukin (IL)-1β, IL-6, IL-8, inducible protein (IP)-10, monocyte chemotactic protein-1, tumor necrosis factor (TNF)-α and soluble CD40 ligand (sCD40L) levels were determined by a multiplex immunoassay. Anticardiolipin antibodies were evaluated using ELISA assays. Thirty-two frequency-matched plasma/serum samples from healthy donors were used as controls. Results Levels of IL-6, IP-10, sCD40L, IFN-α and TNF-α were significantly elevated in SLE patients versus controls. There was a positive but moderate correlation between SLAM-R scores at baseline and levels of IFN-α (p=0.0546). Hydroxychloroquine therapy resulted in a significant decrease in SLAM-R scores (p=0.0157), and the decrease in SLAM-R after hydroxychloroquine therapy strongly correlated with decreases in IFN-α (p=0.0087). Conclusions Hydroxychloroquine therapy resulted in significant clinical improvement in SLE patients, which strongly correlated with reductions in IFN-α levels. This indicates an important role for the inhibition of endogenous TLR activation in the action of hydroxychloroquine in SLE and provides additional evidence for the importance of type I interferons in the pathogenesis of SLE. This study underscores the use of hydroxychloroquine in the treatment of SLE. PMID:22343096

Treatment of trypanosome-infected mice with exogenous interferon, interferon inducers, or antibody to interferon

NASA Technical Reports Server (NTRS)

Degee, Antonie L. W.; Mansfield, John M.; Sonnenfeld, Gerald

1986-01-01

Earlier studies have demonstrated that mice resistant to Trypanosoma brucei rhodesiense (the B10.BR/SgSnJ strain) produces, upon infection by this parasite, two peaks of serum interferon (IFN), while the susceptible mice (C3HeB/FeJ) produces no IFN. In the present study, survival times were compared for B10.BR/SgSnJ, C3HeB/FeJ, and CBA/J (an intermediately resistant strain) mice that were injected, prior to infection with the parasite, with either of the following three preparations (1) IFN-gamma, (2) an antibody to IFN-gamma and (3) polyriboinosinic-polyribocytidylic acid (to induce IFN-alpha/beta). No effect on the survival times of mice by any of these preparations could be demonstrated, contrary to some previous reports.

Anti-alpha interferon immunization: safety and immunogenicity in asymptomatic HIV positive patients at high risk of disease progression.

PubMed

Gringeri, A; Santagostino, E; Mannucci, P M; Siracusano, L; Marinoni, A; Criscuolo, M; Carcagno, M; Fall, L S; M'Bika, J P; Bizzini, B

1995-05-01

A randomized, placebo-controlled trial was designed to evaluate safety and immunogenicity of an anti-cytokine vaccine in high risk HIV-positive patients. This strategy was aimed to modulate the impaired cytokine regulation in AIDS. Twelve asymptomatic patients on antiretroviral therapy for at least 1 year and with CD4 cell counts between 100-300/mm3 were randomized to receive adjuvanted formol-inactivated interferon alpha-2a (IFN alpha) and continue the current antiretroviral treatment, whatever it was, or to receive the adjuvant alone and the current antiretroviral treatment. All patients received 4 i.m. injections monthly, followed by booster injections every 3 months. Clinical status, immunology and virology were monitored. Immune response to vaccination was evaluated in term of antibody detection (ELISA) and serum anti-IFN alpha neutralizing capacity. Only local discomfort and transient fever were reported. All vaccines except one showed increased levels of anti-IFN alpha Abs and developed serum IFN alpha neutralizing capacity. Viral load did not increase in vaccinees while it remained unchanged or even increased in placebo-treated patients. None of them showed HIV-related symptoms and all had their CD4 cell counts stabilized over 18 months, whereas 2 placebo-treated patients developed full-blow AIDS. In conclusion, anti-IFN alpha vaccine was safe and immunogenic. Stable clinical and immunological status over 18 months was observed in vaccinees coupled to increased serum IFN alpha neutralizing capacity.

[Clinical benefit of HCV core antigen assay in patients receiving interferon and ribavirin combination therapy].

PubMed

Higashimoto, Makiko; Takahashi, Masahiko; Jokyu, Ritsuko; Saito, Hidetsugu

2006-02-01

A highly sensitive second generation HCV core antigen assay has recently been developed. We compared viral disappearance and kinetics data between commercially available core antigen assays, Lumipulse Ortho HCV Ag, and a quantitative HCV RNA PCR assay, Cobas Amplicor HCV Monitor Test, Version 2 to estimate the predictive benefit of sustained viral response (SVR) and non-SVR in 59 patients treated with interferon and ribavirin combination therapy. We found a good correlation between HCV core Ag and HCV RNA level regardless of genotype. Although the sensitivity of the core antigen assay was lower than PCR, the dynamic range was broader than that of the PCR assay, so that we did not need to dilute the samples in 59 patients. We detected serial decline of core Ag levels in 24 hrs, 7 days and 14 days after interferon combination therapy. The decline of core antigen levels was significant in SVR patients compared to non-SVR as well as in genotype 2a, 2b patients compared to 1b. Core antigen-negative on day 1 could predict all 10 SVR patients (PPV = 100%), whereas RNA-negative could predict 22 SVR out of 25 on day 14 (PPV = 88.0%). None of the patients who had detectable serum core antigen on day 14 became SVR(NPV = 100%), although NPV was 91.2% on RNA negativity. An easy, simple, low cost new HCV core antigen detecting system seems to be useful for assessing and monitoring IFN treatment for HCV.

Interferon modulation of c-myc expression in cloned Daudi cells: relationship to the phenotype of interferon resistance.

PubMed

Dron, M; Modjtahedi, N; Brison, O; Tovey, M G

1986-05-01

Treatment of interferon-sensitive Daudi cell with electrophoretically pure human interferon alpha markedly reduced the level of c-myc mRNA, increased the level of class I histocompatibility antigen (HLA) mRNA, and did not affect the level of actin mRNA within the same cells. In contrast, the level of c-myc mRNA or HLA mRNA did not change significantly following interferon treatment in different clones of Daudi cells selected for resistance to the antiproliferative action of interferon. These cells possessed interferon receptors, however, and responded to interferon modulation of other genes, including 2',5' oligoisoadenylate synthetase (M. G. Tovey, M. Dron, K. E. Mogensen, B. Lebleu, N. Metchi, and J. Begon-Lours, Guymarho, J. Gen. Virol., 64:2649-2653, 1983; M. Dron, M. G. Tovey, and P. Eid, J. Gen. Virol., 66:787-795, 1985). A clone of interferon-resistant Daudi cells which had reverted to almost complete sensitivity to both the antiproliferative action of interferon and the interferon-enhanced expression of HLA mRNA remained refractory, however, to interferon modulation of c-myc expression, suggesting that a reduced level of c-myc mRNA may not be a prerequisite for inhibition of cell proliferation in interferon-treated cells. Our results do not exclude the possibility, however, that posttranscriptional modification(s) of c-myc expression may precede an inhibition of cell proliferation in interferon-treated cells.

Differential Serum Cytokine Levels and Risk of Lung Cancer between African and European Americans

PubMed Central

Pine, Sharon R.; Mechanic, Leah E.; Enewold, Lindsey; Bowman, Elise D.; Ryan, Bríd M.; Cote, Michele L.; Wenzlaff, Angela S.; Loffredo, Christopher A.; Olivo-Marston, Susan; Chaturvedi, Anil; Caporaso, Neil E.; Schwartz, Ann G.; Harris, Curtis C.

2015-01-01

Background African Americans have a higher risk of developing lung cancer than European Americans. Previous studies suggested that certain circulating cytokines were associated with lung cancer. We hypothesized that variations in serum cytokine levels exist between African Americans and European Americans, and increased circulating cytokine levels contribute to lung cancer differently in the two races. Methods Differences in ten serum cytokine levels, interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, granulocyte macrophage colony-stimulating factor (GMCSF), interferon (IFN)-γ and tumor necrosis factor (TNF)-α between 170 African-American and 296 European-American controls from the National Cancer Institute-Maryland (NCI-MD) case-control study were assessed. Associations of the serum cytokine levels with lung cancer were analyzed. Statistically significant results were replicated in the prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and the Wayne State University (WSU) Karmanos Cancer Institute case-control study. Results Six cytokines: IL-4, IL-5, IL-8, IL-10, IFNγ, and TNFα, were significantly higher among European-American as compared to African-American controls. Elevated IL-6 and IL-8 levels were associated with lung cancer among both races in all three studies. Elevated IL-1β, IL-10 and TNFα levels were associated with lung cancer only among African Americans. The association between elevated TNFα levels and lung cancer among European Americans was significant after adjustment for additional factors. Conclusions Serum cytokine levels vary by race and might contribute to lung cancer differently between African Americans and European Americans. Impact Future work examining risk prediction models of lung cancer can measure circulating cytokines to accurately characterize risk within racial groups. PMID:26711330

Does elevation of serum creatinine in patients with chronic hepatitis C under therapy of telaprevir mean renal impairment?

PubMed

Matsui, Katsuomi; Kamijo-Ikemori, Atsuko; Sugaya, Takeshi; Ikeda, Hiroki; Okuse, Chiaki; Shibagaki, Yugo; Yasuda, Takashi; Kimura, Kenjiro

2015-11-01

Treatment with telaprevir (TVR) entails adverse side-effects including anaemia and elevation of serum creatinine (SCr) level. Our purpose was to evaluate the effects of treatment with TVR on renal function in adults with chronic hepatitis C. Thirteen adult patients with HCV genotype 1b who were scheduled to be treated with TVR, pegylated interferon (PEG IFN), and ribavirin (RBV) were prospectively followed. Patients were divided into two groups: (i) patients with an increase in SCr during the treatment (n = 8), and (ii) patients without an increase in SCr (n = 5). Urine and serum parameters were evaluated. Although there was no difference in SCr level between the two groups before HCV therapy, the SCr level was persistently high in the patients in the increase-in-SCr group during the triple therapy. The SCr level returned to the pre-treatment level after cessation of TVR. There were no differences in urinary L-FABP, NAG, serum cystatin C level and eGFRcys throughout the study between the two groups. The serum cystatin C level at pre-treatment tended to be higher in the increase-in-SCr group. Urinary L-FABP and NAG levels in these groups remained within normal limits during treatment. We found that the increase in SCr was not associated with the degree of renal impairment. The increase in SCr may have been induced as a result of a decrease in creatinine secretion from proximal tubules via inhibition of transporters of creatinine induced by TVR. Elevation of SCr levels with TVR therapy may not suggest renal impairment. © 2015 Asian Pacific Society of Nephrology.

An increase in circulating B cell-activating factor in childhood-onset ocular myasthenia gravis.

PubMed

Motobayashi, Mitsuo; Inaba, Yuji; Nishimura, Takafumi; Kobayashi, Norimoto; Nakazawa, Yozo; Koike, Kenichi

2015-04-01

Myasthenia gravis is a B cell-mediated autoimmune disorder. The pathophysiology of childhood-onset ocular myasthenia gravis remains unclear. We investigated serum B cell-activating factor levels and other immunological parameters in child patients with ocular myasthenia gravis. Blood samples were obtained from 9 children with ocular myasthenia gravis and 20 age-matched controls. We assayed serum concentrations of B cell-activating factor, anti-acetylcholine receptor antibody titers, 7 types of cytokines (interleukins-2, -4, -6, -10, and -17A; interferon-γ; tumor necrosis factor-α) as well as the percentages of peripheral blood CD4+, CD8+, and CD19+ cells. Serum B cell-activating factor levels were significantly higher before immunosuppressive therapy in patients with childhood-onset ocular myasthenia gravis than in controls and decreased after immunosuppressive therapy. A significant positive correlation was observed between serum B cell-activating factor levels and anti-acetylcholine receptor antibody titers in patients with myasthenia gravis. Serum B cell-activating factor concentrations did not correlate with the percentages of CD4+, CD8+, and CD19+ cells or the CD4+/CD8+ ratio. No significant differences were observed in the levels of the 7 different types of cytokines examined, including interleukin-17A, between preimmunosuppressive therapy myasthenia gravis patients and controls. Circulating B cell-activating factor may play a key role in the pathophysiology of childhood-onset ocular myasthenia gravis. Copyright © 2015 Elsevier Inc. All rights reserved.

Current and future directions for treating hepatitis B virus infection

PubMed Central

Tawada, Akinobu; Kanda, Tatsuo; Yokosuka, Osamu

2015-01-01

Hepatitis B virus (HBV) persistently infects approximately 350 million people, and approximately 600000 liver-related deaths are observed per year worldwide. HBV infection is also one of the major risk factors for hepatocellular carcinoma (HCC). The persistence of serum hepatitis B e antigen (HBeAg) and high level of serum HBV DNA are thought to reflect a high HBV replication status in hepatocytes, causing cirrhosis, HCC and liver-related deaths. It has been reported that antiviral therapy, such as peginterferon and nucleos(t)ide analogues (NUCs), could suppress liver-related death by inhibiting the HBV DNA levels and inducing seroconversion from HBeAg to antibody to HBe antigen. Currently, peginterferon is widely used, but there are also several disadvantages in the use of peginterferon, such as various adverse events, the administration route and duration. It is difficult to predict the effects of treatment and interferon is contraindicated for the patients with advanced fibrosis of the liver and cirrhosis. With respect to NUCs, entecavir and tenofovir disoproxil fumarate are current the first-choice drugs. NUCs can be administered orally, and their anti-viral effects are stronger than that of peginterferon. However, because cessation of NUC administration leads to high levels of viral replication and causes severe hepatitis, they must be administered for a long time. On the other hand, the use of both interferon and NUCs cannot eliminate covalently closed circular DNA of HBV. In this review, we evaluate the natural course of chronic HBV infection and then provide an outline of these representative drugs, such as peginterferon, entecavir and tenofovir disoproxil fumarate. PMID:26085913

Cell-Based Systems Biology Analysis of Human AS03-Adjuvanted H5N1 Avian Influenza Vaccine Responses: A Phase I Randomized Controlled Trial.

PubMed

Howard, Leigh M; Hoek, Kristen L; Goll, Johannes B; Samir, Parimal; Galassie, Allison; Allos, Tara M; Niu, Xinnan; Gordy, Laura E; Creech, C Buddy; Prasad, Nripesh; Jensen, Travis L; Hill, Heather; Levy, Shawn E; Joyce, Sebastian; Link, Andrew J; Edwards, Kathryn M

2017-01-01

Vaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood. We compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18-49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination. Both vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination. Using this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed. ClinicalTrials.gov NCT01573312.

Cell-Based Systems Biology Analysis of Human AS03-Adjuvanted H5N1 Avian Influenza Vaccine Responses: A Phase I Randomized Controlled Trial

PubMed Central

Samir, Parimal; Galassie, Allison; Allos, Tara M.; Niu, Xinnan; Gordy, Laura E.; Creech, C. Buddy; Prasad, Nripesh; Jensen, Travis L.; Hill, Heather; Levy, Shawn E.; Joyce, Sebastian; Link, Andrew J.; Edwards, Kathryn M.

2017-01-01

Background Vaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood. Objective and Methods We compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18–49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination. Results Both vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination. Conclusions Using this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed. Trial Registration ClinicalTrials.gov NCT01573312 PMID:28099485

Interferon Response Factors 3 and 7 Protect against Chikungunya Virus Hemorrhagic Fever and Shock

PubMed Central

Rudd, Penny A.; Wilson, Jane; Gardner, Joy; Larcher, Thibaut; Babarit, Candice; Le, Thuy T.; Anraku, Itaru; Kumagai, Yutaro; Loo, Yueh-Ming; Gale, Michael; Akira, Shizuo; Khromykh, Alexander A.

2012-01-01

Chikungunya virus (CHIKV) infections can produce severe disease and mortality. Here we show that CHIKV infection of adult mice deficient in interferon response factors 3 and 7 (IRF3/7−/−) is lethal. Mortality was associated with undetectable levels of alpha/beta interferon (IFN-α/β) in serum, ∼50- and ∼10-fold increases in levels of IFN-γ and tumor necrosis factor (TNF), respectively, increased virus replication, edema, vasculitis, hemorrhage, fever followed by hypothermia, oliguria, thrombocytopenia, and raised hematocrits. These features are consistent with hemorrhagic shock and were also evident in infected IFN-α/β receptor-deficient mice. In situ hybridization suggested CHIKV infection of endothelium, fibroblasts, skeletal muscle, mononuclear cells, chondrocytes, and keratinocytes in IRF3/7−/− mice; all but the latter two stained positive in wild-type mice. Vaccination protected IRF3/7−/− mice, suggesting that defective antibody responses were not responsible for mortality. IPS-1- and TRIF-dependent pathways were primarily responsible for IFN-α/β induction, with IRF7 being upregulated >100-fold in infected wild-type mice. These studies suggest that inadequate IFN-α/β responses following virus infection can be sufficient to induce hemorrhagic fever and shock, a finding with implications for understanding severe CHIKV disease and dengue hemorrhagic fever/dengue shock syndrome. PMID:22761364

Curculigo orchioides Gaertn Effectively Ameliorates the Uro- and Nephrotoxicities Induced by Cyclophosphamide Administration in Experimental Animals

PubMed Central

Murali, Vishnu Priya; Kuttan, Girija

2015-01-01

Background. Curculigo orchioides Gaertn is an ancient medicinal plant (Family: Amaryllidaceae), well known for its immunomodulatory and rejuvenating effects. Cyclophosphamide (CPA) is an alkylating agent widely used for treating a variety of human malignancies, but associated with different toxicities too. Our previous reports regarding the hemoprotective and hepatoprotective effects of the plant against CPA toxicities provide the background for the present study, which is designed to analyze the ameliorative effect of the methanolic extract of C orchioides on the urotoxicity and nephrotoxicity induced by CPA. Methods. CPA was administered to male Swiss albino mice at a single dose of 1.5 mmol/kg body weight to induce urotoxicity after 5 days of prophylactic treatment with C orchioides extract (20 mg/kg body weight). Mesna (2-mercaptoethanesulfonate) was used as a control drug. Serum, tissue, and urine levels of kidney function markers and antioxidant levels were checked along with the serum cytokine levels. Results. The plant extract was found to be effective in ameliorating the urotoxic and nephrotoxic side effects of CPA. Upregulation of serum interferon-γ and interleukin-2 levels were observed with C orchioides treatment, which was decreased by CPA administration. Besides these, serum tumor necrosis factor-α level was also downregulated by C orchioides treatment. Conclusion. Curculigo orchioides was found to be effective against the CPA-induced bladder and renal toxicities by its antioxidant capability and also by regulating the pro-inflammatory cytokine levels. PMID:26424815

Longer period of oral administration of aspartame on cytokine response in Wistar albino rats.

PubMed

Choudhary, Arbind Kumar; Sheela Devi, Rathinasamy

2015-03-01

Aspartame is a non-nutritive sweetener particularly used in 'diet' and 'low calorie' products and also in a variety of foods, drugs and hygiene products. Aspartame is metabolized by gut esterases and peptidases to three common chemicals: the amino acids, aspartic acid and phenylalanine, and small amounts of methanol. The aim of the present study was to assess potential changes in molecular mediators of aspartame as a chemical stressor in rats. The effects of long-term administration of aspartame (40 mg/kg body weight/day) were tested in Wistar Albino rats. The treatment effects were assessed in different conditions, including control groups. After 90 days of treatment, circulating concentrations of different parameters were assessed: corticosterone, lipid peroxidation, antioxidant activity, nitric oxide, reduced glutathione and cytokines (interleukin 2, interleukin 4, tumor necrosis factor-α and interferon-γ). The results show that there was a significant increase in plasma corticosterone, serum lipid peroxidation and nitric oxide level along with a decrease in enzymatic and non-enzymatic antioxidant as well as significant decrease in interleukin 2, tumor necrosis factor-α and interferon-γ. There was also a significant increase in interleukin 4 irrespective of whether the animals were immunized or not. The findings clearly point out that aspartame acts as a chemical stressor because of increased corticosterone level and increased lipid peroxidation and nitric oxide level induce generation of free radicals in serum which may be the reason for variation of cytokine level and finally results in alteration of immune function. Aspartame metabolite methanol or formaldehyde may be the causative factors behind the changes observed. Copyright © 2014 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

Serum MX2 Protein as Candidate Biomarker for Early Pregnancy Diagnosis in Buffalo.

PubMed

Buragohain, L; Kumar, R; Nanda, T; Phulia, S K; Mohanty, A K; Kumar, S; Balhara, S; Ghuman, Sps; Singh, I; Balhara, A K

2016-08-01

Interferon-tau (IFN-τ)-induced molecular markers such as ubiquitin-like modifier (ISG15), 2',5'-oligoadenylate synthetase 1 (OAS1) and myxovirus resistance genes (MX1 and MX2) have generated immense attention towards developing diagnostic tools for early diagnosis of pregnancy in bovine. These molecules are expressed at transcriptional level in peripheral nucleated cells. However, their presence in the serum is still a question mark. This study reports sequential changes in expression of MX2 transcript in whole blood and serum MX2 protein level on days 0, 7, 14, 21, 28 and 35 in pregnant (n = 9) buffalo heifers, and on days 0, 7 and 14 in non-inseminated (n = 8) and inseminated non-pregnant (n = 10) control animals. In non-inseminated and inseminated non-pregnant heifers, the differential expression of MX2 transcript and MX2 protein level remained similar between day 7 and 14 post-oestrus. However, in pregnant heifers, on 14th and 28th day post-insemination MX2 transcript was 16.38 ± 1.57 and 28.16 ± 1.91 times upregulated as compared to day 0. Similarly, serum MX2 protein concentration followed analogous trend as MX2 transcript and increased gradually with the progression of pregnancy. Correlation analysis between expression of MX2 transcript and its serum protein level showed a significant positive correlation in pregnant animals, while it was random in other two groups. Therefore, MX2 surge at transcriptional and serum protein level after day 14-28 of pregnancy in buffalo holds potential for its use in early pregnancy detection. © 2016 Blackwell Verlag GmbH.

Interferon modulation of c-myc expression in cloned Daudi cells: relationship to the phenotype of interferon resistance.

PubMed Central

Dron, M; Modjtahedi, N; Brison, O; Tovey, M G

1986-01-01

Treatment of interferon-sensitive Daudi cell with electrophoretically pure human interferon alpha markedly reduced the level of c-myc mRNA, increased the level of class I histocompatibility antigen (HLA) mRNA, and did not affect the level of actin mRNA within the same cells. In contrast, the level of c-myc mRNA or HLA mRNA did not change significantly following interferon treatment in different clones of Daudi cells selected for resistance to the antiproliferative action of interferon. These cells possessed interferon receptors, however, and responded to interferon modulation of other genes, including 2',5' oligoisoadenylate synthetase (M. G. Tovey, M. Dron, K. E. Mogensen, B. Lebleu, N. Metchi, and J. Begon-Lours, Guymarho, J. Gen. Virol., 64:2649-2653, 1983; M. Dron, M. G. Tovey, and P. Eid, J. Gen. Virol., 66:787-795, 1985). A clone of interferon-resistant Daudi cells which had reverted to almost complete sensitivity to both the antiproliferative action of interferon and the interferon-enhanced expression of HLA mRNA remained refractory, however, to interferon modulation of c-myc expression, suggesting that a reduced level of c-myc mRNA may not be a prerequisite for inhibition of cell proliferation in interferon-treated cells. Our results do not exclude the possibility, however, that posttranscriptional modification(s) of c-myc expression may precede an inhibition of cell proliferation in interferon-treated cells. Images PMID:3785169

Cytokine pattern in blister fluid and serum of patients with bullous pemphigoid: relationships with disease intensity.

PubMed

Ameglio, F; D'Auria, L; Bonifati, C; Ferraro, C; Mastroianni, A; Giacalone, B

1998-04-01

Few and contrasting data are available in the literature concerning the levels of various cytokines in blister fluid (BF) and in the serum of patients affected with bullous pemphigoid (BP). Using commercially available ELISA kits, this study reports the levels of 11 cytokines detected both in BF and sera of 15 BP patients and compares them with those of 15 control subjects' sera. Generally, no significant differences were observed in BP and control sera. In contrast, interleukin (IL) 1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) showed increased BF levels as compared with BP sera. Two cytokines, IL-11 and IL-12 did not show significant differences between BP BF and sera, while an opposite behaviour was observed for transforming growth factor beta 1 (TGF-beta 1), whose serum levels were higher than the concentrations in BF. Using the number of lesions of the patients as a possible disease intensity marker, significant correlations were found with the BF levels of IL-1 beta, IL-8, TNF-alpha and, most closely, IL-5. These data may have pathogenetic relevance and suggest the possibility that these biological modulators may be used as a quantitative marker of disease intensity.

Acute pancreatitis attributed to the use of interferon alfa-2b.

PubMed

Eland, I A; Rasch, M C; Sturkenboom, M J; Bekkering, F C; Brouwer, J T; Delwaide, J; Belaiche, J; Houbiers, G; Stricker, B H

2000-07-01

Two patients experienced episodes of acute pancreatitis shortly after starting treatment with interferon alfa-2b (IFN-alpha) for a chronic hepatitis C infection. The first patient was a 40-year-old man who developed acute pancreatitis after 15 weeks of treatment with 3 MU IFN-alpha subcutaneously (SC) 3 times weekly and 1200 mg ribavirin. After disappearance of symptoms and normalization of laboratory values, oral intake of solid foods and IFN-alpha therapy were restarted. Within hours, a relapse of acute pancreatitis occurred. A rechallenge with IFN-alpha 4 days later was followed by a prompt increase in serum lipase level, and IFN-alpha therapy was discontinued. The second patient was a 38-year-old man who developed acute pancreatitis 2 hours after SC administration of 5 MU IFN-alpha. Ultrasound endoscopy showed sludge in the gallbladder. The patient was rechallenged 5 weeks later with 3 MU IFN-alpha SC. Although serum amylase and lipase levels increased after readministration of IFN-alpha, treatment was continued. The patient was readmitted 2 weeks later with severe abdominal pain, and IFN-alpha administration was discontinued. Considering the temporal relationship between the start of IFN-alpha treatment and development of acute pancreatitis, the absence of other clear etiologic factors for acute pancreatitis, disappearance of symptoms after discontinuation of IFN-alpha, and positive reactions to rechallenge, IFN-alpha is the most probable cause for development of acute pancreatitis in these patients.

Human Interferon Regulatory Factor 2 Gene Expression is Induced in Chronic Hepatitis C Virus Infection—A Possible Mode of Viral Persistence

PubMed Central

Mukherjee, Rathindra M; Bansode, Budhapriyavilas; Gangwal, Puja; Jakkampudi, Aparna; Reddy, Panyala B; Rao, Padaki N; Gupta, Rajesh; Reddy, D Nageshwar

2012-01-01

Background The interferon regulatory factors (IRFs) are a family of transcription factors known to be involved in the modulation of cellular responses to interferons (IFNs) and viral infection. While IRF-1 acts as a positive regulator, IRF-2 is known to repress IFN-mediated gene expression. The increase in the IRF-1/IRF-2 ratio is considered as an important event in the transcriptional activation of IFN-α gene toward development of the cellular antiviral response. Objective This study was performed to assess the expression of IRF mRNAs along with the expression level of IFN-α, its receptor (IFNAR-1), and the signal transduction factor (STAT-1) in treatment naive hepatitis C virus (HCV)-infected subjects. Materials Thirty-five chronically infected (CHC) patients and 39 voluntary blood donors as controls were included in the study. Quantification of HCV-RNA (ribonucleic acid) and genotyping were done by real-time polymerase chain reaction (PCR) and hybridization assays, respectively, using patient's serum/plasma. In both controls and patients, the serum level of IFN-α and IFN-α was measured by flow cytometry. Target gene expressions were studied by retro-transcription of respective mRNAs extracted from peripheral blood mononuclear cells (PBMCs) followed by PCR amplification and densitometry. Minus-strand HCV-RNA as a marker of viral replication in PBMCs was detected by an inhouse PCR assay. Results Both IRF-1 and IRF-2 genes were significantly enhanced in CHC than in control subjects (P < 0.001). A significant positive correlation (r2 = 0.386, P <0.01) was obtained between higher IRF-2 gene expression and increasing level of HCV-RNA. Chronically infected subjects (13%) harboring replicating HCV in PBMCs showed no significant differences in gene expressions than the subjects without HCV in PBMCs. Conclusion Our findings indicate that HCV modulates host immunity by inducing IRF-2 gene to counteract IRF-1-mediated IFN-α gene expression. Since the IRF-2 gene is known to encode oncogenic protein, the role of IRF-2 in CHC patients developing hepatocellular carcinoma warrants further studies. PMID:25755403

Sequential determination of serum viral titers, virus-specific IgG antibodies, and TNF-α, IL-6, IL-10, and IFN-γ levels in patients with Crimean-Congo hemorrhagic fever.

PubMed

Kaya, Safak; Elaldi, Nazif; Kubar, Ayhan; Gursoy, Nevcihan; Yilmaz, Meral; Karakus, Gulderen; Gunes, Turabi; Polat, Zubeyde; Gozel, Mustafa Gokhan; Engin, Aynur; Dokmetas, Ilyas; Bakir, Mehmet; Yilmaz, Neziha; Sencan, Mehmet

2014-07-28

Although there have been a number of studies on the pathogenesis of Crimean-Congo hemorrhagic fever (CCHF) recently, knowledge on this topic is still insufficient. This study aims to reveal the kinetics of serum CCHF virus (CCHFV) titers, serum levels of anti-CCHFV immunoglobulin (Ig)G, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and interferon (IFN)-γ in CCHF patients. In total, 31 CCHF cases (11 fatal) were studied. Serum samples were obtained daily from all patients from the time of admission and continued for a 7-day hospitalization period for serologic (ELISA), virologic (real-time PCR), and cytokine (ELISA) analysis. The mean serum CCHFV titer at admission was 5.5E + 09 copies/mL in fatal cases and 5.7E + 08 copies/mL in survivors (p < 0.001). Compared to survivors, both the mean serum levels of IL-6 and TNF-α at admission were found to be significantly increased in fatal cases. The serum levels of IL-6, TNF-α and serum CCHFV titer at admission were significantly and positively correlated with disseminated intravascular coagulation (DIC) scores (r = 0.626, p = 0.0002; r = 0.461, p = 0.009; and r = 0.625, p = 0.003, respectively). When the data obtained from the sequential determination of CCHFV titer and levels of anti-CCHFV IgG, IL-6, TNF-α, IL-10 and IFN-γ were grouped according to the days of illness, the initial serum CCHFV titer of a fatal patient was 5.5E + 09 (copies/mL) and it was 6.1E + 09 (copies/mL) in a survivor on the 2 day of illness. While significant alterations were observed in all cytokines during the monitoring period, IL-6 levels remained consistently higher in fatal cases and TNF-α levels increased in both in fatal and non-fatal CCHF cases. The increased CCHFV load and higher concentrations of IL-6 and TNF-α, the presence of DIC, and the absence of CCHFV specific immunity are strongly associated with death in CCHF.

Inhibition of macrophage activation and lipopolysaccaride-induced death by seco-steroids purified from Physalis angulata L.

PubMed

Soares, Milena B P; Bellintani, Moema C; Ribeiro, Ivone M; Tomassini, Therezinha C B; Ribeiro dos Santos, Ricardo

2003-01-10

Physalis angulata L. is an annual herb widely used in popular medicine for the treatment of a variety of pathologies. Here, we tested immunomodulatory activities of physalins, seco-steroids purified from P. angulata extracts. Addition of physalins B, F or G, but not D, caused a reduction in nitric oxide production by macrophages stimulated with lipopolysaccaride and interferon-gamma. In the presence of physalin B, macrophages stimulated with lipopolysaccaride, alone or in combination with interferon-gamma, produced lower levels of tumour necrosis factor (TNF)-alpha, interleukin-6 and interleukin-12. The inhibitory activity of physalin B, unlike that of dexamethasone, was not reversed by RU486 [(4-dimethylamino) phenyl-17beta-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one], an antiglucocorticoid. Physalin B-treated mice had lower levels of serum TNF-alpha than control mice after lipopolysaccaride challenge. More importantly, mice injected with physalins B, F or G survived after a lethal lipopolysaccaride challenge. These results demonstrate that seco-steroids from P. angulata are potent immunomodulatory substances and act through a mechanism distinct from that of dexamethasone.

[Serum levels of HCV-RNA determined by branched DNA (bDNA) probe assay in chronic hepatitis C: method and clinical significance on interferon (IFN) therapy].

PubMed

Osada, T; Iwabuchi, S; Takatori, M; Murayama, M; Iino, S

1994-07-01

Recently serum levels of HCV RNA (s-HCV RNA) in chronic hepatitis C has been regarded as one of an important indicator for the activity of disease and outcome of IFN therapy. Quantitative analysis by competitive RT-PCR, however, requires special skills and is too expensive for clinical use. We attempted to determine serial sample of s-HCV RNA and genotypes in 117 cases treated with IFN using bDNA probe assay which has lately been developed by Chiron corporation. Cases with complete response to IFN therapy showed 62% (49/79) in lower than 10(6) levels, 27% (8/30) in 10(6)-10(7) and only 5% (2/41) in higher than 10(7). Genotype III, IV had higher response than type II on the same level of s-HCV RNA. These data indicates that determination of s-HCV levels by bDNA assay may be useful for prediction of the outcome of IFN therapy and making adequate schedule of the therapy in each cases.

Influence of parturition and diets enriched in n-3 or n-6 polyunsaturated fatty acids on immune response of dairy cows during the transition period.

PubMed

Lessard, M; Gagnon, N; Godson, D L; Petit, H V

2004-07-01

The objectives of this study were to evaluate the functional properties of immunocompetent cells in dairy cows fed diets enriched in n-3 or n-6 polyunsaturated fatty acids during the transition period. Six weeks before calving, 21 primiparous and 27 multiparous pregnant Holstein dairy cows were randomly allotted to 1 of 3 dietary fat treatments: calcium salts of palm oil (Megalac), micronized soybeans, or whole flaxseed, which are, respectively, rich in saturated, n-6, or n-3 fatty acids. On wk 6 and 3 before parturition, cows received a subcutaneous injection of ovalbumin to measure the antibody response in colostrum and serum. Colostrum samples were collected at the first milking after calving, and blood samples were taken 6, 3, and 1 wk before the expected calving date and 1, 3, and 6 wk after calving. Blood mononuclear cells were cultured to evaluate the proliferative response to concanavalin A and the in vitro productions of interferon-gamma, tumor necrosis factor-alpha, nitric oxide, and prostaglandin E2. The serum antibody response to ovalbumin was unaffected by dietary fatty acids, but the response was lower in primiparous cows than in multiparous cows. A significant diet x parity interaction indicated that colostral antibody level against ovalbumin was significantly higher in multiparous cows fed soybeans than in those fed flaxseed or Megalac; there was no difference among treatments for primiparous cows. The lymphocyte response to concanavalin A was lower in cows fed soybeans than in those receiving flaxseed or Megalac when the cells were incubated with autologous serum. The proliferative response of mononuclear cells incubated with autologous serum was suppressed in the 1st wk after calving in both primiparous and multiparous cows, and multiparous cows showed a higher response than primiparous cows throughout the experiment. There was a significant interaction between parity and diet as a result of a greater production of interferon-gamma by mononuclear cells incubated with autologous serum in multiparous cows than in primiparous cows fed flaxseed; there was no difference among cows fed the other diets. Interferon-gamma production was reduced around calving while the inverse was observed for productions of nitric oxide and tumor necrosis factor-alpha. Productions of nitric oxide, prostaglandin E2, and tumor necrosis factor-gamma were greater in primiparous cows than in multiparous cows. In conclusion, functional properties of lymphocytes and monocyte/macrophage lineage of dairy cows during the transition period are modulated by parturition and the composition of polyunsaturated fatty acids in the diet.

Th1, Th2, and Th17 Cytokine Involvement in Thyroid Associated Ophthalmopathy

PubMed Central

Shen, Jie; Li, Zhangfang; Li, Wenting; Ge, Ying; Xie, Min; Lv, Meng; Fan, Yanfei; Chen, Zhi; Zhao, Defu; Han, Yajuan

2015-01-01

To determine serum cytokine profiles in Graves' disease (GD) patients with or without active and inactive thyroid associated ophthalmopathy (TAO), we recruited 65 subjects: 10 GD only (without TAO), 25 GD + active TAO, 20 GD + TAO, and 10 healthy controls. Liquid chip assay was used to measure serum Th1/Th2/Th17 cytokines including IFN-γ (interferon-gamma), TNF-α (tumor necrosis factor-alpha), IL-1α (interleukin-1 alpha), IL-1Ra (IL-1 receptor antagonist), IL-2, IL-4, IL-6, and IL-17 and two chemokines: RANTES (regulated upon activation, normal T cell expressed and secreted) and IP-10 (IFN-γ-induced protein 10). Serum levels of TSH (thyroid stimulating hormone) receptor autoantibodies (TRAb) were measured using an enzyme linked immunosorbent assay. Compared with healthy controls, TAO patients showed significantly elevated serum levels of IFN-γ, TNF-α, IL-1α, IL-4, IL-6, IL-17, and IP-10. Comparing active and inactive TAO, serum Th1 cytokines IFN-γ and TNF-α were elevated in active TAO, while serum Th2 cytokine IL-4 was elevated in inactive TAO. Serum Th17 cytokine IL-17 was elevated in GD but reduced in both active and inactive TAO. A positive correlation was found between TRAb and IFN-γ, TNF-α, IL-1α, IL-2, IL-4, and IL-6. Taken together, serum Th1/Th2/Th17 cytokines and chemokines reflect TAO disease activity and may be implicated in TAO pathogenesis. PMID:26089587

Expression of interferon-inducible chemokines and sleep/wake changes during early encephalitis in experimental African trypanosomiasis

PubMed Central

Seke-Etet, Paul F.; La Verde, Valentina; Colavito, Valeria; Grassi-Zucconi, Gigliola; Rodgers, Jean; Montague, Paul; Bentivoglio, Marina

2017-01-01

Background Human African trypanosomiasis or sleeping sickness, caused by the parasite Trypanosoma brucei, leads to neuroinflammation and characteristic sleep/wake alterations. The relationship between the onset of these alterations and the development of neuroinflammation is of high translational relevance, but remains unclear. This study investigates the expression of interferon (IFN)-γ and IFN-inducible chemokine genes in the brain, and the levels of CXCL10 in the serum and cerebrospinal fluid prior to and during the encephalitic stage of trypanosome infection, and correlates these with sleep/wake changes in a rat model of the disease. Methodology/Principal findings The expression of genes encoding IFN-γ, CXCL9, CXCL10, and CXCL11 was assessed in the brain of rats infected with Trypanosoma brucei brucei and matched controls using semi-quantitative end-point RT-PCR. Levels of CXCL10 in the serum and cerebrospinal fluid were determined using ELISA. Sleep/wake states were monitored by telemetric recording. Using immunohistochemistry, parasites were found in the brain parenchyma at 14 days post-infection (dpi), but not at 6 dpi. Ifn-γ, Cxcl9, Cxcl10 and Cxcl11 mRNA levels showed moderate upregulation by 14 dpi followed by further increase between 14 and 21 dpi. CXCL10 concentration in the cerebrospinal fluid increased between 14 and 21 dpi, preceded by a rise in the serum CXCL10 level between 6 and 14 dpi. Sleep/wake pattern fragmentation was evident at 14 dpi, especially in the phase of wake predominance, with intrusion of sleep episodes into wakefulness. Conclusions/Significance The results show a modest increase in Cxcl9 and Cxcl11 transcripts in the brain and the emergence of sleep/wake cycle fragmentation in the initial encephalitic stage, followed by increases in Ifn-γ and IFN-dependent chemokine transcripts in the brain and of CXCL10 in the cerebrospinal fluid. The latter parameter and sleep/wake alterations could provide combined humoral and functional biomarkers of the early encephalitic stage in African trypanosomiasis. PMID:28821016

Inverse relationship between toxic shock syndrome toxin-1 antibodies and interferon-γ and interleukin-6 in peripheral blood mononuclear cells from patients with pediatric tonsillitis caused by Staphylococcus aureus.

PubMed

Chen, Yinshuang; Huang, Yanmei; Liang, Bingshao; Dong, Hui; Yao, Shuwen; Xie, Yongqiang; Long, Yan; Zhong, Huamin; Yang, Yiyu; Zhu, Bing; Gong, Sitang; Zhou, Zhenwen

2017-06-01

Pediatric tonsillitis is frequently caused by Staphylococcus aureus, which is the most common pathogen that causes serious pyogenic infections in humans and endangers human health. S. aureus produces numerous potent virulence factors that play a critical role in the pathogenesis of the infection caused by this bacterium, and one of the most important toxins produced by S. aureus is toxic shock syndrome toxin-1 (TSST-1). The aim of this study is to investigate the first time the levels of IFN-γ and interleukin IL-6 in TSST-1-stimulated PBMCs from pediatric tonsillitis patients and the correlation of these cytokine levels with TSST-1-specific IgG in serum. TSST-1 gene of S. aureus was cloned and expressed in a prokaryotic expression system, and purified recombinant TSST-1 protein was used for measuring TSST-1-specific antibodies in the serum of patients with pediatric tonsillitis caused by S. aureus. Moreover, the levels of interferon (IFN)-γ and interleukin (IL)-6 in TSST-1-stimulated peripheral blood mononuclear cells (PBMCs) from pediatric tonsillitis patients were investigated. In patients with pediatric tonsillitis caused by S. aureus, significantly higher levels of serum TSST-1-specific IgG (P < 0.05) and IgG1 (P < 0.05) were detected than in healthy children. Moreover, PBMCs from the patients exhibited higher IFN-γ (P < 0.05) production in response to TSST-1 than did PBMCs from healthy children. In patients with pediatric tonsillitis caused by S. aureus, the positive rate of TSST-1-specific IgG was 70%, and the patients who tested negative for TSST-1-specific IgG exhibited significantly higher levels of IFN-γ (P < 0.05) and IL-6 (P < 0.05) than did the IgG-positive patients, in accord, the levels of TSST-1-specific IgG correlated inversely with the levels of IFN-γ and IL-6 in patients PBMCs stimulated with TSST-1. TSST-1 induces humoral and cellular immunity in pediatric tonsillitis caused by S. aureus, which suggests that TSST-1 may play an important role in the pathogenesis of pediatric tonsillitis. Copyright © 2017. Published by Elsevier B.V.

The effects of Cordyceps sinensis phytoestrogen on estrogen deficiency-induced osteoporosis in ovariectomized rats.

PubMed

Zhang, Da-wei; Wang, Zhen-lin; Qi, Wei; Zhao, Guang-yue

2014-12-13

Isoflavones are naturally occurring plant chemicals belonging to the "phytoestrogen" class. The aim of the present study was to examine the effects of isoflavones obtained from Cordyceps sinensis (CSIF) on development of estrogen deficiency-induced osteoporosis in ovariectomized rats. After the rats were treated orally with CSIF, serum alkaline phosphatase (ALP), tartarate resistant acid phosphatase (TRAP), serum osteocalcin (OC), homocysteine (HCY), C-terminal crosslinked telopeptides of collagen type I (CTX), estradiol and interferonγ (IFN-γ) level were examined. At the same time, the urine calcium, plasma calcium, plasma phosphorus and the mass of uterus, thymus and body were also examined. The beneficial effects of CSIF on improvement of osteoporosis in rats were attributable mainly to decrease ALP activity, TRAP activity, CTX level and IFN-γ level. At the same time, CSIF also increase the OC and estradiol level in ovariectomized osteopenic rats. The histological examination clearly showed that dietary CSIF can prevent bone loss caused by estrogen deficiency. The significant estrogenic activity of CSIF demonstrated that CSIF has significant estrogenic effects in OVX rats.

Daidzein enhances immune function in late lactation cows under heat stress.

PubMed

Liu, De-Yi; He, Shao-Jun; Liu, Shi-Qing; Tang, Yi-Guo; Jin, Er-Hui; Chen, Hui-Liang; Li, Sheng-He; Zhong, Liang-Ting

2014-01-01

Heat stress decreases natural immunity making cows more vulnerable to diseases. A previous study reported that daidzein can enhance animal resistance to heat stress and regulate animal immunocompetence. However, it is unclear whether daidzein regulates the immune performance of late lactation cows under heat stress. In this study, late lactation cows in four groups were raised in hot weather and fed with basic diet, basic diet plus 200, 300, 400 mg/day daidzein, respectively, and the experimental period was 60 days. Blood was collected to examine the changes of serum total protein (TP), albumin (ALB), immunoglobulin G (IgG), interferon alpha (IFN-α), and interleukin-2 (IL-2). We found the levels of serum IgG and INF-α were significantly higher in late lactation cows after 300 and 400 mg/day daidzein treatment compared to those in the control group and 200 mg/day daidzein treatment (P < 0.05 or P < 0.01). Moreover, 300 and 400 mg/day daidzein treatment markedly increased serum IL-2 (P < 0.01), while the levels of serum TP and ALB were not changed by any concentration of daidzein treatment (P > 0.05). Daidzein can enhance the immunocompetence of late lactation cows and strengthen cow resistance to heat stress. © 2013 Japanese Society of Animal Science.

Type 1 Diabetes Mellitus Associated with Pegylated Interferon-α Plus Ribavirin Treatment for Chronic Hepatitis C: Case Report and Literature Review.

PubMed

Oka, Reiko; Hiroi, Naoki; Shigemitsu, Rika; Sue, Mariko; Oshima, Yasuo; Yoshida-Hiroi, Mayumi

2011-01-01

Combined pegylated interferon (PEG-IFN)+ribavirin (RBV) therapy has been used as a primary treatment for chronic hepatitis C. However, IFN-induced autoimmune disease, including type 1 diabetes mellitus, has been highlighted as one of the problems with this therapy. Here we report the case of a patient who developed type 1 diabetes mellitus during combined PEG-IFN+RBV therapy for hepatitis C but who showed no exacerbation of diabetes despite continued use of IFN. A 63-year-old man with chronic hepatitis C and a nonresponder to previous IFNα treatments, was admitted to our hospital because of excessive thirst, polydipsia, and polyuria 24 weeks after the start of PEG-IFNα+RBV therapy. High levels of blood glucose and glycosylated hemoglobin and low levels of C-peptide and immunoreactive insulin were observed. The serum antiglutamic acid decarboxylase antibody titer was 27,700 U/mL. We diagnosed IFN-induced type 1 diabetes mellitus; however PEG-IFNα+RBV therapy was continued for 48 weeks. Serum HCV remains negative five years after this treatment. Intensive insulin therapy was started immediately after the diagnosis of type 1 diabetes. Although the patient initially required 22 U/day of insulin, the dosage could be gradually reduced after completion of PEG-IFNα+RBV therapy and blood glucose remained well controlled. Prediction of onset of type 1 diabetes mellitus on the basis of baseline measurement of pancreas-associated autoantibodies is difficult. Therefore, it would be advisable to consider the possibility of onset of type 1 diabetes mellitus in all patients receiving IFN+RBV therapy.

Interferon-regulated chemokine score associated with improvement in disease activity in refractory myositis patients treated with rituximab.

PubMed

López De Padilla, Consuelo M; Crowson, Cynthia S; Hein, Molly S; Strausbauch, Michael A; Aggarwal, Rohit; Levesque, Marc C; Ascherman, Dana P; Oddis, Chester V; Reed, Ann M

2015-01-01

The purpose of this study was to investigate whether serum interferon (IFN)-regulated chemokine and distinct cytokine response profiles are associated with clinical improvement in patients with refractory inflammatory myopathy treated with rituximab. In a randomised, placebo-phase trial Rituximab in Myositis Trial (RIM), 200 refractory adult and paediatric myositis subjects received rituximab. Following rituximab, clinical response and disease activity were assessed. Serum samples and clinical data were collected at baseline and several time-points after rituximab treatment. Multiplexed sandwich immunoassays quantified serum levels of IFN-regulated chemokines and other pro-inflammatory cytokines. Composite IFN-regulated chemokine and Th1, Th2, Th17 and regulatory cytokine scores were computed. Baseline IFN-regulated chemokine, Th1, Th2, Th17 and regulatory cytokine scores correlated with baseline physician global VAS, whereas the baseline Th1, Th2 and Th17 cytokine scores correlated with baseline muscle VAS. We also found baseline IFN-regulated chemokine scores correlated with specific non-muscular targets such as baseline cutaneous (r=0.29; p=0.002) and pulmonary (r=0.18; p=0.02) VAS scores. Among all cytokine/chemokines examined, the baseline score of IFN-regulated chemokines demonstrated the best correlation with changes in muscle VAS at 8 (r=-0.19; p=0.01) and 16 weeks (r=-0.17; p=0.03) following rituximab and physician global VAS at 16 weeks (r=-0.16; p=0.04). In vitro experiments showed increased levels of IL-8 (p=0.04), MCP-1 (p=0.04), IL-6 (p=0.03), IL-1β (p=0.04), IL-13 (p=0.04), IL-10 (p=0.02), IL-2 (p=0.04) and IFN-γ (p=0.02) in supernatants of TLR-3 stimulated PBMCs from non-responder compared to patients responders to rituximab. IFN-regulated chemokines before treatment is associated with improvement in disease activity measures in refractory myositis patients treated with rituximab.

Presence of anti-phosphatidylserine-prothrombin complex antibodies and anti-moesin antibodies in patients with polyarteritis nodosa.

PubMed

Okano, Tatsuro; Takeuchi, Sora; Soma, Yoshinao; Suzuki, Koya; Tsukita, Sachiko; Ishizu, Akihiro; Suzuki, Kazuo; Kawakami, Tamihiro

2017-01-01

We measured both serum anti-phosphatidylserine-prothrombin complex (anti-PSPT) antibodies and anti-moesin antibodies, as well as various cytokines (interleukin [IL]-2, IL-4, IL-5, IL-10, IL-13, IL-17, granulocyte macrophage colony-stimulating factor, γ-interferon, tumor necrosis factor-α) levels in polyarteritis nodosa (PAN) patients with cutaneous manifestations. All patients showed the presence of a histological necrotizing vasculitis in the skin specimen. They were treated with i.v. cyclophosphamide pulse therapy (IV-CY) and prednisolone therapy or steroid pulse therapy. The immunological assessments were performed on sera collected prior to and after treatment with IV-CY or steroid pulse therapy. We found a significant positive correlation between serum anti-moesin antibodies and both clinical Birmingham Vasculitis Activity Scores and Vasculitis Damage Index. Anti-PSPT antibody and IL-2 levels after treatment in PAN patients were significantly lower than before treatment. In contrast, anti-moesin antibody levels were higher following IV-CY or steroid pulse therapy compared with the pretreatment levels. In the treatment-resistant PAN patients (n = 8), anti-PSPT antibody levels after treatment were significantly lower than before treatment. In contrast, anti-moesin antibody levels after treatment in the patients were significantly higher compared with the pretreatment levels. Immunohistochemical staining revealed moesin overexpression in mainly fibrinoid necrosis of the affected arteries in the PAN patients. We suggest that measurement of serum anti-PSPT antibody levels could serve as a marker for PAN and aid in earlier diagnosis of PAN. We also propose that elevated serum anti-moesin antibodies could play some role of the exacerbation in patients with PAN. © 2016 Japanese Dermatological Association.

Interferon-Free Treatment of Hepatitis C Virus in HIV/Hepatitis C Virus-Coinfected Subjects Results in Increased Serum Low-Density Lipoprotein Concentration

PubMed Central

Townsend, Kerry; Meissner, Eric G.; Sidharthan, Sreetha; Sampson, Maureen; Remaley, Alan T.; Tang, Lydia; Kohli, Anita; Osinusi, Anu; Masur, Henry

2016-01-01

Abstract Chronic hepatitis C virus (HCV) infection is associated with lower serum concentration of low-density lipoprotein (LDL-C), the primary cholesterol metabolite targeted pharmaceutically to modulate cardiovascular risk. Chronic infection with human immunodeficiency virus (HIV) and treatment with antiretrovirals (ARVs) are associated with dyslipidemia and increased risk of cardiovascular disease. In subjects coinfected with HIV and HCV, lipid abnormalities associated with either infection alone are often attenuated. Treatment of chronic HCV infection in HIV/HCV-coinfected subjects is now possible with interferon (IFN)-free regimens composed of directly acting antivirals (DAAs). We previously observed a marked increase in serum LDL-C in HCV-monoinfected subjects treated with sofosbuvir and ribavirin (SOF/RBV) that correlated with viral decline in serum, suggesting a direct influence of HCV clearance on serum cholesterol. In the present study, we assessed longitudinal changes in cholesterol in HIV/HCV-coinfected subjects during treatment of HCV genotype-1 (GT1) infection with combination DAA therapy. We report a rapid increase in LDL-C and LDL particle size by week 2 of treatment that was sustained during and after treatment in HIV/HCV-coinfected subjects. No change in serum LDL-C was observed at day 3 of treatment, in spite of a marked reduction in serum HCV viral load, suggesting LDL-C increases do not directly reflect HCV clearance as measured in peripheral blood. After effective DAA therapy for HCV, an increase in LDL should be anticipated in HIV/HCV-coinfected subjects. PMID:26559180

Effects of SSM (specific substance maruyama) on HBe antigen-positive chronic hepatitis B -clinical efficacy and modulation of cytokines.

PubMed

Satomura, K; Yin, M; Sekiyama, T; Fujisaki, S; Aramaki, T; Okumura, H; Ohmoto, Y

2000-08-01

Twenty-three patients with HBe antigen-positive chronic hepatitis B were treated with capitalite first letters Maruyama (SSM). HBe antigen turned negative in 15 patients. The levels of various cytokines in pre- and post-treatment frozen serum samples from six patients whose HBe antigen turned negative and from five whose HBe antigen did not were examined. Reduction of serum interleukin (IL) -10 level to below 20 pg/ml was observed after SSM treatment in four of the six patients whose HBe antigen turned negative. SSM was found to stimulate the production of interferon (IFN) -gamma in peripheral blood cells from two healthy volunteers. This stimulatory effect was confirmed in 12 out of 24 healthy volunteers. SSM augmented the production of IFN-gamma in eight out of 10 patients with chronic hepatitis B and nine of 10 with hepatitis C. These results demonstrate for the first time that SSM stimulates the production of IFN-gamma in human peripheral blood cells and also suggest that treatment of HBe antigen-positive chronic hepatitis B patients with SSM leads to the clearance of HBe antigen and normalization of serum aspartate aminotransferase levels through inhibition of IL-10 and stimulation of IFN-gamma.

Serum and gene expression profile of cytokines in first-episode psychosis.

PubMed

Di Nicola, Marco; Cattaneo, Annamaria; Hepgul, Nilay; Di Forti, Marta; Aitchison, Katherine J; Janiri, Luigi; Murray, Robin M; Dazzan, Paola; Pariante, Carmine M; Mondelli, Valeria

2013-07-01

An inflammatory syndrome has been previously reported in chronic schizophrenia. The aims of this study were to investigate: (1) serum levels and leukocyte gene expression of cytokines in patients with first-episode psychosis and controls; and (2) possible causes of abnormal cytokine levels in first-episode psychosis, testing their association with psychosocial stressors, current nicotine and cannabis use, and duration of antipsychotic treatment. We recruited 24 first-episode psychosis patients and 24 healthy controls matched for age, gender, ethnicity and body mass index. Serum interleukin(IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, Tumour Necrosis Factor- α (TNF-α), Interferon- γ (IFN-γ), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and monocyte chemotactic protein-1 (MCP-1) were analysed in all subjects. Leukocyte gene expression analyses were conducted only for those cytokines that were different between-groups in the serum analyses. Patients had significantly higher serum levels of IL-1α (effect size d=0.6, p=0.03), IL-1β (d=0.4, p=0.01), IL-8 (d=0.6, p=0.01) and TNF-α (d=0.7, p=0.05) and a trend for higher IL-6 serum levels (d=0.3, p=0.09) when compared with controls. Leukocyte m-RNA levels of IL-1α (d=0.6, p=0.04), IL-6 (d=0.7, p=0.01) and TNF-α (d=1.6, p<0.001), but not IL-1β and IL-8, were also significantly higher in patients. A history of childhood trauma was associated with higher TNF-α serum levels (p=0.01), while more recent stressful life-events were associated with higher TNF-α mRNA levels in leukocytes (p=0.002). In conclusion, first-episode psychosis is characterised by a pro-inflammatory state supported, at least in part, by activation of leukocytes. Past and recent stressors contribute to this pro-inflammatory state. Copyright © 2012 Elsevier Inc. All rights reserved.

Cytokine Indexes in Pemphigus Vulgaris: Perception of Its Immunpathogenesis and Hopes for Non-Steroidal Treatment

PubMed Central

Masjedi, Mohsen; Esmaeil, Nafiseh; Saffaei, Ali; Abtahi-Naeini, Bahareh; Pourazizi, Mohsen; Haghjooy Javanmard, Shaghayegh; Asilian, Ali

2017-01-01

Pemphigus vulgaris (PV) is a chronic autoimmune blistering disease of the skin, in which loss of adhesion between keratinocytes is caused by autoantibodies. It has been hypothesized that cytokines play an essential role in the pathogenesis of PV. This study aimed to investigate the other immunopathological aspects of PV by determining the serum levels of cytokines in PV patients to find another treatment strategy except corticosteroid therapy. Twenty-three patients with PV and a control group consisting of 24 healthy subjects were studied. Interleukin (IL)-2, IL-4, IL-6, IL10, IL-12, IL-17 and interferon-gamma (IFN-γ) were measured in the sera of patients by the enzyme-linked immunosorbent assay (ELISA) method. The serum levels of IL-2, IL-4, IL-17 and IFN-γ in most patients and controls were undetectable. The serum concentrations of IL-10 in the patients and controls were undetectable, nevertheless, the mean serum levels of this cytokine was 64.375 pg/mL in four patients. The mean serum levels of pro-inflammatory cytokine IL-6 increased significantly in the patients, compared to the controls (169.50 vs. 75.62 pg/mL) (P < 0.05). The same was observed for another pro-inflammatory cytokine, IL-12 (135.33 vs. 86.28 pg/mL) (P < 0.05). Based on the results of this study it can be concluded that the Type 2 T helper cytokine (IL-6) and macrophage-derived cytokine (IL-12) have essential roles in PV pathophysiology. In addition, the potential clinical application of Th1/Th2 type cytokine-based therapy in PV should be considered in next studies. PMID:29201111

Cytokine profiling reveals decreased serum levels of CCL2 in active ocular toxoplasmosis.

PubMed

Rey, Amanda; Molins, Blanca; Llorenç, Victor; Pelegrín, Laura; Mesquida, Marina; Adán, Alfredo

2013-10-01

Toxoplasma gondii infection is an important cause of ocular disease. Although parasite-mediated host cell lysis is probably the principal cause of tissue destruction in immunodeficiency states, hypersensitivity and inflammatory responses may underlie severe disease in otherwise immunocompetent individuals. The purpose of the current investigation was to study the cytokine profiles in serum from patients with ocular toxoplasmosis and to compare them with those obtained from healthy control subjects. Using a multiplex assay, we determined the serum concentration of granulocyte colony-stimulating factor (GCSF), interferon γ (IFNγ), interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, chemokine (C-C motif) ligand 2 (CCL2) and tumour necrosis factor α (TNFα) in patients with inactive ocular toxoplasmosis (n=48), active ocular toxoplasmosis (n=21), and an age-matched and sex-matched healthy control group (n=25). In a subgroup of 17 patients with active disease, a second serum sample was obtained when the disease was inactive. Cytokine profiles were correlated with disease activity, severity and visual outcome. Levels of CCL2 were significantly reduced in patients with active ocular toxoplasmosis compared to the control group (564 ± 42 pg/mL vs 455 ± 35 pg/mL, p<0.05). Moreover, CCL2 levels were significantly lower during active ocular toxoplasmosis compared to inactive disease (569 ± 32 pg/mL vs 433 ± 32 pg/mL, p<0.01). GCSF and TNFα were elevated in patients with toxoplasmosis with poor visual outcome. No significant correlations were found with specific cytokine profiles and disease severity. Decreased serum levels of CCL2 may be associated with active ocular toxoplasmosis and could therefore serve as a marker of disease activity.

A comparison of mucosal inflammatory responses to Giardia muris in resistant B10 and susceptible BALB/c mice.

PubMed

Venkatesan, P; Finch, R G; Wakelin, D

1997-03-01

In the first three weeks of primary Giardia muris infections B10 mice clear infection more rapidly than BALB/c mice. There is evidence that interferon-gamma contributes to the relative resistance of B10 mice. The nature of the functional contribution of interferon-gamma is unclear and does not relate to the secretory or serum antibody response. Mucosal inflammatory events in these strains have been studied. Apart from a small rise in both strains of goblet cell and mucosal mast cell numbers, associated with release of mast cell protease-1 in serum, no inflammatory infiltrate was observed at the time trophozoites were cleared from the intestinal lumen. Inhibition of mast cell products (5-hydroxytryptamine and histamine) by cyproheptadine enhanced the intensity of infection in both strains. The relative resistance of B10 mice could not be explained in terms of the mucosal inflammatory response.

Classical swine fever virus infection modulates serum levels of INF-α, IL-8 and TNF-α in 6-month-old pigs.

PubMed

von Rosen, T; Lohse, L; Nielsen, J; Uttenthal, Å

2013-12-01

Several studies have highlighted the important role of cytokines in disease development of classical swine fever virus (CSFV) infection. In the present study, we examined the kinetics of 7 porcine cytokines in serum from pigs infected with 3 different CSFV strains. Based on the clinical picture in 6-month-old Danish pigs, the strains used for inoculation were classified as being of low (Bergen), low to moderate (Eystrup) and moderate to high (Lithuania) virulence. The cytokines interferon-alpha (INF-α), interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α) showed increased levels after CSFV infection with more or less comparable course in the 3 groups. However, the cytokine level peaked with a 2-3 days delay in pigs infected with the low virulent strain compared to those infected with a moderately or highly virulent strain. These findings may indicate that INF-α, IL-8 and TNF-α are involved in the immune response during CSFV infection with strains of different virulence. Copyright © 2013 Elsevier Ltd. All rights reserved.

Azuki bean (Vigna angularis) extract inhibits the development of experimentally induced atopic dermatitis-like skin lesions in NC/Nga mice.

PubMed

Collantes, Therese Marie; Rho, Mun-Chual; Kwon, Hyoung-Jun; Jung, Bock-Gie; Alfajaro, Mia Madel; Kim, Deok-Song; Kim, Hyun-Jeong; Hosmillo, Myra; Park, Jun-Gyu; Son, Kyu-Yeol; Park, Sang-Ik; Kang, Mun-Il; Park, Su-Jin; Lee, Seung Woong; Lee, Woo-Song; Cho, Kyoung-Oh

2012-06-01

The present study investigated the effects of azuki bean (Vigna angularis) extract (VAE) on the progress of atopic dermatitis (AD)-like skin lesions in NC/Nga mice induced by 1-chloro-2,4-dinitrobenzene. The efficacy of VAE in NC/Nga mice was determined by measuring gross and histological skin lesions, serum IgE levels, eosinophil ratio in peripheral leucocytes, and mRNA expression levels of interleukin (IL)-4, tumour necrosis factor (TNF)-α and interferon (IFN)-γ in splenocytes. Continuous ingestion of VAE inhibited the development of the AD-like skin lesions in a dose-dependent manner. In the VAE-treated mice, the numbers of mast cells in the skin, eosinophil ratio in peripheral leucocytes, relative mRNA expression of inflammatory cytokines in the spleen, and serum IgE levels were significantly reduced. Results suggest that VAE can inhibit the development of AD-like skin lesions in NC/Nga mice by regulating immune mediators and cells, and may be an effective alternative therapy for AD. Copyright © 2011 Elsevier Ltd. All rights reserved.

Dietary apigenin attenuates the development of atopic dermatitis-like skin lesions in NC/Nga mice.

PubMed

Yano, Satomi; Umeda, Daisuke; Yamashita, Shuya; Yamada, Koji; Tachibana, Hirofumi

2009-11-01

One of the flavones, apigenin has various physiological functions including anti-inflammatory activities. Atopic dermatitis (AD) is a chronically relapsing inflammatory disorder that is characterized by pruritic and eczematous skin lesions. To evaluate the anti-allergic effect of apigenin in vivo, we examined the effect of dietary apigenin on picrylchloride (PiCl)-induced AD-like pathology in NC/Nga mice. NC/Nga mice were fed experimental diets containing apigenin from Day 18 after sensitized with PiCl for 4 weeks. Dietary apigenin significantly alleviated the development of skin lesions, accompanied by lower serum immunoglobulin (Ig) G1 and IgE levels in NC/Nga mice. Interferon (IFN)-gamma mRNA expression level in spleen cells from NC/Nga mice was reduced by apigenin feeding. Moreover, interleukin 4-induced signal transducers and activators of transcription 6 phosphorylation in primary spleen cells from BALB/c mice was inhibited by treatment with apigenin. These results suggest that apigenin attenuates exacerbation of AD-like symptoms in part through the reduction of serum IgE level and IFN-gamma expression in NC/Nga mice.

Pentoxifylline attenuates cytokine stress and Fas system in syngeneic liver proteins induced experimental autoimmune hepatitis.

PubMed

Hendawy, Nevien

2017-08-01

Apoptosis is a hallmark in the pathogenesis of autoimmune hepatitis (AIH). Cytokine stresses and extrinsic apoptotic pathway have been implicated in this type of hepatic injury. Pentoxifylline plays an important role in controlling inflammation and apoptosis in different autoimmune diseases. To assess the protective effect of pentoxifylline for 30days against pro-inflammatory cytokines as tumor necrosis factor-alpha (TNF-α), interferon-gamma (INF-γ) and mediators of extrinsic apoptotic pathway involving TNF receptor 1 (TNFR1) and its ligand TNF-α and Fas receptor and its ligand (FasL) in experimental autoimmune hepatitis (EAH) model. EAH was induced by intraperitoneal injection of syngeneic liver antigen emulsified in complete Freund's adjuvant (CFA) in male C57BL/6 mice. Five groups of mice were used: two control groups; Control PBS group and Control CFA group, EAH group and two EAH+pentoxifylline treated groups in doses (100 or 200mg/kg/d, given by oral gavage). Serum transaminase, pro-inflammatory cytokines (TNF-α and interferon-γ) and hepatic caspase-8 and 3 activities were evaluated. Signs of autoimmune hepatitis were confirmed by liver histology. In addition, hepatic TNFR1, Fas and FasL mRNA expression were assayed. Serum transaminase levels and signs of AIH observed in EAH mice were significantly reduced by pentoxifylline. Upregulated serum TNF-α, IFN-γ, hepatic caspase-8 and 3 activities and TNFR1, Fas and FasL mRNA expression in liver tissues in EAH group were significantly downregulated by pentoxifylline. Pentoxifylline protects against syngeneic liver antigen induced hepatitis and associating apoptosis through attenuating the exaggerated cytokine release and extrinsic apoptotic pathway. Thus, this may represent a new therapeutic strategy for hepatitis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Serum CXCL10, CXCL11, CXCL12, and CXCL14 chemokine patterns in patients with acute liver injury.

PubMed

Chalin, Arnaud; Lefevre, Benjamin; Devisme, Christelle; Pronier, Charlotte; Carrière, Virginie; Thibault, Vincent; Amiot, Laurence; Samson, Michel

2018-06-04

The chemokines CXCL10 (interferon ϒ-inducible protein 10 [IP-10]), CXCL11 (Human interferon inducible T cell alpha chemokine [I-TAC]), CXCL12 (stromal cell derived factor 1 [SDF-1]), and CXCL14 (breast and kidney-expressed chemokine [BRAK]) are involved in cell recruitment, migration, activation, and homing in liver diseases and have been shown to be upregulated during acute liver injury in animal models. However, their expression in patients with acute liver injury is unknown. Here, we aimed to provide evidence of the presence of circulating CXCL10, CXCL11, CXCL12, and CXCL14 during human acute liver injury to propose new inflammation biomarkers for acute liver injury. We analyzed the serum concentration of the studied chemokines in healthy donors (n = 36) and patients (n = 163) with acute liver injuries of various etiologies. Serum CXCL10, CXCL11 and CXCL12 levels were elevated in all the studied groups except biliary diseases for CXCL11. CXCL14 was associated with only acute viral infection and vascular etiologies. The strongest correlation was found between the IFN-inducible studied chemokines (CXCL10 and CXCL11) in all patients and more specifically in the acute viral infection group. These data provide evidence for the presence of circulating CXCL10, CXCL11, CXCL12, and CXCL14 during acute liver injury and are consistent with data obtained in animal models. CXCL10, CXCL11 and CXCL12 were the most highly represented and CXCL14 the least represented chemokines. Differential expression patterns were obtained depending on acute liver injury etiology, suggesting the potential use of these chemokines as acute liver injury biomarkers. Copyright © 2018. Published by Elsevier Ltd.

Cold activation of complement for monitoring the response to interferon in patients with chronic hepatitis C.

PubMed

Akahane, Y; Miyazaki, Y; Naitoh, S; Takeda, K; Tsuda, F; Okamoto, H; Itoh, K; Miyakawa, Y; Mayumi, M

1996-02-01

Because of its specific association with hepatitis C virus (HCV) infection, the cold activation of complement is an easy and inexpensive indicator of HCV viremia. It was evaluated for eligibility as a marker of response to interferon in patients with hepatitis C. The cold activation of complement was determined by the loss or decrease of hemolytic activity with the microtitration method in sera that had been stored at 4 degrees C overnight. We observed the loss of hemolytic activity by the cold activation of complement in 236 (72%) and a decrease in 56 (17%) of 327 sera from patients with HCV-associated chronic liver disease, which was much more (p < 0.001) that in 1 (1%) and 13 (14%), respectively, of 49 sera from patients with chronic liver disease associated with hepatitis B virus infection. Interferon-alpha (total dose 516 x 10(6) units) or interferon-alpha 2b (774 x 10(6) units) was given to 67 patients with chronic hepatitis C, of whom 56 had the cold activation of complement. The response to interferon was evaluated by the clearance of serum HCV RNA at 6 months after the completion of therapy. The cold activation of complement disappeared in 18 patients, of whom 15 (86%) responded. It persisted or fluctuated in the remaining 38 patients, only six (16%) of whom responded to interferon (p < 0.001). The cold activation of complement once disappeared at the completion of interferon and then reappeared in patients who relapsed after completing interferon therapy. These results indicate that the cold activation of complement may be associated with the presence of HCV in blood and a lower rate of durable response after completion of interferon therapy.

Serum samples can be substituted by plasma samples for the diagnosis of paratuberculosis.

PubMed

Goodridge, Amador; Correa, Ricardo; Castro, Paul; Escobar, Cecilia; de Waard, Jacobus H

2013-10-01

Employing plasma samples rather than serum samples for serological paratuberculosis diagnosis is practical, especially when bovine TB is assessed in the same cattle herd with the gamma interferon bovine avian (IFN-γ BA) test. We demonstrate that antibody titers in serum and plasma samples, utilizing the PARACHECK(®) ELISA kit, are highly comparable (Cohen's kappa test, k=0.955). We conclude that serum can be replaced with plasma in this commercially available antibody detection assay resulting in working hour savings for sampling and blood sample work-up and cost reductions for materials and sample storage. Copyright © 2013 Elsevier B.V. All rights reserved.

Hemorrhagic shock shifts the serum cytokine profile from pro- to anti-inflammatory after experimental traumatic brain injury in mice.

PubMed

Shein, Steven L; Shellington, David K; Exo, Jennifer L; Jackson, Travis C; Wisniewski, Stephen R; Jackson, Edwin K; Vagni, Vincent A; Bayır, Hülya; Clark, Robert S B; Dixon, C Edward; Janesko-Feldman, Keri L; Kochanek, Patrick M

2014-08-15

Secondary insults, such as hemorrhagic shock (HS), worsen outcome from traumatic brain injury (TBI). Both TBI and HS modulate levels of inflammatory mediators. We evaluated the addition of HS on the inflammatory response to TBI. Adult male C57BL6J mice were randomized into five groups (n=4 [naïve] or 8/group): naïve; sham; TBI (through mild-to-moderate controlled cortical impact [CCI] at 5 m/sec, 1-mm depth), HS; and CCI+HS. All non-naïve mice underwent identical monitoring and anesthesia. HS and CCI+HS underwent a 35-min period of pressure-controlled hemorrhage (target mean arterial pressure, 25-27 mm Hg) and a 90-min resuscitation with lactated Ringer's injection and autologous blood transfusion. Mice were sacrificed at 2 or 24 h after injury. Levels of 13 cytokines, six chemokines, and three growth factors were measured in serum and in five brain tissue regions. Serum levels of several proinflammatory mediators (eotaxin, interferon-inducible protein 10 [IP-10], keratinocyte chemoattractant [KC], monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein 1alpha [MIP-1α], interleukin [IL]-5, IL-6, tumor necrosis factor alpha, and granulocyte colony-stimulating factor [G-CSF]) were increased after CCI alone. Serum levels of fewer proinflammatory mediators (IL-5, IL-6, regulated upon activation, normal T-cell expressed, and secreted, and G-CSF) were increased after CCI+HS. Serum level of anti-inflammatory IL-10 was significantly increased after CCI+HS versus CCI alone. Brain tissue levels of eotaxin, IP-10, KC, MCP-1, MIP-1α, IL-6, and G-CSF were increased after both CCI and CCI+HS. There were no significant differences between levels after CCI alone and CCI+HS in any mediator. Addition of HS to experimental TBI led to a shift toward an anti-inflammatory serum profile--specifically, a marked increase in IL-10 levels. The brain cytokine and chemokine profile after TBI was minimally affected by the addition of HS.

Adjuvant immunotherapy of feline fibrosarcoma with recombinant feline interferon-omega.

PubMed

Hampel, Verena; Schwarz, Bianca; Kempf, Christine; Köstlin, Roberto; Schillinger, Ulrike; Küchenhoff, Helmut; Fenske, Nora; Brill, Thomas; Hirschberger, Johannes

2007-01-01

Recombinant feline interferon-omega (rFeIFN-omega) was tested as a treatment option for cats with fibrosarcoma to assess safety and feasibility. Treatment with rFeIFN-omega in cats with fibrosarcoma is safe and feasible. Twenty domestic cats. In an open-labeled uncontrolled clinical trial 12 injections of 1 x 10(6) U/kg rFeIFN-omega were administered over a 5-week period: the 1st through 4th injections were given intratumorally, and the 5th through 12th injections were administered subcutaneously at the tumor excision site. Wide surgical excision of the tumors was carried out after the 4th injection and before the 5th injection of rFeIFN-omega. A Common Terminology Criteria for Adverse Events (CTCAE) analysis was conducted. Flow cytometry of fibrosarcoma cells after incubation with rFeIFN-omega and recombinant feline interferon-gamma was performed to assess the biological effect of rFeIFN-omega. Changes in blood cell count, increases in serum aspartate-amino-transferase activity, serum bilirubin concentration, serum creatinine and serum electrolyte concentrations, weight loss, anorexia, increased body temperature, and reduced general condition were observed but were mostly minor (grade 1 and 2) and self limiting. Eosinophilia (P = .025), neutropenia (P = .021), and weight loss (P < .001) were statistically correlated with rFeIFN-omega-treatment (analysis of parameters before treatment and after 3 injections of rFeIFN-omega). Flow cytometry of 5 unrelated feline fibrosarcoma cell lines showed increased expression of major histocompatibility complex (MHC) class I molecules (P = .026) in response to in vitro incubation with rFeIFN-omega, whereas expression of MHC class II molecules was not affected significantly. RFeIFN-omega for the treatment of feline fibrosarcoma is safe, well tolerated, and can be easily performed in practice. To assess the efficacy of the treatment, it should be tested in a placebo-controlled trial.

A phase II, open-label study of the efficacy and safety of imiquimod in the treatment of superficial and mixed infantile hemangioma.

PubMed

McCuaig, Catherine C; Dubois, Josée; Powell, Julie; Belleville, Claude; David, Michèle; Rousseau, Elisabeth; Gendron, Roxanne; Jafarian, Fatemeh; Auger, Isabelle

2009-01-01

To explore the efficacy and safety of imiquimod 5% cream as a treatment for infantile hemangioma. Phase II, open-label, noncomparative study of imiquimod applied during 16 weeks, with posttherapy follow-up 16 weeks later (8 months total). Outpatient pediatric tertiary care referral center in Quebec, Canada. Healthy infants up to 8.8 months of age with previously untreated, nonulcerated, proliferative superficial or mixed infantile hemangioma, excluding periorbital, or perineal localization, > or =100 cm2 in size. Topical imiquimod applied three to seven times per week for 16 weeks to infantile hemangioma. Lesion area, volume, depth (Doppler ultrasound), and color (erythema), serum drug, and interferon-alpha levels. Sixteen infants (11 girls, 5 boys) with a mean age at entry of 4.1 months and mean lesion area of 32.89 cm2, and volume of 39.98 cm3 were enrolled. Two participants discontinued treatment early, one for an adverse event (crying upon application), the other because of the lack of compliance. Local skin reactions were consistent with those reported in adults. Two cases had a decrease and three had an increase in lesion parameters; otherwise no meaningful changes in lesion area, volume, or depth were observed. At the 4-month posttreatment visit, 11 of 14 subjects had improvement in erythema (marginal homogeneity test = 2.668, p = 0.008). Measured serum drug and interferon-alpha levels were low or undetectable. Treatment of infants with infantile hemangioma with imiquimod up to seven times per week for 16 weeks was generally well tolerated with low systemic exposure. Improvement was observed in hemangioma coloration, but not lesion size, suggesting effects were limited to the superficial component.

Analysis of Serum Cytokine Profile in Pemphigus.

PubMed

Lee, Sang Hee; Hong, Won Jin; Kim, Soo-Chan

2017-08-01

Pemphigus is a group of autoimmune blistering diseases affecting skin and mucous membranes. While pemphigus is an autoantibody mediated disease, the role of T cells and cytokines in the pathogenesis is being increasingly recognized. This study was conducted to observe alterations in the serum cytokine levels of patients with pemphigus vulgaris (PV), pemphigus foliaceous (PF), paraneoplastic pemphigus (PNP) and compare with bullous pemphigoid (BP) and healthy subjects. A total of 75 subjects (28 PV, 13 PF, 7 PNP, 7 BP, and 20 healthy controls) were included, all patients in active disease state. Serum levels of interferon (IFN)-γ, interleukin (IL)-4, IL-6, IL-17A, IL-10, tumor necrosis factor (TNF)-α, and IL-8 were measured by enzyme-linked immunosorbent assay. The median concentration of IFN-γ was lower in PV and BP patients compared to control (0.77, 0.34 and 1.63 pg/ml, respectively). IL-6 and IL-10 was significantly higher in PNP patients compared to control (4.92 and 0.24 pg/ml for IL-6, 0.86 and <0.12 pg/ml for IL-10, respectively). IL-8 was increased significantly in PV and PNP patients compared with control (11.85, 31.5 and 8.31 pg/ml, respectively). For IL-4, IL-17A and TNF-α, no significant difference was observed between the five groups. The decreased level of IFN-γ in PV may imply suppressed Th1 response in the active disease stage. A Th2 predominant response is suggested in the active stage of PNP, with elevated serum levels of IL-6 and IL-10. Increased level of proinflammatory cytokine IL-8 is observed in the sera of PV and PNP patients.

Analysis of Serum Cytokine Profile in Pemphigus

PubMed Central

Lee, Sang Hee; Hong, Won Jin

2017-01-01

Background Pemphigus is a group of autoimmune blistering diseases affecting skin and mucous membranes. While pemphigus is an autoantibody mediated disease, the role of T cells and cytokines in the pathogenesis is being increasingly recognized. Objective This study was conducted to observe alterations in the serum cytokine levels of patients with pemphigus vulgaris (PV), pemphigus foliaceous (PF), paraneoplastic pemphigus (PNP) and compare with bullous pemphigoid (BP) and healthy subjects. Methods A total of 75 subjects (28 PV, 13 PF, 7 PNP, 7 BP, and 20 healthy controls) were included, all patients in active disease state. Serum levels of interferon (IFN)-γ, interleukin (IL)-4, IL-6, IL-17A, IL-10, tumor necrosis factor (TNF)-α, and IL-8 were measured by enzyme-linked immunosorbent assay. Results The median concentration of IFN-γ was lower in PV and BP patients compared to control (0.77, 0.34 and 1.63 pg/ml, respectively). IL-6 and IL-10 was significantly higher in PNP patients compared to control (4.92 and 0.24 pg/ml for IL-6, 0.86 and <0.12 pg/ml for IL-10, respectively). IL-8 was increased significantly in PV and PNP patients compared with control (11.85, 31.5 and 8.31 pg/ml, respectively). For IL-4, IL-17A and TNF-α, no significant difference was observed between the five groups. Conclusion The decreased level of IFN-γ in PV may imply suppressed Th1 response in the active disease stage. A Th2 predominant response is suggested in the active stage of PNP, with elevated serum levels of IL-6 and IL-10. Increased level of proinflammatory cytokine IL-8 is observed in the sera of PV and PNP patients. PMID:28761292

Hypothyroidism In Hepatitis C Patients On Pegylated Interferon Therapy.

PubMed

Hameed, Muhammad Asim; Mehmood, Asif; Farooq, Muhammad Ahsan; Tayyab, Ghias Un Nabi; Haq Toor, Israr Ul

2016-01-01

Chronic hepatitis has become a major health problem all over the world especially in the third world countries. The most common cause of chronic hepatitis in Pakistan is hepatitis C which can lead Toliver cirrhosis and hepatocellular carcinoma. In Pakistan Pegylated Interferon Alpha is still corner stone of therapy for chronic hepatitis C. One of the major side effects of this therapy is the development of thyroid dysfunction, i.e., hypothyroidism and hyperthyroidism. This study was done to assess the frequency of hypothyroidism in hepatitis C patients after three months of pegylated interferon therapy. This study was conducted from 1st October 2013 to 31st march 2014 at outpatients department (OPD) of Gastroenterology and Hepatology, Lahore General Hospital Lahore. Descriptive case series study design was used. The sample of 200 patients was taken from the patients who visited OPD and fulfil the inclusion criteria of the study. Serum thyroid stimulating hormone level (TSH) was done before and after completion of three months therapy at centre for Nuclear Medicine (CENUM) laboratory, Mayo Hospital, Lahore by immune-radiometric assay (IRMA) and patients having TSH>4.0 mIU/L (normal range: 0.2-4.0 mIU/L) were considered hypothyroid. The mean age of the patients was 36.29±8.5 years. One hundred and twenty-three (61.5%) were male and 77 (38.5%) were female. After 3 months of interferon therapy, 163 (81.5%) patients were euthyroid and 37(18.5%) patients were having thyroid dysfunction. There were total 29 (14.5%) hypothyroid patients; 8 (27.6%) were male and 21 (72.4%) female. It is concluded from this study that frequency of hypothyroidism in patients with chronic hepatitis C was 14.5% after treatment with pegylated interferon therapy for 3 months. Female patients were more prone to develop hypothyroidism as compared to male patients.

Comparison of antibody and cytokine responses to primary Giardia muris infection in H-2 congenic strains of mice.

PubMed

Venkatesan, P; Finch, R G; Wakelin, D

1996-11-01

The course of primary infections with Giardia muris differs between BALB and B10 H-2 congenic strains of mice. In the first 3 weeks of infection, there is a more rapid decline in intestinal trophozoite and fecal cyst counts in B10 strains than in BALB strains. To determine whether this difference could be explained by variation in specific antibody responses, both secretory immunoglobulin A (IgA) and serum antibody responses were compared between these strains. No significant differences in the timing, titer, or specificity of secretory or serum antibodies were found. However, on comparing specific anti-G. muris serum IgG subclass responses, we found that B10 strains produced IgG2a while BALB strains produced IgG1, suggesting differential involvement of T helper 1 and 2 subsets of lymphocytes. When cells harvested from mesenteric lymph nodes were stimulated with concanavalin A in vitro, both gamma interferon and interleukin-5 were secreted by cells from B10 mice, but only interleukin-5 was secreted by cells from BALB/c mice. Specific blockade of gamma interferon by monoclonal antibody administered to B10 mice resulted in an enhanced intensity of infection.

Association between sex, nutritional status, severity of dengue hemorrhagic fever, and immune status in infants with dengue hemorrhagic fever.

PubMed

Nguyen, Thanh Hung; Nguyen, Trong Lan; Lei, Huan-Yao; Lin, Yee-Shin; Le, Bich Lien; Huang, Kao-Jean; Lin, Chiou-Feng; Do, Quang Ha; Vu, Thi Que Huong; Lam, Thi My; Yeh, Trai-Ming; Huang, Jyh-Hsiung; Liu, Ching-Chuan; Halstead, Scott B

2005-04-01

The association between sex, nutritional status, and the severity of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), and immune status was investigated in 245 Vietnamese infants with predominantly primary infections with dengue virus. Male and female infants were at equal risk of developing DHF/DSS. However, infants of low height and weight for age were under-represented among DHF/DSS cases compared with 533 healthy baby clinic infant controls. Acute illness phase blood levels of selected cytokines (interferon-gamma and tumor necrosis factor-alpha) and serum levels of antibodies to dengue virus were elevated in the same range in male and female infants with DHF/DSS, as well as in infants with and without malnutrition.

Cytokines in relation to autoantibodies before onset of symptoms for systemic lupus erythematosus.

PubMed

Eriksson, C; Rantapää-Dahlqvist, S

2014-06-01

A number of cytokines and chemokines were analysed and related to autoantibodies in blood samples pre-dating the onset of symptoms of systemic lupus erythematosus. Thirty-five patients with systemic lupus erythematosus (American College of Rheumatology criteria) were identified as having donated blood samples, prior to symptom onset, to the Biobank of northern Sweden. Altogether, 140 age- and sex-matched controls were also identified. The concentrations of interferon-α, interleukin-4, interleukin-9, interleukin-10, interferon inducible protein-10 and monocyte chemotactic protein-1 were analysed using multiplex technology and related to autoantibodies (ANA, ENA, anti-dsDNA and anti-histone antibodies) analysed from the same blood sample. The interferon-γ inducible protein-10 levels were higher in the pre-symptomatic individuals than in controls (p < 0.05) and correlated with interferon-α (p < 0.01). The interferon-γ inducible protein-10 and interferon-α concentrations were significantly increased in individuals positive for autoantibodies: interferon-γ inducible protein-10 for ANA; anti-SSA/Ro and anti-Jo-1 antibodies; interferon-α with anti-SSB/La antibodies. The levels of interleukin-10, interferon-γ inducible protein-10 and monocyte chemotactic protein-1 increased significantly from the pre-symptomatic individuals to after onset of systemic lupus erythematosus. An increased concentration of interferon-γ inducible protein-10 pre-dated the onset of systemic lupus erythematosus and was related to autoantibodies before the onset of disease. The levels of interferon-γ inducible protein-10 and interferon-α were correlated. These findings support the proposal that the interferon system is important early in the pathogenesis of systemic lupus erythematosus and autoantibody formation. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Increased expression of Toll-like receptors (TLRs) 7 and 9 and other cytokines in systemic lupus erythematosus (SLE) patients: ethnic differences and potential new targets for therapeutic drugs.

PubMed

Lyn-Cook, Beverly D; Xie, Chenghui; Oates, Jarren; Treadwell, Edward; Word, Beverly; Hammons, George; Wiley, Kenneth

2014-09-01

Increased expression of pro-inflammatory cytokines such as interferon, tumor necrosis factors (TNFs) and specific interleukins (ILs) has been found in a number of autoimmune diseases, including systemic lupus erythematous (SLE). These cytokines are induced by toll-like receptors (TLRs). Toll-like receptors are activated in response to accumulation of apoptotic bodies. These receptors play critical roles in innate immune systems. Increased levels of interferon-alpha (INF-α) have also been found in many SLE patients and often correlate with disease severity. The objectives of this study were to examine the expression of selected TLRs and cytokines that have been identified in animal models and some limited human studies in a group of African Americans (AA) and European Americans (EA) women with lupus in comparison to age-matched non-lupus women. Blood samples were consecutively obtained by informed consent from 286 patients, 153 lupus and 136 non-lupus, seen in the rheumatology clinics at East Carolina University. Cytokines were analyzed from blood serum using enzyme linked immunoassay (ELISA) for IL-6 and INF-α. Total RNA was isolated, using a Paxgene kit, from peripheral blood mononuclear cells of African American and European American women blood samples. Quantitative real-time PCR using the CFX real-time system was conducted on all samples to determine TLRs 7 and 9, as well as INF-α expression. Toll-like receptor 7 (p<0.01) and 9 (p=0.001) expression levels were significantly increased in lupus patients compared to age-matched controls. African American women with lupus had a 2-fold increase in TLR-9 expression level when compared to their healthy controls or European American lupus patients. However, there was no ethnic difference in expression of TLR-7 in lupus patients. INF-α expression was significantly higher in lupus patients (p<0.0001) and also showed ethnic difference in expression. Serum levels revealed significant increases in expression of IL-6, IFN-γ and TNF-α in lupus patients compared to non-lupus patients. African American women with lupus had significantly higher serum levels of IL-6 and TNF-α. African American women with lupus demonstrated increased levels of specific pro-inflammatory cytokines and Toll-like receptors when compared to EA women. Increased expression in these lupus patients provides an opportunity for targeting with antagonist as a new therapy for systemic lupus erythematous. Published by Elsevier Ltd.

Direct-acting antiviral-based triple therapy on alpha-fetoprotein level in chronic hepatitis C patients

PubMed Central

Takayama, Koji; Furusyo, Norihiro; Ogawa, Eiichi; Ikezaki, Hiroaki; Shimizu, Motohiro; Murata, Masayuki; Hayashi, Jun

2015-01-01

AIM: To investigate the impact of telaprevir-based triple therapy on the serum alpha-fetoprotein (AFP) level of chronic hepatitis C patients. METHODS: A total of 210 patients with chronic hepatitis C genotype 1 of high viral load (baseline serum hepatitis C virus RNA > 5.0 log10 IU/mL) were divided into two groups by type of treatment: triple therapy with telaprevir, pegylated-interferon-α (PEG-IFNα), and ribavirin (RBV) for 24 wk (n = 88), or dual therapy with PEG-IFNα and RBV for 48 wk (n = 122). The relationship between virological response and the change in the serum AFP level from baseline to 24 wk after the end of treatment was examined. RESULTS: No significant difference in mean baseline AFP level was found between the triple and dual therapy groups (8.8 ng/mL vs 7.8 ng/mL). Triple therapy produced significant declines in the AFP level in sustained virological response (SVR) and non-SVR patients (7.8 ng/mL at baseline to 3.5 ng/mL at 24 wk after the end of treatment, P < 0.001 and 14.3 ng/mL to 9.5 ng/mL, P = 0.004, respectively). In contrast, dual therapy resulted in a significant decline in AFP level only in SVR patients (4.7 ng/mL to 2.8 ng/mL, P < 0.001), but not in non-SVR patients (10.2 ng/mL to 10.1 ng/mL). Among patients with a high-baseline AFP level (≥ 10 ng/mL), the decline in the AFP level was significantly higher in the triple therapy than in the dual therapy group (15.9 ng/mL vs 1.6 ng/mL, P = 0.037). CONCLUSION: Regardless of virological response, telaprevir-based triple therapy reduced the serum AFP level. PMID:25914481

Direct-acting antiviral-based triple therapy on alpha-fetoprotein level in chronic hepatitis C patients.

PubMed

Takayama, Koji; Furusyo, Norihiro; Ogawa, Eiichi; Ikezaki, Hiroaki; Shimizu, Motohiro; Murata, Masayuki; Hayashi, Jun

2015-04-21

To investigate the impact of telaprevir-based triple therapy on the serum alpha-fetoprotein (AFP) level of chronic hepatitis C patients. A total of 210 patients with chronic hepatitis C genotype 1 of high viral load (baseline serum hepatitis C virus RNA > 5.0 log10 IU/mL) were divided into two groups by type of treatment: triple therapy with telaprevir, pegylated-interferon-α (PEG-IFNα), and ribavirin (RBV) for 24 wk (n = 88), or dual therapy with PEG-IFNα and RBV for 48 wk (n = 122). The relationship between virological response and the change in the serum AFP level from baseline to 24 wk after the end of treatment was examined. No significant difference in mean baseline AFP level was found between the triple and dual therapy groups (8.8 ng/mL vs 7.8 ng/mL). Triple therapy produced significant declines in the AFP level in sustained virological response (SVR) and non-SVR patients (7.8 ng/mL at baseline to 3.5 ng/mL at 24 wk after the end of treatment, P < 0.001 and 14.3 ng/mL to 9.5 ng/mL, P = 0.004, respectively). In contrast, dual therapy resulted in a significant decline in AFP level only in SVR patients (4.7 ng/mL to 2.8 ng/mL, P < 0.001), but not in non-SVR patients (10.2 ng/mL to 10.1 ng/mL). Among patients with a high-baseline AFP level (≥ 10 ng/mL), the decline in the AFP level was significantly higher in the triple therapy than in the dual therapy group (15.9 ng/mL vs 1.6 ng/mL, P = 0.037). Regardless of virological response, telaprevir-based triple therapy reduced the serum AFP level.

Type I interferon and pattern recognition receptor signaling following particulate matter inhalation

PubMed Central

2012-01-01

Background Welding, a process that generates an aerosol containing gases and metal-rich particulates, induces adverse physiological effects including inflammation, immunosuppression and cardiovascular dysfunction. This study utilized microarray technology and subsequent pathway analysis as an exploratory search for markers/mechanisms of in vivo systemic effects following inhalation. Mice were exposed by inhalation to gas metal arc – stainless steel (GMA-SS) welding fume at 40 mg/m3 for 3 hr/d for 10 d and sacrificed 4 hr, 14 d and 28 d post-exposure. Whole blood cells, aorta and lung were harvested for global gene expression analysis with subsequent Ingenuity Pathway Analysis and confirmatory qRT-PCR. Serum was collected for protein profiling. Results The novel finding was a dominant type I interferon signaling network with the transcription factor Irf7 as a central component maintained through 28 d. Remarkably, these effects showed consistency across all tissues indicating a systemic type I interferon response that was complemented by changes in serum proteins (decreased MMP-9, CRP and increased VCAM1, oncostatin M, IP-10). In addition, pulmonary expression of interferon α and β and Irf7 specific pattern recognition receptors (PRR) and signaling molecules (Ddx58, Ifih1, Dhx58, ISGF3) were induced, an effect that showed specificity when compared to other inflammatory exposures. Also, a canonical pathway indicated a coordinated response of multiple PRR and associated signaling molecules (Tlr7, Tlr2, Clec7a, Nlrp3, Myd88) to inhalation of GMA-SS. Conclusion This methodological approach has the potential to identify consistent, prominent and/or novel pathways and provides insight into mechanisms that contribute to pulmonary and systemic effects following toxicant exposure. PMID:22776377

Type I interferon and pattern recognition receptor signaling following particulate matter inhalation.

PubMed

Erdely, Aaron; Antonini, James M; Salmen-Muniz, Rebecca; Liston, Angie; Hulderman, Tracy; Simeonova, Petia P; Kashon, Michael L; Li, Shengqiao; Gu, Ja K; Stone, Samuel; Chen, Bean T; Frazer, David G; Zeidler-Erdely, Patti C

2012-07-09

Welding, a process that generates an aerosol containing gases and metal-rich particulates, induces adverse physiological effects including inflammation, immunosuppression and cardiovascular dysfunction. This study utilized microarray technology and subsequent pathway analysis as an exploratory search for markers/mechanisms of in vivo systemic effects following inhalation. Mice were exposed by inhalation to gas metal arc - stainless steel (GMA-SS) welding fume at 40 mg/m3 for 3 hr/d for 10 d and sacrificed 4 hr, 14 d and 28 d post-exposure. Whole blood cells, aorta and lung were harvested for global gene expression analysis with subsequent Ingenuity Pathway Analysis and confirmatory qRT-PCR. Serum was collected for protein profiling. The novel finding was a dominant type I interferon signaling network with the transcription factor Irf7 as a central component maintained through 28 d. Remarkably, these effects showed consistency across all tissues indicating a systemic type I interferon response that was complemented by changes in serum proteins (decreased MMP-9, CRP and increased VCAM1, oncostatin M, IP-10). In addition, pulmonary expression of interferon α and β and Irf7 specific pattern recognition receptors (PRR) and signaling molecules (Ddx58, Ifih1, Dhx58, ISGF3) were induced, an effect that showed specificity when compared to other inflammatory exposures. Also, a canonical pathway indicated a coordinated response of multiple PRR and associated signaling molecules (Tlr7, Tlr2, Clec7a, Nlrp3, Myd88) to inhalation of GMA-SS. This methodological approach has the potential to identify consistent, prominent and/or novel pathways and provides insight into mechanisms that contribute to pulmonary and systemic effects following toxicant exposure.

Disseminated Kaposi's Sarcoma in Patients with HIV Infection Correlates to High Serum Levels of IL-10

PubMed Central

Farias, Kleber Juvenal Silva; Genre, Julieta; Oliveira, Carlo José Freire; Guedes, Paulo Marcos Matta; da Fonseca, Benedito Antônio Lopes

2014-01-01

Abstract Human herpesvirus 8 (HHV-8) is the etiologic agent of all Kaposi's sarcoma (KS), the outcome of which is associated with immuno-dysregulation, resulting in the abnormal production of inflammatory cytokines and chemokines. We quantified by enzyme-linked immunosorbent assay serum levels of interleukin (IL)-10, IL-17, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α from patients with KS-AIDS, classic KS, and human immunodeficiency virus (HIV) without KS. A correlation between HHV-8 molecular detection and cytokine production was also performed. We observed that IL-10 production was higher in patients with KS-AIDS when compared to those with classic KS or HIV. However, no significant differences were seen for IFN-γ, TNF-α, or IL-17 production between studied groups. When patients with KS-AIDS were analyzed according to lesion topography, IL-10 levels were higher in patients with disseminated disease than those observed in patients with only cutaneous lesions or cutaneous and digestive and/or respiratory tract lesions. Finally, patients with KS-AIDS that presented viral DNA for HHV-8 in serum showed a higher production of IL-10 when compared with those patients with a negative result for nested polymerase chain reaction for the virus. The results presented here are the first to demonstrate that there exists a stratification of patients with KS-AIDS according to lesion topography where IL-10 levels are higher in those individuals with disseminated disease than those with only localized lesions. PMID:25026101

Multiplex giant magnetoresistive biosensor microarrays identify interferon-associated autoantibodies in systemic lupus erythematosus

NASA Astrophysics Data System (ADS)

Lee, Jung-Rok; Haddon, D. James; Wand, Hannah E.; Price, Jordan V.; Diep, Vivian K.; Hall, Drew A.; Petri, Michelle; Baechler, Emily C.; Balboni, Imelda M.; Utz, Paul J.; Wang, Shan X.

2016-06-01

High titer, class-switched autoantibodies are a hallmark of systemic lupus erythematosus (SLE). Dysregulation of the interferon (IFN) pathway is observed in individuals with active SLE, although the association of specific autoantibodies with chemokine score, a combined measurement of three IFN-regulated chemokines, is not known. To identify autoantibodies associated with chemokine score, we developed giant magnetoresistive (GMR) biosensor microarrays, which allow the parallel measurement of multiple serum antibodies to autoantigens and peptides. We used the microarrays to analyze serum samples from SLE patients and found individuals with high chemokine scores had significantly greater reactivity to 13 autoantigens than individuals with low chemokine scores. Our findings demonstrate that multiple autoantibodies, including antibodies to U1-70K and modified histone H2B tails, are associated with IFN dysregulation in SLE. Further, they show the microarrays are capable of identifying autoantibodies associated with relevant clinical manifestations of SLE, with potential for use as biomarkers in clinical practice.

Comparison of interferon and bovine herpesvirus-1-specific IgA levels in nasal secretions of dairy cattle administered an intranasal modified live viral vaccine prior to calving or on the day of calving.

PubMed

Cortese, Victor S; Woolums, Amelia; Hurley, David J; Berghaus, Roy; Bernard, John K; Short, Thomas H

2017-05-01

Thirty-two Holstein cows were allocated to receive intranasal vaccination with modified live bovine herpesvirus-1 (BHV-1), bovine respiratory syncytial virus (BRSV) and parainfluenza type 3 virus (PI3V) vaccine either two weeks prior to their projected calving date, or within 24h after calving. Nasal secretions were collected twice at a 12-h interval on the day prior to vaccination (day 0) and at 2, 4, 7, 10 and 14days post vaccination to measure interferon (IFN) alpha, IFN-beta, IFN-gamma, and BHV-1-specific IgA by ELISA. Serum neutralizing antibody titers to BHV-1 and BRSV were measured on days 0, 7, and 14. There was a significant treatment effect (p<0.0004) and interaction (p<0.05) on nasal BHV-1 IgA levels, with higher IgA levels in cows vaccinated within 24h after calving. There was a significant treatment effect on nasal IFN-gamma concentration (p<0.05) and on nasal total IFN concentration (p<0.05), with higher IFN-gamma and total IFN concentrations seen in cows vaccinated within 24h after calving. There was no significant treatment or interaction effect on nasal IFN-alpha or IFN-beta concentrations, or on serum neutralizing titers to BRSV. In spite of prior viral vaccination during the previous lactation, cows vaccinated on the day of calving responded to an intranasal viral vaccination with increased concentrations of IFN-gamma and increased titers of IgA following vaccination which was significantly higher than cows vaccinated precalving. This study is the first to examine respiratory mucosal responses in immunologically mature dairy cattle vaccinated intranasally before and after calving. Copyright © 2017. Published by Elsevier B.V.

Changes in cytokine and chemokine expression distinguish dysthymic disorder from major depression and healthy controls.

PubMed

Ho, Pei-Shen; Yen, Che-Hung; Chen, Chun-Yen; Huang, San-Yuan; Liang, Chih-Sung

2017-02-01

An important area of uncertainty is the inflammatory degree to which depression occurring as part of dysthymic disorder may differ from major depression. Using a 27-plex cytokine assay, we analyzed the serum of 12 patients with dysthymic disorder, 12 with major depression, and an age-, sex-, and body mass index-matched control group of 20 healthy volunteers. We observed that patients with dysthymic disorder exhibited aberrant cytokine and chemokine expression compared with healthy controls and patients with major depression. The levels of interferon-γ-induced protein 10 highly predicted dysthymic disorder. Network analyses revealed that in patients with dysthymic disorder, the vertices were more sparsely connected and adopted a more hub-like architecture, and the connections from neighboring vertices of interleukin 2 and eotaxin-1 increased. After treatment with the same antidepressant, there was no difference between dysthymic disorder and major depression regarding any of the cytokines or chemokines analyzed. For dysthymic disorder, changes in the levels of interferon-γ-induced protein 10 and macrophage inflammatory protein-1α correlated with depression improvement. The findings suggest that the cytokine milieu in dysthymic disorder differs either at the level of individual expression or in network patterns. Moreover, chemokines play an important role in driving the pathophysiology of dysthymic disorder. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Extended follow-up of anti-HBe-positive patients with chronic hepatitis B retreated with ribavirin and interferon-alpha.

PubMed

Carreño, V; Rico, M A; Pardo, M; Quiroga, J A

2001-11-01

In a pilot study of combination therapy with ribavirin and IFN alpha conducted in anti-HBe-positive individuals with chronic hepatitis B, 21% of patients achieved a sustained ALT normalization and clearance of hepatitis B virus (HBV) DNA as measured by PCR. The present work has assessed whether these sustained responses are lasting long-term. In addition, IFN gamma levels were tested serially in serum as a measure of the immune system activation during treatment. By extending the post-treatment follow-up period 2 years the occurrence of delayed HBV DNA relapses was observed. A low serum level of IFN gamma was detected during and after treatment. IFN gamma demonstrated a multiphasic time-course: the amount of IFN gamma increased in parallel with reductions in HBV DNA but also with ALT flare-ups. In conclusion, the extended follow-up study of anti-HBe-positive patients after combined treatment with ribavirin and IFN alpha has shown that sustained responses are lasting in 17% patients but also that a late onset HBV DNA relapse may occur.

The inhibitory effect of naringenin on atopic dermatitis induced by DNFB in NC/Nga mice.

PubMed

Kim, Tae-Ho; Kim, Gun-Dong; Ahn, Hyun-Jong; Cho, Jeong-Je; Park, Yong Seek; Park, Cheung-Seog

2013-10-10

Atopic dermatitis (AD) is a chronic and relapsing inflammatory dermatitis characterized by pruritic and eczematous skin lesions. Here, we investigated the therapeutic effect of the fruit flavonoid naringenin on DNFB induced atopic dermatitis mice model. AD-like skin lesion was induced by repetitive skin contact with DNFB in NC/Nga mice and the effects of the fruit flavonoid naringenin were evaluated on the basis of histopathological findings of skin, ear swelling and cytokine production of CD4(+)T cells. Intraperitoneal injection of naringenin for one week after DNFB challenge significantly lowered ear swelling and improved back skin lesions. In addition, naringenin significantly suppressed production of interferon-gamma (IFN-γ) by activated CD4(+) T cells and serum IgE level. Furthermore, naringenin reduced DNFB-induced infiltration of eosinophils, mast cells, CD4(+) T cells, and CD8(+) T cells in skin lesions. Naringenin may suppress the development of AD-like skin lesions in DNFB-treated NC/Nga mice by reducing IFN-γ production of activated CD4(+) T cells, serum IgE levels and infiltration of immune cells to skin lesion. © 2013.

Comparing the Effects of Combined General/Epidural Anaesthesia and General Anaesthesia on Serum Cytokine Levels in Radical Cystectomy

PubMed Central

Karadeniz, Meltem Savran; Mammadov, Orkhan; Çiftci, Hayriye Şentürk; Usta, Sebahat Akgül; Pembeci, Kamil

2017-01-01

Objective Surgical stress combined with general anaesthesia (GA) suppresses the immune system and leads to cancer cell growth and premature metastasis in major oncological interventions. Epidural analgesia decreases the need for inhalation agents and opioids during surgery by suppressing sympathetic and neuroendocrine responses in the postoperative period. This study aimed to compare the effects of combined general/epidural anaesthesia (GEA)+patient-controlled epidural analgesia (PCEA) and GA+IV patient-controlled analgesia (PCA) on serum tumour necrosis factor-alpha TNF-α), interleukin-1 beta (IL-1β) and interferon-gamma (IFN-γ) levels in patients undergoing radical cystectomy. Methods Sixty-five patients were enrolled in this prospective study. Patients were randomly enrolled to the GEA group, i.e., combined GEA+ PCEA (0.1% bupivacaine+1 μg mL−1 fentanyl), and the GA group, namely combined GA+IV PCA (0.03 mg mL−1 morphine). To evaluate the cytokine response, blood samples were collected at preoperative, postoperative 1st and 24th hours. Results There was no statistically significant difference in serum TNF-α, IL-1β and IFN-γ levels between groups GA and GEA at preoperative and postoperative 1st hour and 24th hour. Total remifentanil consumption was significantly lower and length of hospital stay was significantly shorter in the GEA group than in the GA group (p<0.05). Conclusion There is no difference between two anaesthesia methods in terms of serum cytokine levels; however, combined GEA+PCEA technique appeared to be superior to GA+IV PCA because of lower intraoperative narcotic analgesic consumption and shorter hospital stay. PMID:28868167

Preventive activity of banana peel polyphenols on CCl4-induced experimental hepatic injury in Kunming mice.

PubMed

Wang, Rui; Feng, Xia; Zhu, Kai; Zhao, Xin; Suo, Huayi

2016-05-01

The aim of the present study was to evaluate the preventive effects of banana peel polyphenols (BPPs) against hepatic injury. Mice were divide into normal, control, 100 mg/kg and 200 mg/kg banana peel polyphenol and silymarin groups. All the mice except normal mice were induced with hepatic damage using CCl 4 . The serum and tissue levels of mice were determined by a kit and the tissues were further examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. BPPs reduced the serum levels of aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase in a CCl 4 -induced mouse model of hepatic injury. Furthermore, BPPs reduced the levels of malondialdehyde and triglyceride, while increasing glutathione levels in the serum and liver tissues of mice. In addition, the effects of 200 mg/kg treatment were more evident, and these effects were comparable to those of the drug silymarin. Serum levels of the cytokines, interleukin (IL)-6, IL-12, tumor necrosis factor (TNF)-α and interferon-γ, were reduced in the mice treated with BPPs compared with injury control group mice, and these levels were comparable to those of the normal and silymarin-treated groups. Histopathological examination indicated that BPPs were able to reduce the extent of CCl 4 -induced liver tissue injury and protect the liver cells. Furthermore, the mRNA and protein expression levels of the inflammation-associated factors cyclooxygenase-2, nitric oxide synthase, TNF-α and IL-1β were reduced in mice treated with BPPs compared with the control group mice. Mice that received 200 mg/kg BPP exhibited reduced expression levels of these factors compared with mice that received 100 mg/kg BPP. In conclusion, the results of the present study suggested that BPPs exert a good preventive effect against hepatic injury.

Immunosuppressive and antiviral treatment of hepatitis C virus-associated glomerular disease: A long-term follow-up.

PubMed

Fabrizi, Fabrizio; Aghemo, Alessio; Lampertico, Pietro; Fraquelli, Mirella; Cresseri, Donata; Moroni, Gabriella; Passerini, Patrizia; Donato, Francesca M; Messa, Piergiorgio

2018-06-01

The evidence in the medical literature on the treatment of hepatitis C virus-associated glomerular disease is extremely limited. The advent of nonconventional immunosuppressive agents and direct-acting antivirals promises high efficacy and safety. We conducted an open-label, single-arm clinical study to examine the efficacy and safety of a combined approach for hepatitis C virus-associated glomerular disease. In the first phase of the study, patients with hepatitis C virus-associated glomerular disease received interferon-based antiviral therapy and immunosuppressive agents; since 2013, interferon-free antiviral therapy was adopted and novel immunosuppressants (including B-cell depleting agents and mycophenolate mofetil) or immunomodulators (ribavirin) were choiced. Virological and clinical responses were evaluated over a long observation period (median follow-up of 60 weeks and 46.5 months after the end of treatment with interferon and direct-acting antiviral agents, respectively). We enrolled 25 consecutive patients with hepatitis C virus-associated glomerular disease, 8 being liver transplant recipients for hepatitis C. A total of 13 patients received therapy with direct-acting antivirals and experienced sustained viral response (serum hepatitis C virus RNA <12 IU/mL, 12 weeks after treatment ended, sustained viral response12). The mean (±standard deviation) proteinuria decreased from 2.61 ± 1.01 at baseline to 1.71 ± 1.43 (g/day) at sustained viral response 48, p = 0.031; microscopic hematuria and serum cryoglobulins disappeared in six (50%) and seven (64%) patients, respectively, after sustained viral response by direct-acting antivirals. Adverse events occurred in 69% (9/13) of patients and were mild, with four cases of ribavirin-related anemia requiring blood transfusions (no drop-outs). After sustained viral response by direct-acting antivirals, immunosuppressive and immunomodulatory agents were initiated in clinical relapsers ( n = 2) and nonresponders ( n = 3) with some benefit. Among patients on interferon-based regimens ( n = 12), viral response (sustained viral response 24) and dropout rates were 58% (7/12) and 33% (4/12), respectively. After sustained viral response by interferon-based therapy, clinical relapsers ( n = 3) were successfully managed with immunosuppressive agents in two patients. Treatment with direct-acting antivirals provides excellent rates of viral response and safety in patients with hepatitis C virus-related glomerular disease; viral response was frequently accompanied by clinical improvement. The absence of hepatitis C virus RNA from serum allowed immunosuppressive and immunomodulatory therapies with benefits for glomerular abnormalities and no concern on hepatitis C virus replication.

Pegylated interferons Lambda-1a and alfa-2a display different gene induction and cytokine and chemokine release profiles in whole blood, human hepatocytes and peripheral blood mononuclear cells.

PubMed

Freeman, J; Baglino, S; Friborg, J; Kraft, Z; Gray, T; Hill, M; McPhee, F; Hillson, J; Lopez-Talavera, J C; Wind-Rotolo, M

2014-06-01

Pegylated interferon-lambda-1a (Lambda), a type III interferon (IFN) in clinical development for the treatment of chronic HCV infection, has shown comparable efficacy and an improved safety profile to a regimen based on pegylated IFN alfa-2a (alfa). To establish a mechanistic context for this improved profile, we investigated the ex vivo effects of Lambda and alfa on cytokine and chemokine release, and on expression of IFN-stimulated genes (ISGs) in primary human hepatocytes and peripheral blood mononuclear cells (PBMCs) from healthy subjects. Our findings were further compared with changes observed in blood analysed from HCV-infected patients treated with Lambda or alfa in clinical studies. mRNA transcript and protein expression of the IFN-λ-limiting receptor subunit was lower compared with IFN-α receptor subunits in all cell types. Upon stimulation, alfa and Lambda induced ISG expression in hepatocytes and PBMCs, although in PBMCs Lambda-induced ISG expression was modest. Furthermore, alfa and Lambda induced release of cytokines and chemokines from hepatocytes and PBMCs, although differences in their kinetics of induction were observed. In HCV-infected patients, alfa treatment induced ISG expression in whole blood after single and repeat dosing. Lambda treatment induced modest ISG expression after single dosing and showed no induction after repeat dosing. Alfa and Lambda treatment increased IP-10, iTAC, IL-6, MCP-1 and MIP-1β levels in serum, with alfa inducing higher levels of all mediators compared with Lambda. Overall, ex vivo and in vivo induction profiles reported in this analysis strongly correlate with clinical observations of fewer related adverse events for Lambda vs those typically associated with alfa. © 2014 John Wiley & Sons Ltd.

Results of space experiment program "Interferon". II. Influence of spaceflight conditions on the activity of interferon preparations and interferon inducers ("Interferon II").

PubMed

Tálas, M; Bátkai, L; Stöger, I; Nagy, K; Hiros, L; Konstantinova, I; Kozharinov, V

1983-01-01

The influence of spaceflight conditions on the biological activity of HuIFN-alpha preparations (lyophilized, in solution and in ointment) and interferon inducers was studied. In antiviral activity no difference was observed between the samples kept aboard the spaceship and the controls kept under ground conditions. The interferon inducers poly I:C, poly G:C and gossipol placed in the space laboratory for 7 days maintained their interferon-inducing capacity. The circulating interferon level in mice was the same irrespective of the induction being performed with flight or ground-control samples of inducers.

Oral dydrogesterone treatment during early pregnancy to prevent recurrent pregnancy loss and its role in modulation of cytokine production: a double-blind, randomized, parallel, placebo-controlled trial.

PubMed

Kumar, Ashok; Begum, Nargis; Prasad, Sudha; Aggarwal, Sarita; Sharma, Shashi

2014-11-01

To study the impact of administration of dydrogesterone in early pregnancy on pregnancy outcome and its correlation with Th1 and Th2 cytokine levels. Double-blind, randomized, placebo-controlled study. A medical college and its associated hospital. Women with either: [1] a history of idiopathic recurrent pregnancy loss (RPL), in either a dydrogesterone group or a placebo group, or [2] no history of miscarriage. Dydrogesterone 20 mg/day from confirmation of pregnancy to 20 weeks of gestation. Occurrence of another pregnancy loss and concentrations of T-helper (Th)1 (interferon-γ and tumor necrosis factor-α) and Th2 (interleukin (IL)-4 and IL-10) cytokines in serum at recruitment (4-8 weeks of gestation) and at abortion or 20 weeks of gestation, using commercially available ELISA kits. Occurrence of another abortion after 3 consecutive abortions was significantly higher (29 of 173; 16.76%) in women with RPL compared with healthy pregnant controls (6 of 174; 3.45%). Risk of occurrence of miscarriage after 3 abortions was 2.4 times higher in the placebo group vs. the treatment group (risk ratio=2.4, 95% CI=1.3-5.9). Mean gestational age at delivery (excluding those aborted before 20 weeks of gestation) increased significantly in the dydrogesterone group (38.01±1.96 weeks) compared with the placebo group (37.23±2.41 weeks). Baby weight was significantly lower in the placebo group (2421.4±321.6 g) compared with the healthy pregnant controls (2545.3±554.3 g). At recruitment, serum IL-4 and tumor necrosis factor-α levels were significantly lower in the RPL group compared with the healthy pregnant controls. However, serum interferon-γ level was significantly higher in the RPL group (8.87±0.72 pg/mL) compared with the healthy pregnant controls (8.08±1.27 pg/mL). The present study supports the use of dydrogesterone in women with recurrent abortions to improve pregnancy outcome, such as a reduction in abortions and improved gestational age and baby weight at delivery. However, these outcomes were not modulated by Th1 and Th2 cytokine production. CTRI/2010/091/000373. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Immune function and brain abnormalities in patients with systemic lupus erythematosus without overt neuropsychiatric manifestations.

PubMed

Kozora, E; Filley, C M; Zhang, L; Brown, M S; Miller, D E; Arciniegas, D B; Pelzman, J L; West, S G

2012-04-01

This study examined the relationship between immune, cognitive and neuroimaging assessments in subjects with systemic lupus erythematosus (SLE) without histories of overt neuropsychiatric (NP) disorders. In total, 84 subjects with nonNPSLE and 37 healthy controls completed neuropsychological testing from the American College of Rheumatology SLE battery. Serum autoantibody and cytokine measures, volumetric magnetic resonance imaging, and magnetic resonance spectroscopy data were collected on a subset of subjects. NonNPSLE subjects had lower scores on measures of visual/complex attention, visuomotor speed and verbal memory compared with controls. No clinically significant differences between nonNPSLE patients and controls were found on serum measures of lupus anticoagulant, anticardiolipin antibodies, beta 2-glycoproteins, or pro-inflammatory cytokines (interleukin (IL)-1, IL-6, interferon alpha (IFN-alpha), and interferon gamma (IFN-gamma)). Higher scores on a global cognitive impairment index and a memory impairment index were correlated with lower IFN-alpha. Few associations between immune functions and neuroimaging parameters were found. Results indicated that nonNPSLE patients demonstrated cognitive impairment but not immune differences compared with controls. In these subjects, who were relatively young and with mild disease, no relationship between cognitive dysfunction, immune parameters, or previously documented neuroimaging abnormalities were noted. Immune measures acquired from cerebrospinal fluid instead of serum may yield stronger associations.

High-Dose Intravenous Ribavirin Therapy for Subacute Sclerosing Panencephalitis

PubMed Central

Hosoya, Mitsuaki; Shigeta, Shiro; Mori, Shuichi; Tomoda, Akemi; Shiraishi, Seiji; Miike, Teruhisa; Suzuki, Hitoshi

2001-01-01

Two patients with subacute sclerosing panencephalitis (SSPE) were treated safely and effectively with high doses of intravenous ribavirin combined with intraventricular alpha interferon. The ribavirin concentrations maintained in the serum and cerebrospinal fluid were higher than those which inhibit SSPE virus replication in vitro and in vivo. PMID:11181386

Distribution of the HLA class I allele in chronic hepatitis C and its association with serum ALT level in chronic hepatitis C.

PubMed

Kondo, Yasuteru; Kobayashi, Koju; Kobayashi, Tomoo; Shiina, Masaaki; Ueno, Yoshiyuki; Satoh, Takaomi; Shimosegawa, Tooru

2003-10-01

An essential process for resolution of viral infections is the efficient recognition and elimination of intracellular virus. Recognition of viral antigens in the form of short peptides associated with HLA class I molecule is a major task of CD8+ cytotoxic T lymphocytes. In this study, we have evaluated the frequency of the HLA class I alleles in patients with chronic hepatitis C. HLA-B51, -B52, -B55, -B56, -B61, B70, -Cw1, -Cw3, and -Cw4 are less frequent in patients with chronic hepatitis C than in Japanese individuals. The frequency of HLA-A2 is slightly lower in the patients but tends to be higher in patients with normal alanine aminotransferase (ALT) level than in those with elevated ALT level (p = 0.07). Other HLA alleles are not significantly different between two groups. Comparison of HLA homozygosity at HLA-A and -B or -C or at two or three loci did not show a significant association with levels of serum ALT or with the clinical outcome of interferon therapy in patients with hepatitis C. These results suggest a possibility that the alterations of host response, which depends on genetic background, influence disease activities of HCV infection.

Interferon-gamma alone triggers the production of nitric oxide from serum-starved BNL CL.2, murine embryonic liver cells.

PubMed

Pae, H O; Yoo, J C; Choi, B M; Paik, S G; Kim, Y H; Jin, H S; Chung, H T

1999-01-01

A previous study has demonstrated that both interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS) were needed to induce the production of nitric oxide (NO) in BNL CL.2 cells, murine embryonic liver cells. We here demonstrate that when BNL CL.2 cells were cultured with serum-free medium, they were induced to produce NO by the stimulation of IFN-gamma alone. BNL CL.2 cells were cultured with serum-free or serum-containing medium for 1-3 days and then stimulated to synthesize NO by IFN-gamma. Surprisingly, only serum-starved cells showed significant amount of nitrite accumulation and iNOS protein expression in response to IFN-gamma in dose- and time-dependent manners, but serum-supplied cells did not. When the cells were stimulated with IFN-gamma, tumor necrosis factor-alpha (TNF-alpha), or LPS in combinations, only the combination of IFN-gamma and LPS produced more NO than that produced by IFN-gamma alone. The production of NO by the cells stimulated with IFN-gamma or IFN-gamma plus LPS was blocked by the addition of N(G)-monomethyl-L-arginine (N(G)MMA), a NO synthesis inhibitor. To address the intracellular signal pathway responsible for the production of NO by the cells stimulated with IFN-gamma aloneor IFN-gamma plus LPS, we examined the effects of several protein kinase inhibitors on the production of NO from the cells. The production of NO was significantly inhibited by protein tyrosine kinase (PTK) inhibitors, genistein and herbimycin A, but not by protein kinase A or C inhibitors. These results suggest that the deprivation of serum from BNL CL.2 cell culture medium might prime the cells to induce NO synthesis when the cells are triggered by IFN-gamma and the involvement of PTK signal transduction pathway in the expression of inducible NO synthase gene in murine hepatoma cells.

Hepatoprotective Effect of Wedelolactone against Concanavalin A-Induced Liver Injury in Mice.

PubMed

Luo, Qingqiong; Ding, Jieying; Zhu, Liping; Chen, Fuxiang; Xu, Lili

2018-05-08

Eclipta prostrata L. is a traditional Chinese herbal medicine that has been used in the treatment of liver diseases. However, its biological mechanisms remain elusive. The current study aimed to investigate the hepatoprotective effect of wedelolactone, a major coumarin ingredient of Eclipta prostrata L., on immune-mediated liver injury. Using the well-established animal model of Concanavalin A (ConA)-induced hepatitis (CIH), we found that pretreatment of mice with wedelolactone markedly reduced both the serum levels of transaminases and the severity of liver damage. We further investigated the mechanisms of the protective effect of wedelolactone. In mice treated with wedelolactone prior to the induction of CIH, increases of serum concentrations of tumor necrosis factor (TNF)-[Formula: see text], interferon (IFN)-[Formula: see text], and interleukin (IL)-6 were dramatically attenuated. Additionally, expressions of the interferon-inducible chemokine (C-X-C motif) ligand 10 gene CXCL10 and intercellular adhesion molecule 1 gene ICAM1 were lower in livers of the treated mice. Moreover, wedelolactone-treated CIH mice exhibited reduced leukocyte infiltration and T-cell activation in liver. Furthermore, wedelolactone suppressed the activity of nuclear factor-kappa B (NF-[Formula: see text]B), a critical transcriptional factor of the above-mentioned inflammatory cytokines by limiting the phosphorylation of I kappa B alpha (I[Formula: see text]B[Formula: see text] and p65. In conclusion, these findings demonstrate the inhibitory potential of wedelolactone in immune-mediated liver injury in vivo, and show that this protection is associated with modulation of the NF-[Formula: see text]B signaling pathway.

Cytokine correlations in youth with tic disorders.

PubMed

Parker-Athill, E Carla; Ehrhart, Jared; Tan, Jun; Murphy, Tanya K

2015-02-01

Studies have noted immunological disruptions in patients with tic disorders, including increased serum cytokine levels. This study aimed to determine whether or not cytokine levels could be correlated with tic symptom severity in patients with a diagnosed tic disorder. Twenty-one patients, ages 4-17 years (average 10.63±2.34 years, 13 males), with a clinical diagnosis of Tourette's syndrome (TS) or chronic tic disorder (CTD), were selected based on having clinic visits that coincided with a tic symptom exacerbation and a remission. Ratings of tic severity were assessed using the Yale Global Tic Severity Scale (YGTSS) and serum cytokine levels (interleukin [IL]-2, IL-4, IL-5, IL-10, IL-12p70, IL-13, interferon [IFN]-γ, tumor necrosis factor [TNF]-α, and granulocyte macrophage-colony stimulating factor [GM-CSF]) were measured using Luminex xMAP technology. During tic symptom exacerbation, patients had higher median serum TNF-α levels (z=-1.962, p=0.05), particularly those on antipsychotics (U=9.00, p=0.033). Increased IL-13 was also associated with antipsychotic use during exacerbation (U=4.00, p=0.043) despite being negatively correlated to tic severity scores (ρ=-0.599, p=018), whereas increased IL-5 was associated with antibiotic use (U=6.5, p=0.035). During tic symptom remission, increased serum IL-4 levels were associated with antipsychotic (U=6.00, p=0.047) and antibiotic (U=1.00, p=0.016) use, whereas increased IL-12p70 (U=4.00, p=0.037) was associated with antibiotic use. These findings suggest a role for cytokine dysregulation in the pathogenesis of tic disorders. It also points toward the mechanistic involvement and potential diagnostic utility of cytokine monitoring, particularly TNF-α levels. Larger, systematic studies are necessary to further delineate the role of cytokines and medication influences on immunological profiling in tic disorders.

Cytokine Correlations in Youth with Tic Disorders

PubMed Central

Parker-Athill, E. Carla; Ehrhart, Jared; Tan, Jun

2015-01-01

Abstract Background: Studies have noted immunological disruptions in patients with tic disorders, including increased serum cytokine levels. This study aimed to determine whether or not cytokine levels could be correlated with tic symptom severity in patients with a diagnosed tic disorder. Methods: Twenty-one patients, ages 4–17 years (average 10.63±2.34 years, 13 males), with a clinical diagnosis of Tourette's syndrome (TS) or chronic tic disorder (CTD), were selected based on having clinic visits that coincided with a tic symptom exacerbation and a remission. Ratings of tic severity were assessed using the Yale Global Tic Severity Scale (YGTSS) and serum cytokine levels (interleukin [IL]-2, IL-4, IL-5, IL-10, IL-12p70, IL-13, interferon [IFN]-γ, tumor necrosis factor [TNF]-α, and granulocyte macrophage-colony stimulating factor [GM-CSF]) were measured using Luminex xMAP technology. Results: During tic symptom exacerbation, patients had higher median serum TNF-α levels (z=−1.962, p=0.05), particularly those on antipsychotics (U=9.00, p=0.033). Increased IL-13 was also associated with antipsychotic use during exacerbation (U=4.00, p=0.043) despite being negatively correlated to tic severity scores (ρ=−0.599, p=018), whereas increased IL-5 was associated with antibiotic use (U=6.5, p=0.035). During tic symptom remission, increased serum IL-4 levels were associated with antipsychotic (U=6.00, p=0.047) and antibiotic (U=1.00, p=0.016) use, whereas increased IL-12p70 (U=4.00, p=0.037) was associated with antibiotic use. Conclusions: These findings suggest a role for cytokine dysregulation in the pathogenesis of tic disorders. It also points toward the mechanistic involvement and potential diagnostic utility of cytokine monitoring, particularly TNF-α levels. Larger, systematic studies are necessary to further delineate the role of cytokines and medication influences on immunological profiling in tic disorders. PMID:25658821

Interferon system in women with genital papillomavirus infection receiving immunomodulatory therapy.

PubMed

Rogovskaya, S I; Zhdanov, A V; Loginova, N S; Faizullin, L Z; Prilepskaya, V N; Van'ko, L V; Sukhikh, G T

2002-11-01

The interferon system was studied in women with genital papillomavirus infection. In most patients the interferon system was activated, while the ability of lymphocytes to respond to inductors decreased. Laserotherapy and immunomodulatory therapy with larifan, ridostin, and viferon for 1 month normalized blood interferon concentration (39.4% patients) and interferon-gamma production by lymphocytes in response to inductors (87.9% patients). After laser monotherapy these parameters returned to normal only in 13.2 and 7.6% patients, respectively. Correlation and regression analyses showed that changes in the interferon system were synchronized after immunomodulatory therapy. These data indicate that immunomodulatory therapy produces a complex effect on the interferon system. Measurements of blood interferon level can be used to predict the effect of further treatment with interferon-gamma inductors.

New Insight on a Combination of Policosanol and 10-Dehydrogingerdione Phytochemicals as Inhibitors for Platelet Activation Biomarkers and Atherogenicity Risk in Dyslipidemic Rabbits: Role of CETP and PCSK9 Inhibition.

PubMed

Elseweidy, Mohamed Mahmoud; Amin, Rawia Sarhan; Atteia, Hebatallah Husseini; El-Zeiky, Reham Raafat; Al-Gabri, Naif A

2018-05-09

Platelet markers [soluble p selectin (sP-selectin) and soluble CD40 ligand (sCD40L)] are associated with platelet activation and cardiovascular risk. Both policosanol and 10-dehydrogingerdione are natural products with proven CETP inhibitory and antiatherogenic effects. Present work aimed mainly to investigate the levels of platelet activation biomarkers in the serum of dyslipidemic rabbits and the potential of these phytochemicals either alone or in a combination form to protect against atherogenicity. Additionally, this work clarified their effect on PCSK9, a key player in atherosclerosis progression. Daily administration of policosanol and/or 10-dehydrogingerdione at a dose level 10 mg/kg bw resulted in a CETP inhibitory activity, increasing HDL-C level. This protective effect was associated with improvement in lipid profile components and a reduction in PCSK9 level. Interestingly, this combination strengthened the CETP inhibitory activity of these phytochemicals, leading to a greater increase in serum HDL-C level than monotherapy. However, this combination did not enhance the reduction in PCSK9 level. Both drugs also decreased platelet activation and inflammation markers such as sCD40L, sP-selectin, and interferon-gamma (IFN-γ), and their combination showed a synergistic effect. Therefore, such phytochemicals may be regarded as promising agents in the protection against atherothrombosis risk.

Induction of interleukin 6 and interleukin 8 expression by Broncho-Vaxom (OM-85 BV) via C-Fos/serum responsive element.

PubMed Central

Keul, R.; Roth, M.; Papakonstantinou, E.; Nauck, M.; Perruchoud, A. P.; Block, L. H.

1996-01-01

BACKGROUND: Broncho-Vaxom (OM-85 BV) increases the resistance of the respiratory tract to bacterial infections by modulating host immune responses. The compound increases serum IgG levels but decreases IgE levels in patients suffering from chronic bronchitis or chronic obstructive pulmonary disease. It increases concentrations of gamma-interferon (IFN-gamma), IgA, and interleukin (IL)-2 in bronchoalveolar lavage fluid of patients with bronchitis. Treatment with OM-85 BV increases the number of T helper and natural killer cells. In this study the effects of OM-85 BV on transcription of cytokines is investigated in human lung fibroblasts. METHODS: Transcription and synthesis of IL-6 and IL-8 were assessed in cultured primary human lung fibroblasts using standard methods of Northern blot analysis for the level of mRNAs and enzyme linked immunosorbent assay for proteins. RESULTS: Broncho-Vaxom (OM-85 BV) at different concentrations induced transcription of IL-6 and IL-8. The effect of the drug on transcription of IL-6 and IL-8 genes correlated with secretion of the proteins into cell supernatants. OM-85 BV-dependent expression of the interleukin genes involved C-Fos/serum responsive element (C-Fos/SRE). CONCLUSIONS: The data suggest that the various immunopharmacological activities of OM-85 BV that have been described in clinical studies may be explained by its ability to induce expression of IL-6 and IL-8. Images PMID:8711646

Interferon induction by two 2'-modified double-helical RNAs, poly(2'-fluoro-2'-deoxyinosinic acid) x poly(cytidylic acid) and poly(2'-chloro-2'-deoxyinosinic acid) x poly(cytidylic acid).

PubMed

De Clercq, E; Stollar, B D; Hobbs, J; Fukui, T; Kakiuchi, N; Ikehara, M

1980-01-01

In addition to the 2'-azido analogue of (I)n x (C)n, (dIn3)n x (C)n, we have found two other (I)n x (C)n analogues, (dIfl)n x (C)n and (dIcl)n x (C)n, in which the 2'-hydroxyls of the (I)n strand are replaced by either fluorine or chlorine, to be highly effective in inducing interferon. This contrasted with the lack of interferon-inducing activity noted for various other 2'-halogeno analogues of (I)n x (C)n and (A)n x (U)n, i.e. (I)n x (dCcl)n, (dAfl)n x (U)n, (dAcl)n x (U)n, (A)n x (dUfl)n and (A)n x (dUcl)n. In most assay systems, viz. primary rabbit kidney cells, human diploid fibroblasts, HeLa cells, interferon-primed mouse L-929 cells, and intact rabbits, (dIfl)n x (C)n and (dIcl)n x (C)n induced interferon levels that were comparable to those induced by (I)n x (C)n. There was one particular system (L-929 cells treated with DEAE-dextran), however, in which (dIfl)n x (C)n and (dIcl)n x (C)n, unlike (I)n x (C)n, failed to stimulate interferon production. As monitored by both radiochemical and biological means, (dIfl)n x (C)n and, to a lesser extent, (dIcl)n x (C)n were more resistant to degradation by ribonuclease A, T1 and human serum nucleases than was (I)n x (C)n. In their reactivity towards antibodies to double-stranded RNA (dIfl)n x (C)n and (dIcl)n x (C)n conformed more closely to (I)n x (C)n than did other 2'-substituted (e.g. 2'-O-methyl or 2'-O-ethyl) analogues of (I)n x (C)n. The high interferon-inducing potency of (dIfl)n x (C)n and (dIcl)n x (C)n has both theoretical and practical implications. While our findings suggest that (dIfl)n x (C)n and (dIcl)n x (C)n should be further explored for their therapeutic potentials, they also strengthen the notion that the interferon-inducing capacity, and possibly other biological functions of double-stranded RNAs is dependent on the recognition of the overall conformation of the polynucleotide rather than on the binding of specific functional groups such as the 2'-hydroxyl group.

Inflammation responses in patients with pulmonary tuberculosis in an intensive care unit

PubMed Central

Liu, Qiu-Yue; Han, Fen; Pan, Li-Ping; Jia, Hong-Yan; Li, Qi; Zhang, Zong-De

2018-01-01

Pulmonary tuberculosis caused by Mycobacterium tuberculosis remains a global problem. Inflammatory responses are the primary characteristics of patients with pulmonary tuberculosis in intensive care units (ICU). The aim of the present study was to investigate the clinical importance of inflammatory cells and factors for patients with pulmonary tuberculosis in ICU. A total of 124 patients with pulmonary tuberculosis in ICU were recruited for the present study. The inflammatory responses in patients with pulmonary tuberculosis in ICU were examined by changes in inflammatory cells and factors in the serum. The results indicated that serum levels of lymphocytes, plasma cells, granulocytes and monocytes were increased in patients with pulmonary tuberculosis in ICU compared with healthy controls. The serum levels of inflammatory factors interleukin (IL)-1, IL-6, IL-10, IL-12, and IL-4 were upregulated in patients with pulmonary tuberculosis in ICU. Lower plasma concentrations of IL-2, IL-15 and interferon-γ were detected in patients with pulmonary tuberculosis compared with healthy controls. It was demonstrated that high mobility group box-1 protein expression levels were higher in the serum of patients with pulmonary tuberculosis compared with healthy controls. Notably, an imbalance of T-helper cell (Th)1/Th2 cytokines was observed in patients with pulmonary tuberculosis. Pulmonary tuberculosis caused by M. tuberculosis also upregulated expression of matrix metalloproteinase (MMP)-1 and MMP-9 in hPMCs. In conclusion, these outcomes demonstrated that inflammatory responses and inflammatory factors are associated with the progression of pulmonary tuberculosis, suggesting that inhibition of inflammatory responses and inflammatory factors may be beneficial for the treatment of patients with pulmonary tuberculosis in ICU. PMID:29456674

Regulatory polymorphism of CXCL10 rs1439490 in seronegative occult hepatitis C virus infection.

PubMed

Wang, Xu; Wang, Song; Liu, Zhen-Hua; Qi, Wen-Qian; Zhang, Qian; Zhang, Yong-Gui; Sun, De-Rong; Xu, Yan; Wang, Hong-Guang; Li, Zhong-Xie; Cong, Xian-Ling; Zhao, Ping; Zhou, Chang-Yu; Wang, Jiang-Bin

2018-05-28

To examine the relationship between the single nucleotide polymorphism CXCL10 rs1439490 and seronegative occult hepatitis C virus (HCV) infection (OCI). One hundred and three cases of seronegative OCI and 155 cases of seropositive chronic HCV infection (CHC) were diagnosed at five Liver Centers in Northeastern China, from 2012 to 2016. CXCL10 rs1439490, rs1440802, and IL-28B rs12979860 were analyzed by sequencing. Serum CXCL10 was measured by ELISA. Intrahepatic CXCL10 was determined by quantitative PCR and immunohistochemical semi-quantitative scoring. Liver necroinflammation and fibrosis were scored according to the METAVIR system. CXCL10 rs1439490 G/G was more prevalent in OCI patients ( n = 93/103; 90.3%) than in CHC patients ( n = 116/155; 74.8%; P = 0.008). OCI patients had lower serum CXCL10 levels than CHC patients (192.91 ± 46.50 pg/mL vs 354.78 ± 102.91 pg/mL, P < 0.0001). Of IL-28B rs12979860 C/C patients, OCI patients with rs1439490 G/G had lower serum and liver levels of CXCL10 and lower levels of liver necroinflammation and fibrosis than non-G/G patients. OCI patients had higher alanine aminotransferase normalization rates after Peg-interferon treatment than CHC patients (P < 0.05) and serum CXCL10 decreased significantly (P < 0.0001). Liver necroinflammation and fibrosis were alleviated in 8 OCI patients after treatment. Multivariate analysis indicated that rs1439490 G/G significantly influenced the occurrence of OCI in HCV infection (OR = 0.31, 95%CI: 0.15-0.66, P = 0.002). CXCL10 rs1439490 G/G is positively associated with OCI in HCV infection and antiviral outcome.

Decoy receptor 3 attenuates collagen-induced arthritis by modulating T cell activation and B cell expansion.

PubMed

Cheng, Chia-Pi; Sytwu, Huey-Kang; Chang, Deh-Ming

2011-12-01

To investigate the immune-modulated effects of decoy receptor 3 (DCR3) in an experimental model of rheumatoid arthritis (RA). We delivered DCR3 plasmid into collagen-induced arthritis (CIA) mice using the hydrodynamic method and evaluated the serum level of DCR3 protein by ELISA. After immunization, we assessed disease severity of arthritis incidence, arthritis scores, paw thickness, and means of arthritic limbs, and used hematoxylin and eosin staining to observe synovial hyperplasia. We analyzed numbers of murine splenocytes and inguinal lymphocyte cells, cell populations, and serum proinflammatory cytokines by flow cytometry. We investigated B cell proliferation by carboxyfluorescein succinimidyl ester assay. We evaluated serum levels of total IgG2a and type II collagen-specific IgG and IgG2a using ELISA. DCR3 expression in sera significantly attenuated disease severity in CIA mice. We found that DCR3 inhibited the volume of inguinal lymph nodes, numbers of CD19+ B cells, and populations of interferon-γ, interleukin 4 (IL-4), IL-17A, and Foxp3-producing CD4+ T cell in vivo. We found that DCR3 inhibited Pam3CSK4 (Toll-like receptor 1/2 ligand)-induced B220+ B cell proliferation in vitro. DCR3 treatment reduced the serum level of IL-6, total IgG2a, and CII-specific IgG2a antibody. We postulated that the protective effects of DCR3 in CIA resulted from modulation of the immune system by maintaining the B/T cell balance and decreasing lymphocyte expansion. We suggest DCR3 as a prophylactic and potential therapeutic agent in the treatment of RA.

[Interferons--its method of administration and adverse effect related to pharmacokinetics ].

PubMed

Furue, H

1984-02-01

The potential role of interferons in the treatment of malignant diseases is currently being evaluated. This paper reviews experimental and clinical findings regarding pharmacokinetics, method of administration, and side reactions of interferons. Interferon in the blood is rapidly cleared from the circulation. Intramuscular injection of alpha-interferon causes low but stable interferon levels in the blood. However, in the case of beta-interferon, interferon is never detected consistently in the blood after intramuscular or subcutaneous administration. The studies with animal models suggest that doses higher than those given in current clinical trials will be necessary to obtain clearly beneficial effects in human. The maximum safely tolerated daily dose is appreciably higher than that used in most previous studies, although even at this level, considerable toxicity may be encountered. Adequate method of administration, route, dose and interval are not yet established at all. Exact mechanism of anticancer activity is not yet well defined. The most frequent side reaction is fever. However, the exact mechanism to cause these side reactions is also not yet clarified. Dose limiting central nervous system toxicities, hypotension, hypocalcaemia etc. are occasionally encountered in some instances. Antibody to interferon is demonstrated in some cases. Purification of interferon does not always causes reduction of side reactions. The treatment of cancer cases with interferon has just started and there are many problems to be solved. However, therapeutic beneficial may be achieved in the treatment of malignant tumors by appropriate combinations of interferon with conventional treatment. More laboratory studies as well as carefully controlled clinical observations are warranted.

Interferon gamma-inducible protein-10 (IP-10) and eotaxin as biomarkers in age-related macular degeneration.

PubMed

Mo, Fong Ming; Proia, Alan D; Johnson, Walter H; Cyr, Desiree; Lashkari, Kameran

2010-08-01

To analyze serum cytokine levels in subjects with different stages of AMD and to study the expression of salient cytokines in postmortem eyes with AMD. A suspension array system was used to analyze sera (n = 18 to 20/group) from control subjects and those with early AMD (AREDS stage 1), intermediate dry AMD (AREDS stage 3), advanced AMD with geographic atrophy (GA), or neovascular AMD (CNV). Postmortem eyes with AMD or control eyes were examined immunohistochemically for expression of IP-10 and eotaxin (n = 4 to 8/group). Serum eotaxin and IP-10 levels were significantly elevated in all stages of AMD, except for eotaxin levels in neovascular AMD (P < 0.07). The peak of serum IP-10 concentration was at intermediate dry AMD. In donor eyes, IP-10 and eotaxin expressions were increased in the RPE of eyes with early AMD, GA, and CNV. Eotaxin accumulated within the layer of basal linear/laminar deposits in all stages of AMD, while IP-10 was mainly in eyes with GA and CNV. IP-10 was abundant in the connective tissue matrix associated with CNV, and eotaxin was usually present but more focally and with less intense staining. Both IP-10 and eotaxin were expressed by neovascular endothelial cells. Both IP-10 and eotaxin were expressed in the neurosensory retina, but there was no detectable difference in staining between eyes with or without AMD. IP-10 and eotaxin may be early biomarkers in AMD. The authors hypothesize that the relative balance between levels of IP-10 and eotaxin is critical in regulating the neovascular response.

Deletion of the Ron receptor tyrosine kinase domain in mice provides protection from endotoxin-induced acute liver failure.

PubMed

Leonis, Mike A; Toney-Earley, Kenya; Degen, Sandra J F; Waltz, Susan E

2002-11-01

The targeted deletion of the cytoplasmic domain of the Ron receptor tyrosine kinase (TK) in mice leads to exaggerated responses to injury in several murine models of inflammation as well as increased lethality in response to endotoxin (lipopolysaccharide [LPS]). Using a well-characterized model of LPS-induced acute liver failure (ALF) in galactosamine (GalN)-sensitized mice, we show that Ron TK(-/-) mice display marked protection compared with control Ron TK(+/+) mice. Whereas control mice have profound elevation of serum aminotransferase levels (a marker of hepatocyte injury) and hemorrhagic necrosis of the liver, in dramatic contrast, Ron TK(-/-) mice have mild elevation of aminotransferase levels and relatively normal liver histology. These findings are associated with a reduction in the number of liver cells undergoing apoptosis in Ron TK(-/-) mice. Paradoxically, treatment of Ron TK(-/-) mice with LPS/GalN leads to markedly elevated (3.5-fold) serum levels of tumor necrosis factor (TNF) alpha, a key inflammatory mediator in this liver injury model, as well as reduced amounts of interleukin (IL) 10 (a suppressor of TNF-alpha production) and interferon (IFN)-gamma (a TNF-alpha sensitizer). These results show that ablation of the TK activity of the Ron receptor leads to protection from the development of hepatocellular apoptosis in response to treatment with LPS/GalN, even in the presence of excessive levels of serum TNF-alpha. In conclusion, our studies show that the Ron receptor TK plays a critical role in modulating the response of the liver to endotoxin.

Characterization of Human Disease Phenotypes Associated with Mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1

PubMed Central

Crow, Yanick J.; Chase, Diana S.; Schmidt, Johanna Lowenstein; Szynkiewicz, Marcin; Forte, Gabriella M.A.; Gornall, Hannah L.; Oojageer, Anthony; Anderson, Beverley; Pizzino, Amy; Helman, Guy; Abdel-Hamid, Mohamed S.; Abdel-Salam, Ghada M.; Ackroyd, Sam; Aeby, Alec; Agosta, Guillermo; Albin, Catherine; Allon-Shalev, Stavit; Arellano, Montse; Ariaudo, Giada; Aswani, Vijay; Babul-Hirji, Riyana; Baildam, Eileen M.; Bahi-Buisson, Nadia; Bailey, Kathryn M.; Barnerias, Christine; Barth, Magalie; Battini, Roberta; Beresford, Michael W.; Bernard, Geneviève; Bianchi, Marika; de Villemeur, Thierry Billette; Blair, Edward M.; Bloom, Miriam; Burlina, Alberto B.; Carpanelli, Maria Luisa; Carvalho, Daniel R.; Castro-Gago, Manuel; Cavallini, Anna; Cereda, Cristina; Chandler, Kate E.; Chitayat, David A.; Collins, Abigail E.; Corcoles, Concepcion Sierra; Cordeiro, Nuno J.V.; Crichiutti, Giovanni; Dabydeen, Lyvia; Dale, Russell C.; D’Arrigo, Stefano; De Goede, Christian G.E.L.; De Laet, Corinne; De Waele, Liesbeth M.H.; Denzler, Ines; Desguerre, Isabelle; Devriendt, Koenraad; Di Rocco, Maja; Fahey, Michael C.; Fazzi, Elisa; Ferrie, Colin D.; Figueiredo, António; Gener, Blanca; Goizet, Cyril; Gowrinathan, Nirmala R.; Gowrishankar, Kalpana; Hanrahan, Donncha; Isidor, Bertrand; Kara, Bülent; Khan, Nasaim; King, Mary D.; Kirk, Edwin P.; Kumar, Ram; Lagae, Lieven; Landrieu, Pierre; Lauffer, Heinz; Laugel, Vincent; La Piana, Roberta; Lim, Ming J.; Lin, Jean-Pierre S.-M.; Linnankivi, Tarja; Mackay, Mark T.; Marom, Daphna R.; Lourenço, Charles Marques; McKee, Shane A.; Moroni, Isabella; Morton, Jenny E.V.; Moutard, Marie-Laure; Murray, Kevin; Nabbout, Rima; Nampoothiri, Sheela; Nunez-Enamorado, Noemi; Oades, Patrick J.; Olivieri, Ivana; Ostergaard, John R.; Pérez-Dueñas, Belén; Prendiville, Julie S.; Ramesh, Venkateswaran; Rasmussen, Magnhild; Régal, Luc; Ricci, Federica; Rio, Marlène; Rodriguez, Diana; Roubertie, Agathe; Salvatici, Elisabetta; Segers, Karin A.; Sinha, Gyanranjan P.; Soler, Doriette; Spiegel, Ronen; Stödberg, Tommy I.; Straussberg, Rachel; Swoboda, Kathryn J.; Suri, Mohnish; Tacke, Uta; Tan, Tiong Y.; Naude, Johann te Water; Teik, Keng Wee; Thomas, Maya Mary; Till, Marianne; Tonduti, Davide; Valente, Enza Maria; Van Coster, Rudy Noel; van der Knaap, Marjo S.; Vassallo, Grace; Vijzelaar, Raymon; Vogt, Julie; Wallace, Geoffrey B.; Wassmer, Evangeline; Webb, Hannah J.; Whitehouse, William P.; Whitney, Robyn N.; Zaki, Maha S.; Zuberi, Sameer M.; Livingston, John H.; Rozenberg, Flore; Lebon, Pierre; Vanderver, Adeline; Orcesi, Simona; Rice, Gillian I.

2015-01-01

Aicardi–Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi–Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials. PMID:25604658

Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.

PubMed

Crow, Yanick J; Chase, Diana S; Lowenstein Schmidt, Johanna; Szynkiewicz, Marcin; Forte, Gabriella M A; Gornall, Hannah L; Oojageer, Anthony; Anderson, Beverley; Pizzino, Amy; Helman, Guy; Abdel-Hamid, Mohamed S; Abdel-Salam, Ghada M; Ackroyd, Sam; Aeby, Alec; Agosta, Guillermo; Albin, Catherine; Allon-Shalev, Stavit; Arellano, Montse; Ariaudo, Giada; Aswani, Vijay; Babul-Hirji, Riyana; Baildam, Eileen M; Bahi-Buisson, Nadia; Bailey, Kathryn M; Barnerias, Christine; Barth, Magalie; Battini, Roberta; Beresford, Michael W; Bernard, Geneviève; Bianchi, Marika; Billette de Villemeur, Thierry; Blair, Edward M; Bloom, Miriam; Burlina, Alberto B; Carpanelli, Maria Luisa; Carvalho, Daniel R; Castro-Gago, Manuel; Cavallini, Anna; Cereda, Cristina; Chandler, Kate E; Chitayat, David A; Collins, Abigail E; Sierra Corcoles, Concepcion; Cordeiro, Nuno J V; Crichiutti, Giovanni; Dabydeen, Lyvia; Dale, Russell C; D'Arrigo, Stefano; De Goede, Christian G E L; De Laet, Corinne; De Waele, Liesbeth M H; Denzler, Ines; Desguerre, Isabelle; Devriendt, Koenraad; Di Rocco, Maja; Fahey, Michael C; Fazzi, Elisa; Ferrie, Colin D; Figueiredo, António; Gener, Blanca; Goizet, Cyril; Gowrinathan, Nirmala R; Gowrishankar, Kalpana; Hanrahan, Donncha; Isidor, Bertrand; Kara, Bülent; Khan, Nasaim; King, Mary D; Kirk, Edwin P; Kumar, Ram; Lagae, Lieven; Landrieu, Pierre; Lauffer, Heinz; Laugel, Vincent; La Piana, Roberta; Lim, Ming J; Lin, Jean-Pierre S-M; Linnankivi, Tarja; Mackay, Mark T; Marom, Daphna R; Marques Lourenço, Charles; McKee, Shane A; Moroni, Isabella; Morton, Jenny E V; Moutard, Marie-Laure; Murray, Kevin; Nabbout, Rima; Nampoothiri, Sheela; Nunez-Enamorado, Noemi; Oades, Patrick J; Olivieri, Ivana; Ostergaard, John R; Pérez-Dueñas, Belén; Prendiville, Julie S; Ramesh, Venkateswaran; Rasmussen, Magnhild; Régal, Luc; Ricci, Federica; Rio, Marlène; Rodriguez, Diana; Roubertie, Agathe; Salvatici, Elisabetta; Segers, Karin A; Sinha, Gyanranjan P; Soler, Doriette; Spiegel, Ronen; Stödberg, Tommy I; Straussberg, Rachel; Swoboda, Kathryn J; Suri, Mohnish; Tacke, Uta; Tan, Tiong Y; te Water Naude, Johann; Wee Teik, Keng; Thomas, Maya Mary; Till, Marianne; Tonduti, Davide; Valente, Enza Maria; Van Coster, Rudy Noel; van der Knaap, Marjo S; Vassallo, Grace; Vijzelaar, Raymon; Vogt, Julie; Wallace, Geoffrey B; Wassmer, Evangeline; Webb, Hannah J; Whitehouse, William P; Whitney, Robyn N; Zaki, Maha S; Zuberi, Sameer M; Livingston, John H; Rozenberg, Flore; Lebon, Pierre; Vanderver, Adeline; Orcesi, Simona; Rice, Gillian I

2015-02-01

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials. © 2015 Wiley Periodicals, Inc.

Feasibility of commercial space manufacturing, production of pharmaceuticals. Volume 2: Technical analysis

NASA Technical Reports Server (NTRS)

1978-01-01

A technical analysis on the feasibility of commercial manufacturing of pharmaceuticals in space is presented. The method of obtaining pharmaceutical company involvement, laboratory results of the separation of serum proteins by the continuous flow electrophoresis process, the selection and study of candidate products, and their production requirements is described. The candidate products are antihemophilic factor, beta cells, erythropoietin, epidermal growth factor, alpha-1-antitrypsin and interferon. Production mass balances for antihemophelic factor, beta cells, and erythropoietin were compared for space versus ground operation. A conceptual description of a multiproduct processing system for space operation is discussed. Production requirements for epidermal growth factor of alpha-1-antitrypsin and interferon are presented.

Supplemental vitamin D increases serum cytokines in those with initially low 25-hydroxyvitamin D: a randomized, double blind, placebo-controlled study.

PubMed

Barker, Tyler; Rogers, Victoria E; Levy, Mark; Templeton, Jenna; Goldfine, Howard; Schneider, Erik D; Dixon, Brian M; Henriksen, Vanessa T; Weaver, Lindell K

2015-02-01

The purpose of this study was to determine if vitamin D status before supplementation influences the cytokine response after supplemental vitamin D. Forty-six reportedly healthy adults (mean(SD); age, 32(7) y; body mass index (BMI), 25.3(4.5) kg/m(2); serum 25-hydroxyvitamin D (25(OH)D), 34.8(12.2) ng/mL) were randomly assigned (double blind) to one of three groups: (1) placebo (n=15), or supplemental vitamin D (cholecalciferol) at (2) 4000 (n=14) or (3) 8000IU (n=17). Supplements were taken daily for 35days. Fasting blood samples were obtained before (Baseline, Bsl) and 35-days after (35-d) supplementation. Serum 25(OH)D, 1,25-dihydroxyvitamin D (1,25(OH)D), cytokines, and intact parathyroid hormone with calcium were measured in each blood sample. Supplemental vitamin D increased serum 25(OH)D (4000IU, ≈29%; 8000IU, ≈57%) and 1,25(OH)D (4000IU, ≈12%; 8000IU, ≈38%) without altering intact parathyroid hormone or calcium. The vitamin D metabolite increases in the supplemental vitamin D groups (n=31) were dependent on initial levels as serum 25(OH)D (r=-0.63, p<0.05) and 1,25(OH)D (r=-0.45, p<0.05) at Bsl correlated with their increases after supplementation. Supplemental vitamin D increased interferon (IFN)-γ and interleukin (IL)-10 in subjects that were vitamin D insufficient (serum 25(OH)D<29ng/mL) compared to sufficient (serum 25(OH)D⩾30ng/mL) at Bsl. We conclude that supplemental vitamin D increase a pro- and anti-inflammatory cytokine in those with initially low serum 25(OH)D. Copyright © 2014 Elsevier Ltd. All rights reserved.

Gamma Interferon-Induced Expression of Class II MHC Antigens by Human Keratinocytes: Effects of Conditions of Culture

DTIC Science & Technology

1987-01-01

containing or serum-free medium. / -3- Introduction In a number of skin diseases including lichen planus , contact dermatitis, and mycosis fungoides...Tjernlund, U. M. 1980. Ia-like antigens in lichen planus . Acta Dermatovenerol. (Stockholm) 60:309-315. 2. MacKie, R. M. & M. L. Turbitt. 1983

Experimental miniature piglet model for the infection of human norovirus GII.

PubMed

Seo, Dong Joo; Jung, Day; Jung, Soontag; Ha, Seung-Kwon; Ha, Sang-Do; Choi, In-Soo; Myoung, Jinjong; Choi, Changsun

2018-04-01

Ten Yucatan miniature piglets were challenged with the human norovirus (NoV) GII.12/GII.3 CAU140599 strain and five piglets were used as negative controls. Stool, serum, and organs were collected and processed from two NoV-infected piglets and one negative piglet at 1, 2, 3, 5, and 7 days post-inoculation (dpi). NoV was detected in stool and serum samples by real-time RT-PCR. Mild diarrhea was observed at 1-3 dpi. Fecal shedding and viremia were detected intermittently at 1, 3, and 7 dpi. While interferon-α was significantly elevated at 2-3 dpi, interferon-γ was not changed. Immunohistochemistry demonstrated that the NoV capsid antigen was present in macrophages, lymphocytes, and dendritic cells of the stomach, intestines, lymph nodes, spleen, and tonsils. Intestinal epithelium did not exhibit a positive signal for NoV. In addition, negative-sense viral RNA was confirmed in immune cells by fluorescence in situ hybridization. Therefore, NoV might be associated with macrophages and lymphocytes in gastrointestinal tract and immune organs of experimentally infected miniature piglets. © 2017 Wiley Periodicals, Inc.

Enhancement of immune cytokines and splenic CD4+ T cells by electroacupuncture at ST36 acupoint of SD rats.

PubMed

Chen, Longyun; Xu, Anli; Yin, Nina; Zhao, Min; Wang, Zhigang; Chen, Tao; Gao, Yisheng; Chen, Zebin

2017-01-01

Electroacupuncture at the ST36 acupoint can enhance the body's immune function. However, the mechanism for this enhancement has not been fully described. Our study was designed to investigate the effect of electroacupuncture on the immune function of Sprague-Dawley (SD) rats. The rats were randomly divided into three groups: a control group, a non-acupoint group (abdominal muscle acupuntured) and a ST36 acupoint group. Our results showed that successive electroacupuncture at the ST36 acupoint for 3 d significantly enhanced the interferon-γ (IFN-γ) level in the serum of SD rats. The results also showed that the serum and extracts from spleen cells of the ST36 acupoint group contained higher levels of interleukin (IL)-2 and IL-17 compared to those of the other two groups. Immunohistochemical analysis showed that electroacupuncture applied to the ST36 acupoint enhanced the expression level of CD4 in spleen cells. Furthermore, it was observed that CD4 co-localized with transient receptor potential vanilloid (TRPV) channels at the membrane of splenic CD4+ T cells and the expression level of CD4 was related to TRPV channels in the electroacupuncture treatment. These observations indicated that electroacupuncture stimulation at the ST36 acupoint enhanced the level of immune cytokines and splenic CD4+ T cells through TRPV channels in this system.

Enhancement of immune cytokines and splenic CD4+ T cells by electroacupuncture at ST36 acupoint of SD rats

PubMed Central

Yin, Nina; Zhao, Min; Wang, Zhigang; Chen, Tao; Gao, Yisheng; Chen, Zebin

2017-01-01

Electroacupuncture at the ST36 acupoint can enhance the body’s immune function. However, the mechanism for this enhancement has not been fully described. Our study was designed to investigate the effect of electroacupuncture on the immune function of Sprague-Dawley (SD) rats. The rats were randomly divided into three groups: a control group, a non-acupoint group (abdominal muscle acupuntured) and a ST36 acupoint group. Our results showed that successive electroacupuncture at the ST36 acupoint for 3 d significantly enhanced the interferon-γ (IFN-γ) level in the serum of SD rats. The results also showed that the serum and extracts from spleen cells of the ST36 acupoint group contained higher levels of interleukin (IL)-2 and IL-17 compared to those of the other two groups. Immunohistochemical analysis showed that electroacupuncture applied to the ST36 acupoint enhanced the expression level of CD4 in spleen cells. Furthermore, it was observed that CD4 co-localized with transient receptor potential vanilloid (TRPV) channels at the membrane of splenic CD4+ T cells and the expression level of CD4 was related to TRPV channels in the electroacupuncture treatment. These observations indicated that electroacupuncture stimulation at the ST36 acupoint enhanced the level of immune cytokines and splenic CD4+ T cells through TRPV channels in this system. PMID:28406959

Parasite Specific Antibody Levels, Interferon-γ and TLR2 and TLR4 Transcripts in Blood from Dogs with Different Clinical Stages of Leishmaniosis

PubMed Central

Montserrat-Sangrà, Sara; Ordeix, Laura; Martínez-Orellana, Pamela; Solano-Gallego, Laia

2018-01-01

Canine leishmaniosis has a wide range of disease severity from mild (stage I), to severe (stages II–III), or very severe disease (stage IV). The objective of the study was to evaluate and compare serum antibody levels, Leishmania infantum specific IFN-γ production and TLR2 and TLR4 transcripts in non-stimulated blood from dogs with different clinical stages at the time of diagnosis as well as blood parasitemia. Enzyme-Linked ImmunoSorbent Assay (ELISAs) were performed to determine serum antibody levels and IFN-γ production and quantitative polymerase chain reaction (qPCRs) in order to determine blood parasite load and TLR2 and TLR4 transcripts. Older dogs were significantly affected by more severe disease with higher antibody levels and blood parasitemia than dogs with mild disease. IFN-γ production was significantly higher in dogs with stage I disease when compared to dogs with more severe disease. Relative quantification of TLR2 in dogs with mild disease was similar to that of control dogs. On the other hand, TLR2 transcripts were significantly higher in dogs with severe disease as compared with that from control healthy dogs. No differences were found in TLR4 relative quantification between groups. This study demonstrates that dogs with different clinical stages of leishmaniosis present different levels of biological markers indicative of different immune responses. PMID:29547503

Tributyltin exposure alters cytokine levels in mouse serum.

PubMed

Lawrence, Shanieek; Pellom, Samuel T; Shanker, Anil; Whalen, Margaret M

2016-11-01

Tributyltin (TBT), a toxic environmental contaminant, has been widely utilized for various industrial, agricultural and household purposes. Its usage has led to a global contamination and its bioaccumulation in aquatic organisms and terrestrial mammals. Previous studies suggest that TBT has debilitating effects on the overall immune function of animals, rendering them more vulnerable to diseases. TBT (at concentrations that have been detected in human blood) alters secretion of inflammatory cytokines from human lymphocytes ex vivo. Thus, it is important to determine if specified levels of TBT can alter levels of cytokines in an in vivo system. Mice were exposed to biologically relevant concentrations of TBT (200, 100 or 25 nM final concentrations). The quantitative determination of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL2, IL5, IL7, IL12βp40, IL13, IL15, keratinocyte chemoattractant (KC), macrophage inflammatory protein 1β (MIP), MIP2 and regulated on activation normal T-cell-expressed and secreted (RANTES) was performed in mouse sera by MAGPIX analysis and Western blot. Results indicated alterations (both decreases and increases) in several cytokines. The pro-inflammatory cytokines IFNγ, TNFα, IL-1β, IL-2, IL5, IL12βp40 and IL-15 were altered as were the chemokines MIP-1 and RANTES and the anti-inflammatory cytokine IL-13. Increases in IFNγ and TNFα were seen in the serum of mice exposed to TBT for less than 24 h. Levels of IL1β, IL-12 βp40, IL-5 and IL-15 were also modulated in mouse serum, depending on the specific experiment and exposure level. IL-2 was consistently decreased in mouse serum when animals were exposed to TBT. There were also TBT-induced increases in MIP-1β, RANTES and IL-13. These results from human and murine samples clearly suggest that TBT exposures modulate the secretion inflammatory cytokines.

Sex differences in the phagocytic and migratory activity of microglia and their impairment by palmitic acid.

PubMed

Yanguas-Casás, Natalia; Crespo-Castrillo, Andrea; de Ceballos, Maria L; Chowen, Julie A; Azcoitia, Iñigo; Arevalo, Maria Angeles; Garcia-Segura, Luis M

2018-03-01

Sex differences in the incidence, clinical manifestation, disease course, and prognosis of neurological diseases, such as autism spectrum disorders or Alzheimer's disease, have been reported. Obesity has been postulated as a risk factor for cognitive decline and Alzheimer's disease and, during pregnancy, increases the risk of autism spectrum disorders in the offspring. Obesity is associated with increased serum and brain levels of free fatty acids, such as palmitic acid, which activate microglial cells triggering a potent inflammatory cascade. In this study, we have determined the effect of palmitic acid in the inflammatory profile, motility, and phagocytosis of primary male and female microglia, both in basal conditions and in the presence of a pro-inflammatory stimulus (interferon-γ). Male microglia in vitro showed higher migration than female microglia under basal and stimulated conditions. In contrast, female microglia had higher basal and stimulated phagocytic activity than male microglia. Palmitic acid did not affect basal migration or phagocytosis, but abolished the migration and phagocytic activity of male and female microglia in response to interferon-γ. These findings extend previous observations of sex differences in microglia and suggest that palmitic acid impairs the protective responses of these cells. © 2017 Wiley Periodicals, Inc.

TLR9 Polymorphisms Are Associated with Altered IFN-γ Levels in Children with Cerebral Malaria

PubMed Central

Sam-Agudu, Nadia A.; Greene, Jennifer A.; Opoka, Robert O.; Kazura, James W.; Boivin, Michael J.; Zimmerman, Peter A.; Riedesel, Melissa A.; Bergemann, Tracy L.; Schimmenti, Lisa A.; John, Chandy C.

2010-01-01

Toll-like receptor (TLR) polymorphisms have been associated with disease severity in malaria infection, but mechanisms for this association have not been characterized. The TLR2, 4, and 9 single nucleotide polymorphism (SNP) frequencies and serum interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) levels were assessed in Ugandan children with cerebral malaria (CM, N = 65) and uncomplicated malaria (UM, N = 52). The TLR9 C allele at −1237 and G allele at 1174 were strongly linked, and among children with CM, those with the C allele at −1237 or the G allele at 1174 had higher levels of IFN-γ than those without these alleles (P = 0.03 and 0.008, respectively). The TLR9 SNPs were not associated with altered IFN-γ levels in children with UM or altered TNF-α levels in either group. We present the first human data that TLR SNPs are associated with altered cytokine production in parasitic infection. PMID:20348497

[Immunologic indexes, enzyme status of lymphocytes and functional activity of blood neutrophils in children with infectious mononucleosis caused by Epstein-Barr virus].

PubMed

Kurtasova, L M; Tolstikova, A E; Savchenko, A A

2013-01-01

Explore the immunological parameters, levels of activity of NAD(P)-dependent dehydrogenases lymphocytes, interferon status parameters, phagocytic activity and chemiluminescence response of neutrophils in the blood of children in the acute phase of infectious mononucleosis caused by the Epstein-Barr virus. 65 children at the age of 4-6 years old with infectious mononucleosis caused by EBV in acute phase were observed. Such indexes as cell-mediated, humoral and interferon immunity, NAD(P)-depended dehydrogenases activity in blood lymphocyte, phagocytes activity, levels of spontaneous and induced chemiluminescence ofperipheral blood neutrophils were studied. Children with EVB-infection have immunophenotype spectrum changes and changes of enzymes status of blood lymphocytes against the increasing in leucocytes and the useful increasing in lymphocytes. The useful increasing in IgA, IgM, IgG contenting in serum blood were found. The decreasing of spontaneous production of IFN alpha and the decreasing of induced production of IFNalpha, IFNgamma were determined. The breach of phagocytes activity and chemiluminescent response of blood neutrophils were found. The children in the acute phase of infectious mononucleosis caused by the Epstein-Barr virus, there are changes in the immune status, changes the activity of NAD(P)-dependent dehydrogenases in blood lymphocytes, marked changes in functional and metabolic state of peripheral blood neutrophils.

Micro-RNA-122 levels in acute liver failure and chronic hepatitis C.

PubMed

Dubin, Perry H; Yuan, Hejun; Devine, Robert K; Hynan, Linda S; Jain, Mamta K; Lee, William M

2014-09-01

MicroRNA-122 (miR-122) is the foremost liver-related micro-RNA, but its role in the hepatocyte is not fully understood. To evaluate whether circulating levels of miR-122 are elevated in chronic-HCV for a reason other than hepatic injury, we compared serum level in patients with chronic hepatitis C to other forms of liver injury including patients with acute liver failure and healthy controls. MiR-122 was quantitated using sera from 35 acute liver failure patients (20 acetaminophen-induced, 15 other etiologies), 39 chronic-HCV patients and 12 controls. In parallel, human genomic DNA (hgDNA) levels were measured to reflect quantitatively the extent of hepatic necrosis. Additionally, six HIV-HCV co-infected patients, who achieved viral clearance after undergoing therapy with interferon and ribavirin, had serial sera miR-122 and hgDNA levels measured before and throughout treatment. Serum miR-122 levels were elevated approximately 100-fold in both acute liver failure and chronic-HCV sera as compared to controls (P < 0.001), whereas hgDNA levels were only elevated in acute liver failure patients as compared to both chronic-HCV and controls (P < 0.001). Subgroup analysis showed that chronic-HCV sera with normal aminotransferase levels showed elevated miR-122 despite low levels of hepatocyte necrosis. All successfully treated HCV patients showed a significant Log10 decrease in miR-122 levels ranging from 0.16 to 1.46, after sustained viral response. Chronic-HCV patients have very elevated serum miR-122 levels in the range of most patients with severe hepatic injury leading to acute liver failure. Eradication of HCV was associated with decreased miR-122 but not hgDNA. An additional mechanism besides hepatic injury may be active in chronic-HCV to explain the exaggerated circulating levels of miR-122 observed. © 2014 Wiley Periodicals, Inc.

Pharmacokinetic and pharmacodynamic characterization of a new formulation containing synergistic proportions of interferons alpha-2b and gamma (HeberPAG®) in patients with mycosis fungoides: an open-label trial

PubMed Central

2012-01-01

Background The synergistic combination of interferon (IFN) alpha-2b and IFN gamma results in more potent in vitro biological effects mediated by both IFNs. The aim of this investigation was to evaluate by first time the pharmacokinetics and pharmacodynamics of this combination in patients with mycosis fungoides. Methods An exploratory, prospective, open-label clinical trial was conducted. Twelve patients, both genders, 18 to 75 years-old, with mycosis fungoides at stages IB to III, were eligible for the study. All of them received intramuscularly a single high dose (23 × 106 IU) of a novel synergistic IFN mixture (HeberPAG®) for pharmacokinetic and pharmacodynamic studies. Serum IFN alpha-2b and IFN gamma concentrations were measured during 96 hours by commercial enzyme immunoassays (EIA) specific for each IFN. Other blood IFN-inducible markers and laboratory variables were used as pharmacodynamics and safety criteria. Results The pharmacokinetic evaluation by EIA yielded a similar pattern for both IFNs that are also in agreement with the well-known described profiles for these molecules when these are administered separately. The average values for main parameters were: Cmax: 263 and 9.3 pg/mL; Tmax: 9.5 and 6.9 h; AUC: 4483 and 87.5 pg.h/mL, half-life (t1/2): 4.9 and 13.4 h; mean residence time (MRT): 13.9 and 13.5 h, for serum IFN alpha-2b and IFN gamma, respectively. The pharmacodynamic variables were strongly stimulated by simultaneous administration of both IFNs: serum neopterin and beta-2 microglobulin levels (β2M), and stimulation of 2’-5’ oligoadenylate synthetase (OAS1) mRNA expression. The most encouraging data was the high increment of serum neopterin, 8.0 ng/mL at 48 h, not been described before for any unmodified or pegylated IFN. Additionally, β2M concentration doubled the pre-dose value at 24–48 hours. For both variables the values remained clearly upper baseline levels at 96 hours. Conclusions HeberPAG®possesses improved pharmacodynamic properties that may be very useful in the oncologic setting. Efficacy trials can be carried out to confirm these findings. Trial registration Registro Público Cubano de Ensayos Clínicos RPCEC00000130 PMID:23272809

Risperidone-Related Improvement of Irritability in Children with Autism Is not Associated with Changes in Serum of Epidermal Growth Factor and Interleukin-13

PubMed Central

Tobiasova, Zuzana; van der Lingen, Klaas H. B.; Scahill, Lawrence; Leckman, James F.; Zhang, Yan; Chae, Wookjin; McCracken, James T.; McDougle, Christopher J.; Vitiello, Benedetto; Tierney, Elaine; Aman, Michael G.; Arnold, L. Eugene; Katsovich, Liliya; Hoekstra, Pieter J.; Volkmar, Fred; Bothwell, Alfred L. M.

2011-01-01

Abstract Risperidone has been shown to improve serious behavioral problems in children with autism. Here we asked whether risperidone-associated improvement was related to changes in concentrations of inflammatory molecules in the serum of these subjects. Seven molecules were identified as worthy of further assessment by performing a pilot analysis of 31 inflammatory markers in 21 medication-free subjects with autism versus 15 healthy controls: epidermal growth factor (EGF), interferon-γ (IFN-γ), interleukin (IL)-13, IL-17, monocyte chemoattractant protein-1 (MCP-1), IL-1 and IL-1-receptor antagonist. Serum concentrations of these markers were then established in a different set of subjects that participated in a double-blind, clinical trial and an expanded group of healthy subjects. In the first analysis, samples obtained from subjects with autism at baseline visits were compared to visits after 8-week treatment with placebo (n=37) or risperidone (n=40). The cytokine concentrations remained stable over the 8-week period for both risperidone and placebo groups. In the second analysis, we explored further the differences between medication-free subjects with autism (n=77) and healthy controls (recruited independently; n=19). Serum levels of EGF were elevated in subjects with autism (median=103 pg/mL, n=75) in comparison to healthy controls (75 pg/mL, n=19; p<0.05), and levels of IL-13 were decreased in autism (median=0.8 pg/mL, n=77) in comparison to controls (9.8 pg/mL, n=19; p=0.0003). These changes did not correlate with standardized measures used for a diagnosis of autism. In summary, risperidone-induced clinical improvement in subjects with autism was not associated with changes in the serum inflammatory markers measured. Whether altered levels of EGF and IL-13 play a role in the pathogenesis or phenotype of autism requires further investigation. PMID:22070180

Anti-inflammatory nutritional intervention in patients with relapsing-remitting and primary-progressive multiple sclerosis: A pilot study

PubMed Central

Rossano, Rocco; Larocca, Marilena; Trotta, Vincenzo; Mennella, Ilario; Vitaglione, Paola; Ettorre, Michele; Graverini, Antonio; De Santis, Alessandro; Di Monte, Elisabetta; Coniglio, Maria Gabriella

2016-01-01

The aim of this work was to assess the influence of nutritional intervention on inflammatory status and wellness in people with multiple sclerosis. To this end, in a seven-month pilot study we investigated the effects of a calorie-restricted, semi-vegetarian diet and administration of vitamin D and other dietary supplements (fish oil, lipoic acid, omega-3 polyunsaturated fatty acids, resveratrol and multivitamin complex) in 33 patients with relapsing-remitting multiple sclerosis and 10 patients with primary-progressive multiple sclerosis. At 0/3/6 months, patients had neurological examination, filled questionnaires and underwent anthropometric measurements and biochemical analyses. Serum fatty acids and vitamin D levels were measured as markers of dietary compliance and nutritional efficacy of treatment, whereas serum gelatinase levels were analyzed as markers of inflammatory status. All patients had insufficient levels of vitamin D at baseline, but their values did not ameliorate following a weekly administration of 5000  IU, and rather decreased over time. Conversely, omega-3 polyunsaturated fatty acids increased already after three months, even under dietary restriction only. Co-treatment with interferon-beta in relapsing-remitting multiple sclerosis was irrelevant to vitamin D levels. After six months nutritional treatment, no significant changes in neurological signs were observed in any group. However, serum levels of the activated isoforms of gelatinase matrix metalloproteinase-9 decreased by 59% in primary-progressive multiple sclerosis and by 51% in relapsing-remitting multiple sclerosis patients under nutritional intervention, including dietary supplements. This study indicates that a healthy nutritional intervention is well accepted by people with multiple sclerosis and may ameliorate their physical and inflammatory status. PMID:26785711

Anti-inflammatory nutritional intervention in patients with relapsing-remitting and primary-progressive multiple sclerosis: A pilot study.

PubMed

Riccio, Paolo; Rossano, Rocco; Larocca, Marilena; Trotta, Vincenzo; Mennella, Ilario; Vitaglione, Paola; Ettorre, Michele; Graverini, Antonio; De Santis, Alessandro; Di Monte, Elisabetta; Coniglio, Maria Gabriella

2016-03-01

The aim of this work was to assess the influence of nutritional intervention on inflammatory status and wellness in people with multiple sclerosis. To this end, in a seven-month pilot study we investigated the effects of a calorie-restricted, semi-vegetarian diet and administration of vitamin D and other dietary supplements (fish oil, lipoic acid, omega-3 polyunsaturated fatty acids, resveratrol and multivitamin complex) in 33 patients with relapsing-remitting multiple sclerosis and 10 patients with primary-progressive multiple sclerosis. At 0/3/6 months, patients had neurological examination, filled questionnaires and underwent anthropometric measurements and biochemical analyses. Serum fatty acids and vitamin D levels were measured as markers of dietary compliance and nutritional efficacy of treatment, whereas serum gelatinase levels were analyzed as markers of inflammatory status. All patients had insufficient levels of vitamin D at baseline, but their values did not ameliorate following a weekly administration of 5000  IU, and rather decreased over time. Conversely, omega-3 polyunsaturated fatty acids increased already after three months, even under dietary restriction only. Co-treatment with interferon-beta in relapsing-remitting multiple sclerosis was irrelevant to vitamin D levels. After six months nutritional treatment, no significant changes in neurological signs were observed in any group. However, serum levels of the activated isoforms of gelatinase matrix metalloproteinase-9 decreased by 59% in primary-progressive multiple sclerosis and by 51% in relapsing-remitting multiple sclerosis patients under nutritional intervention, including dietary supplements. This study indicates that a healthy nutritional intervention is well accepted by people with multiple sclerosis and may ameliorate their physical and inflammatory status. © 2016 by the Society for Experimental Biology and Medicine.

A small animal peripheral challenge model of yellow fever using interferon-receptor deficient mice and the 17D-204 vaccine strain.

PubMed

Thibodeaux, Brett A; Garbino, Nina C; Liss, Nathan M; Piper, Joseph; Blair, Carol D; Roehrig, John T

2012-05-02

Yellow fever virus (YFV), a member of the genus Flavivirus, is a mosquito-borne pathogen that requires wild-type (wt), virulent strains to be handled at biosafety level (BSL) 3, with HEPA-filtration of room air exhaust (BSL3+). YFV is found in tropical regions of Africa and South America and causes severe hepatic disease and death in humans. Despite the availability of effective vaccines (17D-204 or 17DD), YFV is still responsible for an estimated 200,000 cases of illness and 30,000 deaths annually. Besides vaccination, there are no other prophylactic or therapeutic strategies approved for use in human YF. Current small animal models of YF require either intra-cranial inoculation of YF vaccine to establish infection, or use of wt strains (e.g., Asibi) in order to achieve pathology. We have developed and characterized a BSL2, adult mouse peripheral challenge model for YFV infection in mice lacking receptors for interferons α, β, and γ (strain AG129). Intraperitoneal challenge of AG129 mice with 17D-204 is a uniformly lethal in a dose-dependent manner, and 17D-204-infected AG129 mice exhibit high viral titers in both brain and liver suggesting this infection is both neurotropic and viscerotropic. Furthermore the use of a mouse model permitted the construction of a 59-biomarker multi-analyte profile (MAP) using samples of brain, liver, and serum taken at multiple time points over the course of infection. This MAP serves as a baseline for evaluating novel therapeutics and their effect on disease progression. Changes (4-fold or greater) in serum and tissue levels of pro- and anti-inflammatory mediators as well as other factors associated with tissue damage were noted in AG129 mice infected with 17D-204 as compared to mock-infected control animals. Published by Elsevier Ltd.

A large‐scale, multicentre, double‐blind trial of ursodeoxycholic acid in patients with chronic hepatitis C

PubMed Central

Omata, Masao; Yoshida, Haruhiko; Toyota, Joji; Tomita, Eiichi; Nishiguchi, Shuhei; Hayashi, Norio; Iino, Shiro; Makino, Isao; Okita, Kiwamu; Toda, Gotaro; Tanikawa, Kyuichi; Kumada, Hiromitsu

2007-01-01

Background Combined pegylated interferon and ribavirin has improved chronic hepatitis C (CH‐C) therapy; however, sustained virological response is achieved in only about half of the patients with a 1b genotype infection. We assessed oral ursodeoxycholic acid (UDCA) on serum biomarkers as a possible treatment for interferon non‐responders. Methods CH‐C patients with elevated alanine aminotransferase (ALT) were assigned randomly to 150 (n = 199), 600 (n = 200) or 900 mg/day (n = 197) UDCA intake for 24 weeks. Changes in ALT, aspartate aminotransferase (AST) and gamma‐glutamyl transpeptidase (GGT) were assessed. This study is registered at ClinicalTrial.gov, identifier NCT00200343. Results ALT, AST and GGT decreased at week 4 and then remained constant during drug administration. The median changes (150, 600 and 900 mg/day, respectively) were: ALT, −15.3, −29.2 and −36.2%; AST, −13.6, −25.0 and −29.8%; GGT, −22.4, −41.0 and −50.0%. These biomarkers decreased significantly less in the 150 mg/day than in the other two groups. Although changes in ALT and AST did not differ between the 600 and 900 mg/day groups, GGT was significantly lower in the 900 mg/day group. In subgroup analysis, ALT decreased significantly in the 900 mg/day group when the baseline GGT exceeded 80 IU/l. Serum HCV‐RNA did not change in any group. Adverse effects were reported by 19.1% of the patients, with no differences between groups. Conclusions A 600 mg/day UDCA dose was optimal to decrease ALT and AST levels in CH‐C patients. The 900 mg/day dose decreased GGT levels further, and may be preferable in patients with prevailing biliary injuries. PMID:17573387

Epigallocatechin-3-gallate (EGCG) attenuates concanavalin A-induced hepatic injury in mice.

PubMed

Liu, Dongmei; Zhang, Xiaoli; Jiang, Li; Guo, Yun; Zheng, Changqing

2014-05-01

(-)-Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenolic compound present in green tea and has been shown to possess anti-inflammatory and anti-oxidative properties. In this study, we investigated the protective effects of EGCG against concanavalin A (ConA)-induced liver injury and the underlying mechanisms. EGCG (5 mg/kg) was administered orally by gavage to mice twice daily for 10 days before an intravenous injection of ConA. We found that EGCG effectively rescued lethality, improved hepatic pathological damage, and decreased serum levels of alanine aminotransaminase (ALT) in ConA-challenged mice. Furthermore, EGCG also significantly prevented the release of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-4, and IL-6 in serum, reduced malondialdehyde (MDA) levels, and restored glutathione (GSH) content and superoxide dismutase (SOD) activity in liver tissues from ConA-challenged mice. Finally, nuclear factor (NF)-κB activation and expression levels of Toll-like receptor (TLR) 2, TLR4 and TLR9 protein in liver tissues were significantly inhibited by EGCG pretreatment. Taken together, our data suggest that EGCG possesses hepatoprotective properties against ConA-induced liver injury through its anti-inflammatory and anti-oxidant actions. Copyright © 2013 Elsevier GmbH. All rights reserved.

Serum Adiponectin, Vitamin D, and Alpha-Fetoprotein in Children with Chronic Hepatitis C: Can They Predict Treatment Response?

PubMed Central

Khedr, Mohamed Ahmed; Sira, Ahmad Mohamed; Saber, Magdy Anwar; Raia, Gamal Yousef

2015-01-01

Background & Aims. The currently available treatment for chronic hepatitis C (CHC) in children is costly and with much toxicity. So, predicting the likelihood of response before starting therapy is important. Methods. Serum adiponectin, vitamin D, and alpha-fetoprotein (AFP) were measured before starting pegylated-interferon/ribavirin therapy for 50 children with CHC. Another 21 healthy children were recruited as controls. Results. Serum adiponectin, vitamin D, and AFP were higher in the CHC group than healthy controls (p < 0.0001, p = 0.071, and p = 0.87, resp.). In univariate analysis, serum adiponectin was significantly higher in responders than nonresponders (p < 0.0001) and at a cutoff value ≥8.04 ng/mL it can predict treatment response by 77.8% sensitivity and 92.9% specificity, while both AFP and viremia were significantly lower in responders than nonresponders, p < 0.0001 and p = 0.0003, respectively, and at cutoff values ≤3.265 ng/mL and ≤235,384 IU/mL, respectively, they can predict treatment response with a sensitivity of 83.3% for both and specificity of 85.7% and 78.6%, respectively. In multivariate analysis, adiponectin was found to be the only independent predictor of treatment response (p = 0.044). Conclusions. The pretreatment serum level of adiponectin can predict the likelihood of treatment response, thus avoiding toxicities for those unlikely to respond to therapy. PMID:26640716

Serum Adiponectin, Vitamin D, and Alpha-Fetoprotein in Children with Chronic Hepatitis C: Can They Predict Treatment Response?

PubMed

Khedr, Mohamed Ahmed; Sira, Ahmad Mohamed; Saber, Magdy Anwar; Raia, Gamal Yousef

2015-01-01

Background & Aims. The currently available treatment for chronic hepatitis C (CHC) in children is costly and with much toxicity. So, predicting the likelihood of response before starting therapy is important. Methods. Serum adiponectin, vitamin D, and alpha-fetoprotein (AFP) were measured before starting pegylated-interferon/ribavirin therapy for 50 children with CHC. Another 21 healthy children were recruited as controls. Results. Serum adiponectin, vitamin D, and AFP were higher in the CHC group than healthy controls (p < 0.0001, p = 0.071, and p = 0.87, resp.). In univariate analysis, serum adiponectin was significantly higher in responders than nonresponders (p < 0.0001) and at a cutoff value ≥8.04 ng/mL it can predict treatment response by 77.8% sensitivity and 92.9% specificity, while both AFP and viremia were significantly lower in responders than nonresponders, p < 0.0001 and p = 0.0003, respectively, and at cutoff values ≤3.265 ng/mL and ≤235,384 IU/mL, respectively, they can predict treatment response with a sensitivity of 83.3% for both and specificity of 85.7% and 78.6%, respectively. In multivariate analysis, adiponectin was found to be the only independent predictor of treatment response (p = 0.044). Conclusions. The pretreatment serum level of adiponectin can predict the likelihood of treatment response, thus avoiding toxicities for those unlikely to respond to therapy.

Comparative Analysis of the Lambda-Interferons IL-28A and IL-29 regarding Their Transcriptome and Their Antiviral Properties against Hepatitis C Virus

PubMed Central

Diegelmann, Julia; Beigel, Florian; Zitzmann, Kathrin; Kaul, Artur; Göke, Burkhard; Auernhammer, Christoph J.; Bartenschlager, Ralf; Diepolder, Helmut M.; Brand, Stephan

2010-01-01

Background Specific differences in signaling and antiviral properties between the different Lambda-interferons, a novel group of interferons composed of IL-28A, IL-28B and IL-29, are currently unknown. This is the first study comparatively investigating the transcriptome and the antiviral properties of the Lambda-interferons IL-28A and IL-29. Methodology/Principal Findings Expression studies were performed by microarray analysis, quantitative PCR (qPCR), reporter gene assays and immunoluminometric assays. Signaling was analyzed by Western blot. HCV replication was measured in Huh-7 cells expressing subgenomic HCV replicon. All hepatic cell lines investigated as well as primary hepatocytes expressed both IFN-λ receptor subunits IL-10R2 and IFN-λR1. Both, IL-28A and IL-29 activated STAT1 signaling. As revealed by microarray analysis, similar genes were induced by both cytokines in Huh-7 cells (IL-28A: 117 genes; IL-29: 111 genes), many of them playing a role in antiviral immunity. However, only IL-28A was able to significantly down-regulate gene expression (n = 272 down-regulated genes). Both cytokines significantly decreased HCV replication in Huh-7 cells. In comparison to liver biopsies of patients with non-viral liver disease, liver biopsies of patients with HCV showed significantly increased mRNA expression of IL-28A and IL-29. Moreover, IL-28A serum protein levels were elevated in HCV patients. In a murine model of viral hepatitis, IL-28 expression was significantly increased. Conclusions/Significance IL-28A and IL-29 are up-regulated in HCV patients and are similarly effective in inducing antiviral genes and inhibiting HCV replication. In contrast to IL-29, IL-28A is a potent gene repressor. Both IFN-λs may have therapeutic potential in the treatment of chronic HCV. PMID:21170333

Natural Killer Cell Activity and Interleukin-12 in Metabolically Healthy versus Metabolically Unhealthy Overweight Individuals

PubMed Central

Kim, Minjoo; Kim, Minkyung; Yoo, Hye Jin; Lee, Jong Ho

2017-01-01

The purpose of this study was to determine whether the immune system is involved in the different metabolic circumstances in healthy and unhealthy overweight individuals. We examined the metabolic and immune characteristics of 117 overweight individuals. Subjects were classified as metabolically healthy overweight (MHO, n = 72) or metabolically unhealthy overweight (MUO, n = 45). The immune response was measured by circulating levels of natural killer (NK) cell activity and cytokines. Both groups were comparable with regards to age, sex distribution, smoking and drinking status, and body mass index. When compared to the MHO group, the MUO group showed higher systolic and diastolic blood pressure, serum levels of triglyceride, glucose, glucose-related markers, and lower levels of HDL cholesterol. Compared to the MHO group, the MUO group showed 39% lower interferon-γ levels (not significant) and 41% lower interleukin (IL)-12 levels (significant). The MUO group also showed lower NK cell activity at E:T ratios of 10:1, 5:1, 2.5:1, and 1.25:1 (all Ps < 0.05) than the MHO group. This study indicates that individuals displaying the MUO phenotype present an unfavorable immune system with lower NK cell activities under all assay conditions and lower serum levels of IL-12 than the activities and levels in similarly overweight MHO individuals. This result suggests that the immune system may be altered in overweight individuals who are at risk for overweight/obesity-related comorbidities. PMID:29238351

Prokaryotic expression of chicken interferon-γ fusion protein and its effect on expression of poultry heat shock protein 70 under heat stress.

PubMed

Sun, Jinhua; Chen, Yinglin; Qin, Feiyue; Guan, Xueting; Xu, Wei; Xu, Liangmei

2017-06-01

Interferons have attracted considerable attention due to their vital roles in the host immune response and low induction of antibiotic resistance. In this study, total RNA was extracted from spleen cells of chicken embryos inoculated with Newcastle disease vaccine, and the full-length chicken interferon-γ (ChIFN-γ) gene was amplified by RT-PCR. The full complementary DNA sequence of the ChIFN-γ gene was 495 bp long and was cloned into the prokaryotic expression vector pProEX™HT b . The plasmid was transformed into Escherichia coli DH5α and the expression of ChIFN-γ was induced by isopropyl β-D-1-thiogalactopyranoside. Sodium dodecyl sulfate - polyacrylamide gel electrophoresis and Western blot results showed the expressed fusion protein had a molecular weight of approximately 18 kDa and was recognized by an anti-His mAb. Moreover, ChIFN-γ was found to demonstrate anti-viral activity in vitro. To test the in vivo function of ChIFN-γ in broilers under heat stress, a total of 100 broilers were randomly assigned to either a control group or a treated group, in which they were hypodermically injected with recombinant ChIFN-γ. Results demonstrated ChIFN-γ affects the messenger RNA expression levels of heat shock protein 70 (HSP70) in the heart and lung tissues, and decreases the concentration of HSP70 in serum. Therefore, we conclude recombinant ChIFN-γ can reduce heat stress to some extent in vivo. © 2016 Japanese Society of Animal Science.

Circulating exosomes from patients with systemic lupus erythematosus induce an proinflammatory immune response.

PubMed

Lee, Joo Youn; Park, Jin Kyun; Lee, Eun Young; Lee, Eun Bong; Song, Yeong Wook

2016-11-16

Exosomes are involved in intercellular communication. The aim of this study was to investigate whether circulating exosomes effectively contribute to the inflammatory response in systemic lupus erythematosus (SLE). Exosomes were purified from SLE patients and healthy controls (HCs). Healthy peripheral blood mononuclear cells (PBMCs) were stimulated with exosomes isolated from SLE patients and HCs in the presence or absence of Toll-like receptor (TLR) inhibitors. Production of interferon (IFN)-α, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were measured. Correlation between exosome levels and SLE disease activity was examined. The serum exosomes levels were significantly higher in SLE patients than in HCs. SLE exosomes induced a higher production of IFN-α, TNF-α, IL-1β, and IL-6 compared to healthy exosomes. SLE serum that was depleted of exosomes and SLE exosomes that were mechanically disrupted failed to induce any significant cytokine production. Exosome-mediated production of TNF-α, IL-1β, and IL-6 was decreased by the TLR4 antagonist, whereas that of IFN-α was suppressed by the TLR1/2, TLR7, and TLR9 antagonists. Exosome levels correlated with disease activity in SLE patients (rho = 0.846, p = 0.008). The circulating exosomes are immunologically active and their levels correlate with disease activity in SLE patients. The circulating exosomes might serve as novel biomarkers of SLE disease activity.

Aging is Associated with Impaired Renal Function, INF-gamma Induced Inflammation and with Alterations in Iron Regulatory Proteins Gene Expression.

PubMed

Costa, Elísio; Fernandes, João; Ribeiro, Sandra; Sereno, José; Garrido, Patrícia; Rocha-Pereira, Petronila; Coimbra, Susana; Catarino, Cristina; Belo, Luís; Bronze-da-Rocha, Elsa; Vala, Helena; Alves, Rui; Reis, Flávio; Santos-Silva, Alice

2014-12-01

Our aim was to contribute to a better understanding of the pathophysiology of anemia in elderly, by studying how aging affects renal function, iron metabolism, erythropoiesis and the inflammatory response, using an experimental animal model. The study was performed in male Wistar, a group of young rats with 2 months age and an old one with 18 months age. Old rats presented a significant higher urea, creatinine, interferon (INF)-gamma, ferritin and soluble transferrin receptor serum levels, as well as increased counts of reticulocytes and RDW. In addition, these rats showed significant lower erythropoietin (EPO) and iron serum levels. Concerning gene expression of iron regulatory proteins, old rats presented significantly higher mRNA levels of hepcidin (Hamp), transferrin (TF), transferrin receptor 2 (TfR2) and hemojuvelin (HJV); divalent metal transporter 1 (DMT1) mRNA levels were significantly higher in duodenal tissue; EPO gene expression was significantly higher in liver and lower in kidney, and the expression of the EPOR was significantly higher in both liver and kidney. Our results showed that aging is associated with impaired renal function, which could be in turn related with the inflammatory process and with a decline in EPO renal production. Moreover, we also propose that aging may be associated with INF-gamma-induced inflammation and with alterations upon iron regulatory proteins gene expression.

Age-related differences in interferon regulatory factor-4 and -5 signaling in ischemic brains of mice.

PubMed

Zhao, Shou-Cai; Wang, Chun; Xu, Heng; Wu, Wen-Qian; Chu, Zhao-Hu; Ma, Ling-Song; Zhang, Ying-Dong; Liu, Fudong

2017-11-01

Stroke is a disease that mainly affects the elderly. Since the age-related differences in stroke have not been well studied, modeling stroke in aged animals is clinically more relevant. The inflammatory responses to stroke are a fundamental pathological procedure, in which microglial activation plays an important role. Interferon regulatory factor-5 (IRF5) and IRF4 regulate M1 and M2 activation of macrophages, respectively, in peripheral inflammation; but it is unknown whether IRF5/IRF4 are also involved in cerebral inflammatory responses to stroke and whether age-related differences of the IRF5/IRF4 signaling exist in ischemic brain. Here, we investigated the influences of aging on IRF5/IRF4 signaling and post-stroke inflammation in mice. Both young (9-12 weeks) and aged (18 months) male mice were subjected to middle cerebral artery occlusion (MCAO). Morphological and biochemical changes in the ischemic brains and behavior deficits were assessed on 1, 3, and 7 d post-stroke. After MCAO, the aged mice showed smaller infarct sizes but higher neurological deficits and corner test scores than young mice. Young mice had higher levels of IRF4 and CD206 microglia in the ischemic brains, whereas the aged mice expressed more IRF5 and MHCII microglia. After MCAO, serum pro-inflammatory cytokines (TNF-α, iNOS, IL-6) were more prominently up-regulated in aged mice, whereas serum anti-inflammatory cytokines (TGF-β, IL-4, IL-10) were more prominently up-regulated in young mice. Our results demonstrate that aging has a significant influence on stroke outcomes in mice, which is probably mediated by age-specific inflammatory responses.

Assessment of Spontaneous Fluctuations of Viral Load in Untreated Patients with Chronic Hepatitis C by Two Standardized Quantitation Methods: Branched DNA and Amplicor Monitor

PubMed Central

Halfon, Philippe; Bourlière, Marc; Halimi, Gilles; Khiri, Hacène; Bertezene, Patrice; Portal, Isabelle; Botta-Fridlund, Danielle; Gauthier, André Pierre; Jullien, Monique; Feryn, Jean Marc; Gerolami, Victoria; Cartouzou, Guy

1998-01-01

Quantitation of hepatitis C virus (HCV) RNA in serum has been used to predict and monitor the efficacy of interferon therapy in chronic HCV infection. We prospectively studied the fluctuation of viremia by a longitudinal follow-up of HCV RNA levels for 2 months in six untreated patients. Spontaneous fluctuations of HCV RNA ranged from 2.8- to 5.7-fold with branched DNA assay and from 2.9- to 5.6-fold with Monitor. These large spontaneous fluctuations (up to 0.75 log), observed daily, weekly, and monthly, raise doubt about the clinical value of a single assessment of pretherapeutic viremia. PMID:9650965

The effect of centaurein on interferon-{gamma} expression and Listeria infection in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chang, S.-L.; Department of Biological Science and Technology, National Chiao Tung University, 1001, Ta Hsueh Road, Hsinchu 300, Taiwan; Yeh, H.-H.

2007-02-15

We previously found that centaurein enhanced IFN-{gamma} transcription in T cells. Here, we demonstrate that centaurein increased the IFN-{gamma} expression in T and NK cells and the serum IFN-{gamma} level in mice. Centaurein elevated the transcription of T-bet but not GATA-3, which is consistent with its effect on that of IFN-{gamma} but not IL-4. Additionally, centaurein effectively protected mice against Listeria infection. Moreover, centaurein per se or in combination with antibiotics could treat Listeria infection. Our mechanistic studies suggest that centaurein augments IFN-{gamma} expression via a transcriptional up-regulation of T-bet and that centaurein protects against or treats Listeria infection viamore » a modulation of IFN-{gamma} expression.« less

Innate immune function and mortality in critically ill children with influenza: a multicenter study.

PubMed

Hall, Mark W; Geyer, Susan M; Guo, Chao-Yu; Panoskaltsis-Mortari, Angela; Jouvet, Philippe; Ferdinands, Jill; Shay, David K; Nateri, Jyotsna; Greathouse, Kristin; Sullivan, Ryan; Tran, Tram; Keisling, Shannon; Randolph, Adrienne G

2013-01-01

To prospectively evaluate relationships among serum cytokine levels, innate immune responsiveness, and mortality in a multicenter cohort of critically ill children with influenza infection. Prospective, multicenter, observational study. Fifteen pediatric ICUs among members of the Pediatric Acute Lung Injury and Sepsis Investigators network. Patients ≤18 yrs old admitted to a PICU with community-acquired influenza infection. A control group of outpatient children was also evaluated. ICU patients underwent sampling within 72 hrs of ICU admission for measurement of a panel of 31 serum cytokine levels and quantification of whole blood ex vivo lipopolysaccharide-stimulated tumor necrosis factor-α production capacity using a standardized stimulation protocol. Outpatient control subjects also underwent measurement of tumor necrosis factor-α production capacity. Fifty-two patients (44 survivors, eight deaths) were sampled. High levels of serum cytokines (granulocyte macrophage colony-stimulating factor, interleukin-6, interleukin-8, interferon-inducible protein-10, monocyte chemotactic protein-1, and macrophage inflammatory protein-1α) were associated with mortality (p < 0.0016 for each comparison) as was the presence of secondary infection with Staphylococcus aureus (p = 0.007), particularly methicillin-resistant S. aureus (p < 0.0001). Nonsurvivors were immunosuppressed with leukopenia and markedly reduced tumor necrosis factor-α production capacity compared with outpatient control subjects (n = 21, p < 0.0001) and to ICU survivors (p < 0.0001). This association remained after controlling for multiple covariables. A tumor necrosis factor-α response <250 pg/mL was highly predictive of death and longer duration of ICU stay (p < 0.0001). Patients with S. aureus coinfection demonstrated the greatest degree of immunosuppression (p < 0.0001). High serum levels of cytokines can coexist with marked innate immune suppression in children with critical influenza. Severe, early innate immune suppression is highly associated with both S. aureus coinfection and mortality in this population. Multicenter innate immune function testing is feasible and can identify these high-risk children.

Induction of virus-specific effector immune cell response limits virus replication and severe disease in mice infected with non-lethal West Nile virus Eg101 strain.

PubMed

Kumar, Mukesh; Roe, Kelsey; O'Connell, Maile; Nerurkar, Vivek R

2015-09-22

West Nile virus (WNV) is a neurotropic flavivirus that has emerged globally as a significant cause of viral encephalitis in humans. Herein, we investigated the immunological responses induced by two phylogenetically related WNV strains of lineage 1, WNV NY99, and WNV Eg101. Eight-week-old C57BL/6J mice were inoculated with WNV NY99 or WNV Eg101 and mortality, virus burden in the periphery and brain, type 1 interferon response, WNV-specific antibodies, leukocyte infiltration, and inflammatory responses were analyzed. As expected, WNV NY99 infected mice demonstrated high morbidity and mortality, whereas no morbidity and mortality was observed in WNV Eg101 infected mice. Virus titers were comparable in the serum of both WNV NY99 and WNV Eg101 infected mice at day 3 after inoculation; however, at day 6, the virus was cleared from WNV Eg101 infected mice but the virus titer remained high in the WNV NY99 infected mice. Virus was detected in the brains of both WNV NY99 and Eg101 infected mice, albeit significantly higher in the brains of WNV NY99 infected mice. Surprisingly, levels of type 1 interferon and WNV-specific antibodies were significantly higher in the serum and brains of WNV NY99 infected mice. Similarly, protein levels of multiple cytokines and chemokines were significantly higher in the serum and brains of WNV NY99 infected mice. In contrast, we observed significantly higher numbers of innate and adaptive immune cells in the spleens and brains of WNV Eg101 infected mice. Moreover, total number and percentage of IFN-γ and TNF-α producing WNV-specific CD8(+) T cells were also significantly high in WNV Eg101 infected mice. Our data demonstrate that induction of virus-specific effector immune cell response limits virus replication and severe WNV disease in Eg101 infected mice. Our data also demonstrate an inverse correlation between leukocyte accumulation and production of pro-inflammatory mediators in WNV-infected mice. Moreover, increased production of pro-inflammatory mediators was associated with high-virus titers and increased mortality in WNV NY99 infected mice.

Treatment of lymphatic malformations of head and neck with OK-432 sclerotherapy induce systemic inflammatory response.

PubMed

Närkiö-Mäkelä, Mervi; Mäkelä, Teppo; Saarinen, Pia; Salminen, Päivi; Julkunen, Ilkka; Pitkäranta, Anne

2011-01-01

Systemic immune responses after OK-432 (Picibanil) sclerotherapy in patients with head and neck lymphatic malformations (LM) were examined to achieve a better understanding of the mechanism of OK-432 sclerotherapy and to evaluate the long-term treatment outcome. Serum samples from 17 consecutive patients with head and neck LMs were collected during a total of 26 OK-432 treatment episodes. Serum C-reactive protein (CRP), interleukins (IL) 1β, 6, 8, 10, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, RANTES, immune protein (IP)-10 and macrophage chemoattractant protein (MCP)-1 as well as blood leukocyte counts were determined. Clinical outcome of the treatment was evaluated at the last visit and from patient files. Elevated serum levels of IP-10 (means at baseline 702 ng/L, after 1 day 1180 ng/L, after 4 weeks 691 ng/L) were seen on day one after OK-432 sclerotherapy (p < 0.05). C-reactive protein and leukocyte counts 1 day after treatment differed statistically significantly (p < 0.05) from the baseline. No significant differences with other cytokines investigated were observed. Patients with macrocystic LM responded better than patients with microcystic LM (p = 0.01). The elevated levels of IP-10, C-reactive protein and leukocyte levels indicate that OK-432 sclerotherapy induces systemic immune responses in patients with LM. The mechanisms of OK-432 sclerotherapy are still not precisely understood, but the IP-10 elevation may reflect local antiangiogenetic properties of immunoactivation induced by OK-432.

Lipopolysaccharide and Its Analog Antagonists Display Differential Serum Factor Dependencies for Induction of Cytokine Genes in Murine Macrophages

PubMed Central

Perera, Pin-Yu; Qureshi, Nilofer; Christ, William J.; Stütz, Peter; Vogel, Stefanie N.

1998-01-01

Monocytes/macrophages play a central role in mediating the effects of lipopolysaccharide (LPS) derived from gram-negative bacteria by the production of proinflammatory mediators. Recently, it was shown that the expression of cytokine genes for tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and interferon-inducible protein-10 (IP-10) by murine macrophages in response to low concentrations of LPS is entirely CD14 dependent. In this report, we show that murine macrophages respond to low concentrations of LPS (≤2 ng/ml) in the complete absence of serum, leading to the induction of TNF-α and IL-1β genes. In contrast to the TNF-α and IL-1β genes, the IP-10 gene is poorly induced in the absence of serum. The addition of recombinant human soluble CD14 (rsCD14) had very little effect on the levels of serum-free, LPS-induced TNF-α, IL-1β, and IP-10 genes. In contrast, the addition of recombinant human LPS-binding protein (rLBP) had opposing effects on the LPS-induced TNF-α or IL-1β and IP-10 genes. rLBP inhibited LPS-induced TNF-α and IL-1β genes, while it reconstituted IP-10 gene expression to levels induced in the presence of serum. These results provide further evidence that the induction of TNF-α or IL-1β genes occurs via a pathway that is distinct from one that leads to the induction of the IP-10 gene and that the pathways diverge at the level of the initial interaction between LPS and cellular CD14. Additionally, the results presented here indicate that LPS structural analog antagonists Rhodobacter sphaeroides diphosphoryl lipid A and SDZ 880.431 are able to inhibit LPS-induced TNF-α and IL-1β in the absence of serum, while a synthetic analog of Rhodobacter capsulatus lipid A (B 975) requires both rsCD14 and rLBP to function as an inhibitor. PMID:9596717

Using Interferon Alfa Before Tyrosine Kinase Inhibitors May Increase Survival in Patients With Metastatic Renal Cell Carcinoma: A Turkish Oncology Group (TOG) Study.

PubMed

Artaç, Mehmet; Çoşkun, Hasan Şenol; Korkmaz, Levent; Koçer, Murat; Turhal, Nazım Serdar; Engin, Hüseyin; Dede, İsa; Paydaş, Semra; Öksüzoğlu, Berna; Bozcuk, Hakan; Demirkazık, Ahmet

2016-08-01

We aimed to investigate the outcomes of interferon alfa and sequencing tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma. This multicenter study assessing the efficacy of TKIs after interferon alfa therapy in the first-line setting in patients with metastatic renal cell carcinoma. Patients (n = 104) from 8 centers in Turkey, who had been treated with interferon alfa in the first-line setting, were included in the study. Prognostic factors were evaluated for progression-free survival (PFS). The median age of the patients was 57 years. The median PFS of the patients treated with interferon alfa in the first-line was 3.6 months. A total of 61 patients received TKIs (sunitinib, n = 58; sorafenib, n = 3) after progression while on interferon alfa. The median PFS among the TKI-treated patients was 13.2 months. In the univariate analysis for interferon alfa treatment, neutrophil and hemoglobin level, platelet count, and Karnofsky performance status were the significant factors associated with PFS. In the univariate analysis for TKI treatment, neutrophil and hemoglobin levels were the significant factors for PFS. The median total PFS of the patients who had been treated with first-line interferon alfa and second-line TKIs was 24.9 months. This study showed that first-line interferon alfa treatment before TKIs may improve the total PFS in patients with metastatic renal cell carcinoma. Copyright © 2016 Elsevier Inc. All rights reserved.

B Cell Depletion Therapy Normalizes Circulating Follicular Th Cells in Primary Sjögren Syndrome.

PubMed

Verstappen, Gwenny M; Kroese, Frans G M; Meiners, Petra M; Corneth, Odilia B; Huitema, Minke G; Haacke, Erlin A; van der Vegt, Bert; Arends, Suzanne; Vissink, Arjan; Bootsma, Hendrika; Abdulahad, Wayel H

2017-01-01

To assess the effect of B cell depletion therapy on effector CD4+ T cell homeostasis and its relation to objective measures of disease activity in patients with primary Sjögren syndrome (pSS). Twenty-four patients with pSS treated with rituximab (RTX) and 24 healthy controls (HC) were included. Frequencies of circulating effector CD4+ T cell subsets were examined by flow cytometry at baseline and 16, 24, 36, and 48 weeks after the first RTX infusion. Th1, Th2, follicular Th (TFH), and Th17 cells were discerned based on surface marker expression patterns. Additionally, intracellular cytokine staining was performed for interferon-γ, interleukin (IL)-4, IL-21, and IL-17 and serum levels of these cytokines were analyzed. In patients with pSS, frequencies of circulating TFH cells and Th17 cells were increased at baseline compared with HC, whereas frequencies of Th1 and Th2 cells were unchanged. B cell depletion therapy resulted in a pronounced decrease in circulating TFH cells, whereas Th17 cells were only slightly lowered. Frequencies of IL-21-producing and IL-17-producing CD4+ T cells and serum levels of IL-21 and IL-17 were also reduced. Importantly, the decrease in circulating TFH cells was associated with lower systemic disease activity over time, as measured by the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index scores and serum IgG levels. B cell depletion therapy in patients with pSS results in normalization of the elevated levels of circulating TFH cells. This reduction is associated with improved objective clinical disease activity measures. Our observations illustrate the pivotal role of the crosstalk between B cells and TFH cells in the pathogenesis of pSS.

Increased levels of immunological markers in the respiratory tract but not in serum correlate with active pulmonary mycobacterial infection in mice.

PubMed

Arko-Mensah, J; Rahman, M J; Julián, E; Horner, G; Singh, M; Fernández, C

2009-08-01

Immunological tests for the diagnosis of tuberculosis (TB) have relied mostly on detection of immune markers in serum or release of cytokines by mononuclear cells in vitro. These tests, although useful, sometimes fail to discriminate between active infection and contact with mycobacteria or vaccination. TB is primarily a disease of the lung, and therefore identification of immunological markers in the respiratory tract will be more likely to reflect the infection status or disease activity. In this study, it is demonstrated that active infection of mice with Mycobacterium bovis bacille Calmette-Guérin (BCG), but not exposure to heat-killed BCG, induced production of interleukin-12 (IL-12), interferon-gamma (IFN-gamma) or soluble tumour necrosis factor receptors (sTNFRs) locally in the lungs, as detected in bronchoalveolar lavage (BAL) fluid. There was a strong correlation between bacterial growth in the lung and levels of sTNFRs, and to some extent IL-12 and IFN-gamma, in BAL fluid. Furthermore, sTNFR levels increased significantly in BAL fluid after reactivation of controlled infection with dexamethasone, and this correlated with increased bacterial growth in the lungs. Finally, infection, but not exposure to non-replicating mycobacteria, induced specific IgG and IgA in BAL fluid. Elevated levels of all biomarkers measured were also detected in the serum, but correlation with infection was not as clear as in the case of BAL fluid. Taken together, the detection of sTNFRs and mycobacterium-specific antibodies, especially IgA, locally in the lungs could be used as immunological markers for the diagnosis of TB.

Cytokine Profile in Patients with Progressive Multiple Sclerosis and Its Association with Disease Progression and Disability.

PubMed

Kallaur, Ana Paula; Oliveira, Sayonara Rangel; Simão, Andréa Name Colado; Alfieri, Daniela Frizon; Flauzino, Tamires; Lopes, Josiane; de Carvalho Jennings Pereira, Wildea Lice; de Meleck Proença, Caio; Borelli, Sueli Donizete; Kaimen-Maciel, Damacio Ramón; Maes, Michael; Reiche, Edna Maria Vissoci

2017-05-01

Inflammation is the driving force for brain injury in patients with multiple sclerosis (MS). The objective of the present study is to delineate the serum cytokine profile in patients with progressive MS in a Southern Brazilian population compared with healthy controls and patients with relapsing-remitting MS (RRMS) and its associations with disease progression and disability. We included 32 patients with progressive MS, 126 with RRMS, and 40 healthy controls. The patients were evaluated using the Expanded Disability Status Scale (EDSS) and magnetic resonance imaging (MRI) with gadolinium. Serum interleukin (IL)-1β, IL-6, IL-12, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-10, IL-4, and IL-17 levels were assessed using an enzyme-linked immunosorbent assay. IL-1β, IL-6, TNF-α, IFN-γ, IL-17, IL-4, and IL-10 levels were higher in progressive MS than in controls. Increased IL-1β and IFN-γ and decreased IL-12 and IL-4 levels were found in progressive MS compared with RRMS. Patients with progressive MS with disease progression presented higher TNF-α, IFN-γ, and IL-10 levels than those without disease progression. Patients with progressive MS with disease progression showed a higher frequency of positive gadolinium-enhanced lesions in MRI; higher TNF-α, IFN-γ, and IL-17 levels; and decreased IL-12 levels compared with RRMS patients with progression. There was a significant inverse correlation between IL-10 levels and EDSS score in patients with progressive MS. The results underscore the complex cytokine network imbalance exhibited by progressive MS patients and show the important involvement of TNF-α, IFN-γ, and IL-17 in the pathophysiology and progression of the disease. Moreover, serum IL-10 levels were inversely associated with disability in patients with progressive MS.

Association between vitamin D deficiency and pre-existing resistance-associated hepatitis C virus NS5A variants.

PubMed

Okubo, Tomomi; Atsukawa, Masanori; Tsubota, Akihito; Shimada, Noritomo; Abe, Hiroshi; Yoshizawa, Kai; Arai, Taeang; Nakagawa, Ai; Itokawa, Norio; Kondo, Chisa; Aizawa, Yoshio; Iwakiri, Katsuhiko

2017-06-01

Although interferon-free therapy with direct-acting antivirals has developed as a standard of care for chronic hepatitis C, the existence of resistance-associated variants (RAVs) has a negative impact on treatment results. Recently, several studies indicated a relationship between chronic hepatitis C and serum vitamin D levels. However, the relationship between RAVs at the hepatitis C virus non-structure 5A (NS5A) region and serum vitamin D level has not yet been examined. Among patients with genotype 1 chronic hepatitis C who were enrolled in a multicenter cooperative study, our subjects comprised 247 patients in whom it was possible to measure RAVs at the NS5A region. These RAVs were measured using a direct sequencing method. The median age of patients was 70 years (range, 24-87 years), and the number of female patients was 135 (54.7%). The median serum 25(OH) D3 level was 22 ng/mL (range, 6-64 ng/mL). L31 and Y93 RAVs at the NS5A region were detected in 3.7% (9/247) and 13.4% (33/247) of patients, respectively. Multivariate analysis identified vitamin D deficiency (serum 25(OH) D3 ≤ 20 ng/mL) (P = 5.91 × 10⁻ 5 , odds ratio = 5.015) and elderly age (>70 years) (P = 1.85 × 10 -3 , odds ratio = 3.364) as contributing independent factors associated with the presence of the L31 and/or Y93 RAVs. The Y93H RAV was detected in 25.9% (29/112) of patients with a vitamin D deficiency, and in 8.9% (12/135) of those with a serum 25(OH) D3 level >20 ng/mL (P = 4.90 × 10 -3 ). We showed that RAVs at the NS5A region are associated with vitamin D deficiency and elderly age, which may have a negative influence on innate/adaptive immune responses to hepatitis C virus infection. © 2016 The Japan Society of Hepatology.

EFFECT OF INTERFERON-α ON CORTICAL GLUTAMATE IN PATIENTS WITH HEPATITIS C: A PROTON MRS STUDY

PubMed Central

Taylor, Matthew J; Godlewska, Beata; Near, Jamie; Christmas, David; Potokar, John; Collier, Jane; Klenerman, Paul; Barnes, Eleanor; Cowen, Philip J

2013-01-01

Background The development of depressive symptomatology is a recognised complication of treatment with the cytokine, interferon-α, and has been seen as supporting inflammatory theories of the pathophysiology of major depression. Major depression has been associated with changes in glutamatergic activity and recent formulations of interferon-induced depression have implicated neurotoxic influences which could also lead to changes in glutamate function. The present study used magnetic resonance spectroscopy (MRS) to measure both glutamate and its major metabolite, glutamine in patients with hepatitis C who received treatment with pegylated-interferon-α and ribavirin. Methods MRS measurements of glutamate and glutamine were taken from a 25×20×20mm voxel including pregenual anterior cingulate cortex in 12 patients before and after 4-6 weeks treatment with interferon. Results Interferon treatment led to an increase in cortical levels of glutamine (p= 0.02) and a significant elevation in the ratio of glutamine to glutamate (p<.01). Further, changes in glutamine level correlated significantly with ratings of depression and anxiety at the time of the second scan. Conclusions We conclude that treatment with interferon-α is associated with MRS-visible changes in glutamatergic metabolism. However, the changes seen differ from those reported in major depression which suggests that the pathophysiology of interferon-induced depression may be distinct from that of major depression more generally. PMID:23659574

Interferon-gamma inhibits HIV-induced invasiveness of monocytes.

PubMed

Dhawan, S; Wahl, L M; Heredia, A; Zhang, Y; Epstein, J S; Meltzer, M S; Hewlett, I K

1995-12-01

HIV-infected monocytes form highly invasive network on basement membrane matrix and secrete high levels of 92-kd metalloproteinase (MMP-9), an enzyme that degrades basement membrane proteins. In the present study, using matrigel as a model basement membrane system, we demonstrate that treatment of human immunodeficiency virus (HIV)-infected monocytes with interferon-gamma at 50 U/ml inhibited the ability of infected monocytes to form an invasive network on matrigel and their invasion through the matrigel matrix. These effects were associated with a significant reduction in the levels of MMP-9 produced by HIV-infected monocytes treated with interferon-gamma 1 day prior to infection with HIV as compared with that of untreated HIV-infected monocytes. Monocytes treated with interferon-gamma 1 day after HIV infection showed the presence of integrated HIV sequences; however, the levels of MMP-9 were substantially lower than those produced by monocytes inoculated with live HIV, heat-inactivated HIV, or even the control uninfected monocytes. Exposure of monocytes to heat-inactivated HIV did not result in increased invasiveness or high MMP-9 production, suggesting that regulation of metalloproteinase by monocytes was independent of CD4-gp120 interactions and required active virus infection. Furthermore, addition of interferon-gamma to monocytes on day 10 after infection inhibited MMP-9 production by more than threefold with no significant reduction of virus replication. These results indicate that the mechanism of interferon-gamma-induced down-regulation of MMP-9 levels and reduced monocyte invasiveness may be mediated by a mechanism independent of antiviral activity of IFN-gamma in monocytes. Down-regulation of MMP-9 in HIV-infected monocytes by interferon-gamma may play an important role in the control of HIV pathogenesis.

Preliminary investigation of human serum albumin-Vβ inhibition on toxic shock syndrome induced by staphylococcus enterotoxin B in vitro and in vivo.

PubMed

Yuan, Qifeng; Li, Lin; Pian, Yaya; Hao, Huaijie; Zheng, Yuling; Zang, Yating; Jiang, Hua; Jiang, Yongqiang

2016-04-01

Staphylococcus enterotoxin B (SEB) is a superantigen that can induce massive activation of T cells with specific Vβ and inflammatory cytokine cascades, which mediate shock. To date, no SEB vaccine has been developed for preventing toxic shock syndrome (TSS). Here, we evaluated the therapeutic effect of a fusion protein human serum albumin-Vβ (HSA-Vβ) on TSS induced by SEB. Compared with Vβ, the preparation of HSA-Vβ was much easier to handle owing to its solubility. Affinity testing showed that HSA-Vβ had high affinity for SEB. In vitro results showed that HSA-Vβ could effectively inhibit interferon (IFN)-γ and tumor necrosis factor (TNF)-α secretion by human peripheral blood mononuclear cells. Moreover, in vivo, HSA-Vβ reduced IFN-γ and TNF-α levels in the serum and protected mice from SEB lethal challenge when administered simultaneously with SEB or 30 min after SEB. In summary, we simplified the preparation of Vβ by fusion with HSA, creating the HSA-Vβ protein, which effectively inhibited cytokine production and protected mice from lethal challenge with SEB. These data indicated that HSA-Vβ may represent a novel therapeutic strategy for the treatment of SEB-induced TSS. Copyright © 2016 Elsevier Ltd. All rights reserved.

Improved viability and activity of neutrophils differentiated from HL-60 cells by co-culture with adipose tissue-derived mesenchymal stem cells.

PubMed

Park, Yoon Shin; Lim, Goh-Woon; Cho, Kyung-Ah; Woo, So-Youn; Shin, Meeyoung; Yoo, Eun-Sun; Chan Ra, Jeong; Ryu, Kyung-Ha

2012-06-22

Neutropenia is a principal complication of cancer treatment. We investigated the supportive effect of adipose tissue-derived mesenchymal stem cells (AD-MSCs) on the viability and function of neutrophils. Neutrophils were derived from HL-60 cells by dimethylformamide stimulation and cultured with or without AD-MSCs under serum-starved conditions to evaluate neutrophil survival, proliferation, and function. Serum starvation resulted in the apoptosis of neutrophils and decreased cell survival. The co-culture of neutrophils and AD-MSCs resulted in cell survival and inhibited neutrophil apoptosis under serum-starved conditions. The survival rate of neutrophils was prolonged up to 72 h, and the expression levels of interferon (IFN)-α, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, and transforming growth factor (TGF)-β in AD-MSCs were increased after co-culture with neutrophils. AD-MSCs promoted the viability of neutrophils by inhibiting apoptosis as well as enhancing respiratory burst, which could potentially be mediated by the increased expression of IFN-α, G-CSF, and TGF-β. Thus, we conclude that the use of AD-MSCs may be a promising cell-based therapy for increasing immunity by accelerating neutrophil function. Copyright © 2012 Elsevier Inc. All rights reserved.

Serum cytokine profiles of children with human enterovirus 71-associated hand, foot, and mouth disease.

PubMed

Han, Jun; Wang, Ying; Gan, Xing; Song, Juan; Sun, Peng; Dong, Xiao-Ping

2014-08-01

Cytokine profiles may impact the pathogenicity and severity of hand, foot, and mouth disease caused by human enterovirus (HEV) 71. In 91 severe or mild HEV 71-associated hand, foot, and mouth disease children, serum was collected between days 2 and 10 or day >10. Serum cytokines including Type 1 T helper (Th1) cytokines: interleukin (IL)-2, interferon-gamma (IFN-γ), IL-12, and IL-18, Type 1 T helper (Th2) cytokines: IL-4, IL-10, IL-13, proinflammatory cytokines: IL-1α, IL-1β, IL-6, IL-8, IL-17, and tumor necrosis factor alpha (TNF-α), were assessed during the early stage and recovery. In the patients with mild illness, the peaks of IL-8 and IL-10 were observed on day 6 and that of IL-18 was on day 4. In the patients with severe illness, all cytokines spiked on day 3 and peaked on day 11. All cytokines except IL-6, IL-8, IL-18, and TNF-α were significantly correlated with immunoglobulin M levels by the end of the disease course. Cytokine profile variations between the patients with mild and severe illness may indicate prognosis and strain virulence, useful in clinical treatment of patients. © 2014 Wiley Periodicals, Inc.

Consumption of protein-enriched milk has minor effects on inflammation in older adults-A 12-week double-blind randomized controlled trial.

PubMed

Gjevestad, Gyrd O; Ottestad, Inger; Biong, Anne Sofie; Iversen, Per Ole; Retterstøl, Kjetil; Raastad, Truls; Skålhegg, Bjørn S; Ulven, Stine M; Holven, Kirsten B

2017-03-01

Aging is associated with increased levels of circulating inflammatory markers and reduced muscle mass and strength. We investigated whether intake of protein-enriched milk for 12 weeks would influence markers of inflammation among adults ≥70years of age with reduced physical strength. In a double-blind randomized controlled intervention study, subjects were randomly allocated into two groups, receiving a protein-enriched milk (2×20g protein/d, n=14, mean (±SD) age 76.9±4.9 yrs) or an isocaloric carbohydrate drink (n=17, age 77.7±4.8 yrs) for 12 weeks. We measured serum and mRNA expression levels of inflammatory markers in PBMCs. Significant differences in the mRNA expression of nuclear receptor subfamily, group H, member 3 (NR1H3, encoding the LXRα transcription factor) and interferon gamma (INFG) were observed between groups. The mRNA level of TNFRSF1A was significantly reduced, while the mRNA level of dipeptidyl-peptidase 4 (DPP4) was significantly increased, in the control group. The serum level of TNFα increased significantly in the control group, while sTNFRSF1A increased significantly in both groups, but with no significant differences between groups. Consumption of a low-fat, protein-enriched milk for 12 weeks had minor effects on inflammatory related markers in older adults compared to an isocaloric carbohydrate drink. Copyright © 2017 Elsevier B.V. All rights reserved.

Fibrosing cholestatic hepatitis after successful interferon and ribavirin therapy for recurrent hepatitis C post living related liver transplantation: a case report.

PubMed

Yamamoto, Takatsugu; Tanaka, Shogo; Uenishi, Takahiro; Kanazawa, Akishige; Kubo, Shoji; Hirohashi, Kazuhiro

2014-12-01

A 33-year-old Japanese man who had suffered from liver cirrhosis due to hepatitis C virus (HCV) underwent living related liver transplantation (LRLT). The allograft was given by his brother, who was healthy with no history of hepatitis or hepatic virus infection. After LRLT, the patient's hepatitis C recurred. Liver biopsy revealed chronic viral hepatitis and no allograft rejection such as shown by portal lymphocytic infiltration or mild bridging fibrosis. Interferon and ribavirin were administered, and sustained viral response (SVR) was obtained. Although serum hepatitis B virus (HBV)-DNA/HCV-RNA polymerase chain reaction found no presence of hepatic virus, the serum examination demonstrated liver dysfunction seven months after SVR. Liver biopsies histopathologically showed portal fibrosis invading to the sinusoids, cholestasis, mild hyperplasia of the cholangioles, and no features of allograft rejection. Fibrosing cholestatic hepatitis (FCH) was diagnosed. The FCH was resistant to treatment and advanced, and the patient died 17 months post-LRLT. Several serum examinations failed to demonstrate the existence of HBV/HCV during the patient's course. FCH is a type of viral hepatitis that is characterized by recurrent viral hepatitis after allograft transplantation. Because SVR obtained by anti-viral therapy commonly resolves FCH, we believe that this patient represented a rare case of FCH. The present case suggests that not only direct viral cytotoxicity, but other factors as well, promote the development of fibrosis and cholestasis. FCH sometimes progresses irreversibly despite the absence of serum viral load. The present case informed us that immediate anti-viral therapy should be initiated when recurrent allograft viral hepatitis is diagnosed.

Inflammatory Biomarkers Predict Airflow Obstruction After Exposure to World Trade Center Dust

PubMed Central

Nolan, Anna; Naveed, Bushra; Comfort, Ashley L.; Ferrier, Natalia; Hall, Charles B.; Kwon, Sophia; Kasturiarachchi, Kusali J.; Cohen, Hillel W.; Zeig-Owens, Rachel; Glaser, Michelle S.; Webber, Mayris P.; Aldrich, Thomas K.; Rom, William N.; Kelly, Kerry; Prezant, David J.

2012-01-01

Background: The World Trade Center (WTC) collapse on September 11, 2001, produced airflow obstruction in a majority of firefighters receiving subspecialty pulmonary evaluation (SPE) within 6.5 years post-September 11, 2001. Methods: In a cohort of 801 never smokers with normal pre-September 11, 2001, FEV1, we correlated inflammatory biomarkers and CBC counts at monitoring entry within 6 months of September 11, 2001, with a median FEV1 at SPE (34 months; interquartile range, 25-57). Cases of airflow obstruction had FEV1 less than the lower limit of normal (LLN) (100 of 801; 70 of 100 had serum), whereas control subjects had FEV1 greater than or equal to LLN (153 of 801; 124 of 153 had serum). Results: From monitoring entry to SPE years later, FEV1 declined 12% in cases and increased 3% in control subjects. Case subjects had elevated serum macrophage derived chemokine (MDC), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor, and interferon inducible protein-10 levels. Elevated GM-CSF and MDC increased the risk for subsequent FEV1 less than LLN by 2.5-fold (95% CI, 1.2-5.3) and 3.0-fold (95% CI, 1.4-6.1) in a logistic model adjusted for exposure, BMI, age on September 11, 2001, and polymorphonuclear neutrophils. The model had sensitivity of 38% (95% CI, 27-51) and specificity of 88% (95% CI, 80-93). Conclusions: Inflammatory biomarkers can be risk factors for airflow obstruction following dust and smoke exposure. Elevated serum GM-CSF and MDC levels soon after WTC exposure were associated with increased risk of airflow obstruction in subsequent years. Biomarkers of inflammation may help identify pathways producing obstruction after irritant exposure. PMID:21998260

Significance of day-1 viral response of hepatitis C virus in patients with chronic hepatitis C receiving direct-acting antiviral therapy.

PubMed

Toyoda, Hidenori; Kumada, Takashi; Tada, Toshifumi; Yama, Tsuyoki; Mizuno, Kazuyuki

2018-06-01

On-treatment response of serum hepatitis C virus (HCV) is reportedly less useful to predict the outcome of anti-HCV therapy with interferon (IFN)-free regimen with direct-acting antivirals than with IFN-based regimens in clinical trials. We evaluated the significance of very early viral response after the start of therapy, which indicates direct HCV response to the drugs, on therapeutic outcome. Reductions in serum HCV-RNA levels were measured at 1 day after the start of therapy in 544 patients who underwent IFN-free direct-acting antiviral regimens. The association between these reductions and the achievement or failure of sustained virologic response (SVR) was evaluated. Patient characteristics did not influence 1-day reduction in serum HCV-RNA except for liver fibrosis. There was no difference in 1-day HCV reduction between SVR and non-SVR patients treated with a 24-week regimen. In contrast, in patients treated with a 12-week regimen, 1-day reduction was significantly greater in SVR than in non-SVR patients (P = 0.0013) and was predictive of SVR versus non-SVR (area under the receiver-operating characteristics curve: 0.80). Whereas the reduction in serum HCV-RNA levels at 1 day after the start of therapy was not associated with treatment outcomes in patients who underwent a 24-week regimen of IFN-free therapy, there was an association in patients receiving a 12-week regimen, and this reduction was predictive of SVR, thus potentially serving as a factor to identify patients at risk of treatment failure. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Expression Profile of Interferon Regulatory Factor 1 in Chronic Hepatitis B Virus-Infected Liver Transplant Patients.

PubMed

Janfeshan, Sahar; Yaghobi, Ramin; Eidi, Akram; Karimi, Mohammad Hossein; Geramizadeh, Bita; Malekhosseini, Seyed Ali; Kafilzadeh, Farshid

2017-12-01

Hepatitis B virus, which mainly affects normal liver function, leads to severe acute and chronic hepatitis, resulting in cirrhosis and hepatocellular carcinoma, but can be safely treated after liver transplant. Evaluation of determinative biomarkers may facilitate more effective treatment of posttransplant rejection. Therefore, we investigated interferon regulatory factor 1 expression in hepatitis B virus-infected liver transplant patients with and without previous rejection compared with controls. Hepatitis B virus-infected liver recipients were divided into those with (20 patients) and without a rejection (26 patients), confirmed by pathologic analyses in those who had a rejection. In addition, a healthy control group composed of 13 individuals was included. Expression levels of interferon regulatory factor 1 were evaluated during 3 follow-ups after transplant using an in-house comparative SYBR green real-time polymerase chain reaction method. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 16.0, IBM Corporation, Armonk, NY, USA). Modifications of interferon regulatory factor 1 gene expression levels in patient groups with and without rejection were not significant between days 1, 4, and 7 after liver transplant. Interferon regulatory factor 1 mRNA expression levels were down-regulated in patients without rejection versus patients with rejection, although not significantly at day 1 (P = .234) and day 4 (P = .302) but significantly at day 7 (P = .004) after liver transplant. Down-regulation of interferon regulatory factor 1 gene expression in hepatitis B virus patients without rejection emphasized counteraction between hepatitis B virus replication and interferon regulatory factor 1 production. On the other hand, interferon regulatory factor 1 gene overexpression in patients with rejection may result in inflammatory reactions and ischemic-reperfusion injury. Therefore, a better understanding of the association between interferon regulatory factor 1 and hepatitis B virus pathogenesis in a larger population with longer follow-up is needed.

Cellular and humoral immunity after vaccination or natural mumps infection.

PubMed

Terada, Kihei; Hagihara, Kimiko; Oishi, Tomohiro; Miyata, Ippei; Akaike, Hiroto; Ogita, Satoko; Ohno, Naoki; Ouchi, Kazunobu

2017-08-01

This study measured cell-mediated immunity (CMI) and serum antibody to clarify the basis of breakthrough after vaccination and reinfection after mumps. From a pool of 54 college students, 17 seronegative subjects and 14 subjects with intermediate level of antibodies against mumps were vaccinated with a monovalent mumps vaccine, and CMI was assessed using interferon-γ release assay. CMI positivity according to pre-existing antibody level, defined as titer <2.0 index units, negative; 2.0-3.9 index units, intermediate; and ≥4.0 index units, positive, was 8/17 (47.1%), 9/14 (64.3%) and 19/23 (82.6%) before vaccination, respectively. Of the 17 seronegative subjects, seven (41.2%) had a history of vaccination and/or natural infection, four (57.1%) of whom were CMI positive or intermediate. Ten (71%) of 14 subjects with intermediate antibody level had a history of vaccination or natural infection, eight (80%) of whom were CMI positive or intermediate. After vaccination the interferon (IFN)-γ and antibody titers increased significantly, but seven (41.2%) of the 17 seronegative subjects and 13 (92.9%) of the 14 intermediate-level subjects tested positive for both antibody and CMI. In a comparison of the natural infection group (confirmed as IgG seropositive and/or CMI positive without vaccination) versus the vaccination group, IgG antibody titer (mean ± SD) was 14.4 ± 8.0 versus 3.6 ± 2.4 index units (P < 0.01) and IFN-γ was 122.7 ± 90.0 pg/mL versus 59.5 ± 37.8 pg/mL (P > 0.05), respectively. Vaccination or even natural mumps infection did not always induce both cellular and humoral immunity. © 2017 Japan Pediatric Society.

Possible importance of macrophage-derived mediators in acute malaria.

PubMed Central

Clark, I A; Virelizier, J L; Carswell, E A; Wood, P R

1981-01-01

Tumor necrosis factor, lymphocyte-activating factor, and enhanced levels of type I interferon were found in serum samples taken 2 h after mice infected with Plasmodium vinckei subsp. petteri received a small intravenous injection of endotoxin. These three mediators are among those released when mice receive an endotoxin injection 2 weeks after Mycobacterium bovis BCG or Corynebacterium parvum have been administered. There is indirect evidence that this wider range of mediators is also released in P. vinckei subsp. petteri-infected mice given parenteral endotoxin. A recent report that endotoxin is detectable in the plasma of malaria-infected mice and children implies that these mediators may also be released in the acute phase of the natural infection. We propose that these macrophage-derived mediators may be important in the glucocorticoid antagonism, bone marrow depression, fever, hypergammaglobulinemia, splenomegaly, elevation of serum amyloid A, consumptive coagulopathy, and shock syndrome with associated organ damage which can accompany malaria. The intraerythrocytic parasite death seen at crisis in some malarias, as well as the subsequent development of specific protective immunity, may also depend on these mediators. PMID:6166564

Rapid activation of the interferon system in vivo.

PubMed Central

Dianzani, F; Gullino, P; Baron, S

1978-01-01

Experiments were carried out to study the kinetics of local interferon production in the subcutaneous tissues of rats stimulated with Newcastle disease virus. Specifically, the interferon produced and released in the extracellular fluids was collected at various intervals of time in micropore chambers implanted into the subcutaneous tissue of rats. Interferon was detected at moderate titers 1 h after induction, and it was present at high titer at 2 h. The interferon levels remained remarkably high in the samples collected after 3, 5, and 24 h, and in some rats it was still detectable after 48 and 72 h. Since control experiments showed that it requires 2 to 3 h for interferon to penetrate the chambers, it may be concluded that high concentrations of interferon are present in the extracellular fluid within 1 h of induction. The evaluation of the kinetics of production and of the concentrations attained in the extracellular fluid suggests that in a solid tissue a cell infected by a potent interferon inducer may produce interferon early enough and in sufficient quantity to protect neighboring cells before the production of progeny virions. PMID:669799

Fluorosis increases the risk of postmenopausal osteoporosis by stimulating interferon γ.

PubMed

Lv, Yun-Gang; Kang, Li; Wu, Guangyao

2016-10-14

Estrogen deficiency in postmenopausal women frequently activates osteoclasts (OC), accelerates bone resorption, and leads to osteoporosis (OP). Previous studies have demonstrated that interferon γ (IFNγ) could increase bone resorption and may be involved in postmenopausal OP. Fluorosis also increased the risk of fractures and dental fluorosis, and fluoride may enhance osteoclast formation and induce osteoclastic bone destruction in postmenopausal women, but the underlying mechanisms are as yet unknown. Here, we show that serum fluoride and IFNγ levels are negatively correlated with bone mineral density (BMD) in postmenopausal women residing in a fluorotic area. Estrogen suppresses IFNγ, which is elevated by fluoride, playing a pivotal role in triggering bone loss in estrogen-deficient conditions. In vitro, IFNγ is inhibited by estrogen treatment and increased by fluoride in Raw264.7 cell, an osteoclast progenitor cell line. In ovariectomized (Ovx) mice, estrogen loss and IFNγ promote OC activation and subsequent bone loss in vivo. However, IFNγ deficiency prevents bone loss in Ovx mice even in fluoride conditions. Interestingly, fluoride fails to increase IFNγ expression in estrogen receptor α (ERα)-deficient conditions, but not in ERβ-deficient conditions. These findings demonstrate that fluorosis increases the bone loss in postmenopausal OP through an IFNγ-dependent mechanism. IFNγ signaling activates OC and aggravates estrogen deficiency inducing OP. Thus, stimulation of IFNγ production is a pivotal ''upstream'' mechanism by which fluoride promotes bone loss. Suppression of IFNγ levels may constitute a therapeutic approach for preventing bone loss. Copyright © 2016 Elsevier Inc. All rights reserved.

Maternal serum but not breast milk IL-5, IL-6, and IL-13 immune markers are associated with scratching among infants.

PubMed

Soto-Ramírez, Nelís; Boyd, Keith; Zhang, Hongmei; Gangur, Venugopal; Goetzl, Laura; Karmaus, Wilfried

2016-01-01

Scratching in infants is considered to be related to early development of eczema. Little is known about the effects of maternal immune markers on scratching among infants. The objective is to compare the risks related to maternal serum immune markers (IMs) during pregnancy and IMs in breast milk for the occurrence of scratching in infants at 6 and 12 months of age. Pregnant women were recruited in Columbia and Charleston, South Carolina. Blood (median 3 weeks prepartum) and breast milk (3 weeks postpartum) samples were collected. The concentrations of interferon (IFN)-γ, IFN gamma-induced protein 10 (IP-10) (or CXCL10), CCL11, interleukin (IL) 1β, IL-4, IL-5, IL-6, IL-8 (CXCL8), IL-10, IL-12 (p70), IL-13, transforming growth factor (TGF)-β1, and immunoglobulin (Ig) A in both maternal serum and whey were assayed using optimized immunoassays. Scratching and skin manifestations were ascertained at 6 and 12 months. Generalized estimating equations were used to estimate relative risks (RRs) of IMs for repeated measurements of scratching, considering intra-individual correlations and adjusting for confounders. Of 178 women, 161 provided blood and 115 breast milk samples. IL-1β, IL-4, IL-10, IL-12, and CCL11 in maternal serum and whey were not analyzed due to a large proportion of non-detectable values. Infants in the highest tertile of IL-6 and IL-13 in maternal serum were at higher risk of scratching (RR 1.73 and 1.84, respectively; p ≤ 0.002) compared to infants in the first tertile; similarly, infants born to mothers with high (versus low) levels of serum IL-5 were also at increased risk (RR 1.60, p = 0.002). None of the breast milk IMs studied were associated with scratching. Scratching but not doctors diagnosed eczema was associated with higher levels of maternal IL-5, IL-6, and IL-13 during pregnancy. Further investigations are necessary to determine how maternal serum IMs influence infants scratching.

Impact of heart rate variability, a marker for cardiac health, on lupus disease activity.

PubMed

Thanou, Aikaterini; Stavrakis, Stavros; Dyer, John W; Munroe, Melissa E; James, Judith A; Merrill, Joan T

2016-09-02

Decreased heart rate variability (HRV) is associated with adverse outcomes in cardiovascular diseases and has been observed in patients with systemic lupus erythematosus (SLE). We examined the relationship of HRV with SLE disease activity and selected cytokine pathways. Fifty-three patients from the Oklahoma Lupus Cohort were evaluated at two visits each. Clinical assessments included the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group (BILAG) index, physician global assessment (PGA), and Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI Flare Index. HRV was assessed with a 5-minute electrocardiogram, and the following HRV parameters were calculated: square root of the mean of the squares of differences between adjacent NN intervals (RMSSD), percentage of pairs of adjacent NN intervals differing by more than 50 milliseconds (pNN50), high-frequency power (HF power), and low frequency to high frequency (LF/HF) ratio, which reflects sympathetic/vagal balance. Plasma cytokine levels were measured with a multiplex, bead-based immunoassay. Serum B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) were measured with an enzyme-linked immunosorbent assay. Linear regression analysis was applied. Baseline HRV (pNN50, HF power, LF/HF ratio) was inversely related to disease activity (BILAG, PGA) and flare. Changes in RMSSD between visits were inversely related to changes in SLEDAI (p = 0.007). Age, caffeine, tobacco and medication use had no impact on HRV. Plasma soluble tumor necrosis factor receptor II (sTNFRII) and monokine induced by interferon gamma (MIG) were inversely related with all baseline measures of HRV (p = 0.039 to <0.001). Plasma stem cell factor (SCF), interleukin (IL)-1 receptor antagonist (IL-1RA), and IL-15 showed similar inverse relationships with baseline HRV, and weaker trends were observed for interferon (IFN)-α, interferon gamma-induced protein (IP)-10, and serum BLyS. Changes in the LF/HF ratio between visits were also associated with changes in sTNFRII (p = 0.021), MIG (p = 0.003), IFN-α (p = 0.012), SCF (p = 0.001), IL-1RA (p = 0.023), and IL-15 (p = 0.010). On the basis of multivariate linear regression, MIG was an independent predictor of baseline HRV after adjusting for plasma IL-1RA, SCF, IFN-α, IP-10, and serum BLyS. In a similar model, the sTNFRII impact remained significant after adjusting for the same variables. Impaired HRV, particularly the LF/HF ratio, is associated with lupus disease activity and several cytokines related to IFN type II and TNF pathways. The strongest association was with MIG and sTNFRII, expanding previous immune connections of vagal signaling.

Successful control of juvenile dermatomyositis-associated macrophage activation syndrome and interstitial pneumonia: distinct kinetics of interleukin-6 and -18 levels.

PubMed

Wakiguchi, Hiroyuki; Hasegawa, Shunji; Hirano, Reiji; Kaneyasu, Hidenobu; Wakabayashi-Takahara, Midori; Ohga, Shouichi

2015-11-18

Macrophage activation syndrome (MAS) is the secondary hemophagocytic lymphohistiocytosis associated with rheumatic diseases. Recently, the different cytokine profiles between systemic juvenile idiopathic arthritis (sJIA)-associated MAS (sJIA-MAS) and juvenile systemic lupus erythematosus (JSLE)-associated MAS (JSLE-MAS) were reported. However, there is little information about juvenile dermatomyositis (JDM)-associated MAS (JDM-MAS). A 4-year-old girl with JDM was hospitalized because of fever, erythema, hepatosplenomegaly, cytopenia, liver dysfunction and coagulopathy. Bone marrow aspiration revealed appreciable numbers of activated and hemophagocytosing macrophages. She was diagnosed as having JDM-MAS complicated with interstitial pneumonia (IP) based on the findings of the elevation of serum Krebs von den Lungen-6 (KL-6) levels and chest computed tomography findings. We analyzed circulating levels of interleukin (IL)-2,4,6,10,18, tumor necrosis factor-α and interferon-γ in the patient. Hypercytokinemia occurred at the diagnosis of MAS and IP, showing with the prominent elevations of IL-6 and IL-18 levels. The cytokine profiles were distinct from those reported in patients with sJIA-MAS or JSLE-MAS. High-dose corticosteroid and cyclosporine therapy led to a drastic improvement of MAS with decreased IL-6 levels. Subsequent cyclophosphamide therapy successfully controlled IP, paralleled with the declining pattern of IL-18 and KL-6 levels. This is the first report to describe a successful treatment and the cytokine profile of JDM-MAS and IP. Serum IL-6 and IL-18 levels may be useful for predicting the disease activity of JDM-MAS and IP, respectively.

Localized mucosal response to intranasal live attenuated influenza vaccine in adults.

PubMed

Barría, Maria Ines; Garrido, Jose Luis; Stein, Cheryl; Scher, Erica; Ge, Yongchao; Engel, Stephanie M; Kraus, Thomas A; Banach, David; Moran, Thomas M

2013-01-01

Influenza virus infection is a major public health burden worldwide. Available vaccines include the inactivated intramuscular trivalent vaccine and, more recently, an intranasal live attenuated influenza vaccine (LAIV). The measure of successful vaccination with the inactivated vaccine is a systemic rise in immunoglobulin G (IgG) level, but for the LAIV no such correlate has been established. Seventy-nine subjects were given the LAIV FluMist. Blood was collected prior to vaccination and 3 days and 30 days after vaccination. Nasal wash was collected 3 days and 30 days after vaccination. Responses were measured systemically and in mucosal secretions for cytokines, cell activation profiles, and antibody responses. Only 9% of subjects who received LAIV seroconverted, while 33% of patients developed at least a 2-fold increase in influenza virus-specific immunoglobulin A (IgA) antibodies in nasal wash. LAIV induced a localized inflammation, as suggested by increased expression of interferon-response genes in mucosal RNA and increased granulocyte colony-stimulating factor (G-CSF) and IP-10 in nasal wash. Interestingly, patients who seroconverted had significantly lower serum levels of G-CSF before vaccination. Protection by LAIV is likely provided through mucosal IgA and not by increases in systemic IgG. LAIV induces local inflammation. Seroconversion is achieved in a small fraction of subjects with a lower serum G-CSF level.

Serial cytokine alterations and abnormal neuroimaging in newborn infants with encephalopathy.

PubMed

O'Hare, Fiona M; Watson, R William G; O'Neill, Amanda; Segurado, Ricardo; Sweetman, Deirdre; Downey, Paul; Mooney, Eoghan; Murphy, John; Donoghue, Veronica; Molloy, Eleanor J

2017-04-01

Inflammatory cytokines may play a role in the final common pathway in the pathogenesis of hypoxic-ischaemic injury in experimental models. We aimed to profile the systemic pro-and anti-inflammatory response over the first week of life in term infants at risk of neonatal encephalopathy. In a tertiary referral university neonatal intensive care unit, serial blood samples were analysed from 41 term infants (requiring resuscitation at birth) in this prospective observational pilot study. Serum levels of 10 pro-and anti-inflammatory cytokines were evaluated including interleukin(IL)-1α, IL-1β, IL-6, IL-8, IL-10, tumour necrosis factor(TNF)-α, interferon (IFN)-γ, vascular endothelial growth factor (VEGF), granulocyte/colony-stimulating factor (G-CSF) and granulocyte macrophage/colony-stimulating factor (GM-CSF). Infants with neonatal encephalopathy and abnormal neuroimaging (n = 15) had significantly elevated granulocyte macrophage/colony-stimulating factor at 0-24 h and interleukin-8, interleukin-6 and interleukin-10 at 24-48 hour. Tumour necrosis factor-α and vascular endothelial growth factor levels were lower at 72-96 hour (p < 0.05). Significantly elevated levels of interleukin-10 were associated with mortality. Serum cytokine changes and innate immune dysregulation in the first week of life may be indicators of outcome in neonatal encephalopathy but require validation in larger studies. ©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

Virologic response to treatment with Pegylated Interferon alfa-2b and Ribavirin for chronic hepatitis C in children.

PubMed

Pawłowska, Malgorzata; Pilarczyk, Malgorzata; Halota, Waldemar

2010-12-01

This study assessed the efficacy and safety of treatment of chronic hepatitis C in children with pegylated interferon alpha and ribavirin. Investigations were performed on 53 children with chronic hepatitis C, aged 8-17 years. Children were divided into 2 groups: naïve (n=29) and retreated (n=24). All children were administered a combined therapy with pegylated interferon (IFN) alpha-2b 1.5 mcg/kg/wk and ribavirin 15 mg/kg/d for 48 weeks. Mean baseline viral load was 0.456×10(6) IU/mL, mean alanine aminotransferase (ALT) activity was 45.8±24.3 IU/mL. No child had liver disease assessed greater than grade 2, stage 2 according to modified Scheuer scale. Serum hepatitis C virus (HCV) RNA in TW 12-EVR, TW 48-ETR, and W 72-sustained virologic response (SVR) with the polymerase chain reaction (PCR) method (Roche TaqMan) were evaluated. Sustained virologic response was achieved in 47% of children. The prevalence of relapses was 7.5%. The most important predictor of SVR in both groups was undetectable HCV RNA at TW 12. All retreated children who achieved partial EVR - (the HCV RNA level decreased more than 2 logs relative to baseline) were relapsers. In responders from both groups, baseline ALT activity was higher and baseline viral load was lower. In all children who achieved SVR, HCV RNA was undetectable 12 months later. Pegylated IFN and ribavirin are effective in treating chronic hepatitis C in children. Complete EVR is predictive of a sustained viral response. And high rate of relapses in retreated patients may suggest a longer duration of retherapy.

Interleukin 6 production in experimental cerebral malaria: modulation by anticytokine antibodies and possible role in hypergammaglobulinemia

PubMed Central

1990-01-01

The production of Interleukin 6 (IL-6) was studied during experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA (PbA) infection. IL-6 is present in the serum of mice with ECM, the highest concentrations being observed in mice with full-blown neurological syndrome. High IL-6 levels were also observed, however, in the absence of pathology in nonlethal malaria infection. These data suggest that IL- 6 is produced in large amounts during malaria infection, but does not play a major role in the pathogenesis of ECM. A modulation of IL-6 production in ECM was achieved by in vivo treatment with other anticytokine antibodies: antibodies to interferon (IFN-gamma) or to tumor necrosis factor (TNF) abolished the rise of IL-6, while anti-IL-3 and anti-granulocyte/macrophage colony-stimulating factor antibodies only partially prevented this rise, suggesting that the two cytokines IFN-gamma and TNF are important intermediates in IL-6 production. Passive immunization against IL-6 did not prevent ECM, but significantly reduced serum IgG levels in malaria-infected mice. Thus, by its effects on B cells, IL-6 may be involved in hypergammaglobulinemia and immune-complex diseases, e.g., glomerulonephritis observed during malaria infection. PMID:2121890

Influence of Anti-Mouse Interferon Serum on the Growth and Metastasis of Tumor Cells Persistently Infected with Virus and of Human Prostatic Tumors in Athymic Nude Mice

NASA Astrophysics Data System (ADS)

Reid, Lola M.; Minato, Nagahiro; Gresser, Ion; Holland, John; Kadish, Anna; Bloom, Barry R.

1981-02-01

Baby hamster kidney or HeLa cells form tumors in 100% of athymic nude mice. When such cells are persistently infected (PI) with RNA viruses, such as mumps or measles virus, the tumor cells either fail to grow or form circumscribed benign nodules. Neither the parental nor the virus PI tumor cells form invasive or metastatic lesions in nude mice. Previous studies have indicated a correlation between the susceptibility of virus-PI tumor cells in vitro and the cytolytic activity of natural killer (NK) cells and their failure to grow in vivo. Because interferon (IF) is the principal regulatory molecule governing the differentiation of NK cells, it was possible to test the relevance of the IF--NK cell system in vivo to restriction of tumor growth by treatment of nude mice with anti-IF globulin. This treatment was shown to reduce both IF production and NK activity in spleen cells. Both parental and virus-PI tumor cells grew and formed larger tumors in nude mice treated with anti-IF globulin than in control nude mice. The viral-PI tumor cells and the uninfected parental cells formed tumors in treated mice that were highly invasive and often metastatic. Some human tumor types have been notoriously difficult to establish as tumor lines in nude mice (e.g., primary human prostatic carcinomas). When transplanted into nude mice treated either with anti-IF globulin or anti-lymphocyte serum, two prostatic carcinomas grew and produced neoplasms with local invasiveness and some metastases. The results are consistent with the view that interferon may be important in restricting the growth, invasiveness, and metastases of tumor cells by acting indirectly through components of the immune system, such as NK cells.

A new type of natural bispecific antibody with potential protective effect in Hashimoto thyroiditis.

PubMed

Li, Wenli; Fan, Gaowei; Chen, Lida; Zhang, Rui; Zhang, Kuo; Sun, Yu; Lin, Guigao; Xie, Jiehong; Wang, Lunan; Li, Jinming

2014-09-01

As a new antibody concept, natural bispecific antibodies (nBsAbs) have been detected in long-term passive immunization and some diseases, but their potential immunomodulatory role remains unclear. Hashimoto thyroiditis (HT) appears to fulfill the condition for nBsAb production but has not yet been characterized. The objective of the study was to identify a new nBsAb against thyroid peroxidase (TPO) and thyroglobulin (Tg) in HT patients and to preliminarily explore its immunomodulatory role. Serum samples were obtained from 136 HT patients, 92 diseased controls, and 99 healthy controls for anti-TPO/Tg nBsAb detection. The relationship between anti-TPO/Tg nBsAb and other clinical parameters was also analyzed. The anti-TPO/Tg nBsAb was detected using a double-antigen sandwich ELISA. Higher nBsAb levels were found to be associated with decreased inflammation in HT patients. The prevalence of anti-TPO/Tg nBsAb in HT was 44.9% (61 of 136), significantly higher than that of diseased controls (2.2%, 2 of 92) (P < .0001) and healthy controls (0%, 0 of 99) (P < .0001). HT patients who were nBsAb positive were prone to have significantly lower levels of serum C-reactive protein and TNF-α compared with the nBsAb-negative individuals (P < .05). The serum amyloid A and interferon-γ levels also showed a similar trend in the two groups. The IgG subclass of anti-TPO/Tg nBsAb was IgG4. Further analysis showed a negative correlation between anti-TPO/Tg nBsAb and serum total IgG4 (r = -0.697, P = .025) in IgG4 thyroiditis patients. A new type of nBsAb against TPO and Tg in HT patients is identified. Our data also indicate a protective effect of anti-TPO/Tg nBsAb in the pathogenesis of HT and extend prior knowledge about nBsAb in diseases.

Aquaporin-4 antibodies in patients treated with natalizumab for suspected MS

PubMed Central

Gahlen, Anna; Trampe, Anne-Kathrin; Haupeltshofer, Steffen; Ringelstein, Marius; Aktas, Orhan; Berthele, Achim; Wildemann, Brigitte; Gold, Ralf; Jarius, Sven

2017-01-01

Objective: To evaluate (1) the frequency of aquaporin-4 antibody (AQP4-ab)-seropositive cases among patients treated with natalizumab (NAT) and previously diagnosed with MS (MSNAT) in a nationwide cohort, (2) the clinical course of NAT-treated AQP4-ab–seropositive neuromyelitis optica spectrum disorder (NMOSD) patients (NMONAT), (3) AQP4-ab titers in NMONAT and AQP4-ab–seropositive NMOSD treated with other immunotherapies (NMOIT), and (4) immune mechanisms influencing disease activity in NMONAT. Methods: MSNAT serum samples were retrospectively screened with a cell-based assay for AQP4-IgG and titers determined by ELISA. The annualized relapse rate (ARR) and disability progression were assessed. Serum levels of proinflammatory cytokines (interleukin [IL]-1β, IL-4, IL-6, IL-8, IL-10, IL-17, IL-21, and interferon [IFN]-γ) and the chemokine CXCL-10 of NMONAT patients identified in this (n = 4) and a previous study (n = 5) were measured by cytometric bead array and ELISA. Results: Of the 1,183 MSNAT patients (851 female, median 9 NAT infusions), only 4 (0.33%; 3 female, 1 male) had AQP4-IgG. Of these, 2 fulfilled the 2006 NMO criteria and all met the 2015 NMOSD criteria. The ARR was higher in NMONAT vs MSNAT (p = 0.0182). All 4 NMONAT patients had relapses and 2 had an increase of disability. AQP4-ab titers were higher in NMONAT (n = 9) vs NMOIT (n = 13; p = 0.0059). IL-8, IL-1β, and IFN-γ serum levels were significantly higher, and CXCL-10 was significantly lower in NMONAT vs NMOIT. Conclusions: Misdiagnosis of NMOSD with MS is rare. NAT was not able to control disease activity in NMONAT patients, who had higher serum levels of AQP4-IgG and proinflammatory cytokines than patients with NMOSD treated with other immunotherapies. PMID:28642888

Increased PD-1+CD154+ Tfh cells are possibly the most important functional subset of PD-1+ T follicular helper cells in adult patients with minimal change disease.

PubMed

Li, Tao; Shi, Yunpeng; Sun, Weixia; Wang, Haifeng; Wang, Quan; Jiang, Yanfang

2018-02-01

T follicular helper (Tfh) cells, especially programmed cell death protein 1 (PD-1) + Tfh cells, exert important functions in the normal immune response. The purpose of this study was to determine the frequency of different subsets of PD-1 + Tfh cells and their functional effects in adult patients with minimal change disease (MCD). The frequencies of circulating PD-1 + , PD-1 + CD154 + , and PD-1 + interleukin (IL)-21 + Tfh cells, and CD38 + CD19 + and CD38 + CD19 + CD40 + B cells, as well as serum IL-2, IL-4, IL-17A, IL-6, IL-21, and interferon (IFN)-γ were significantly increased in the MCD patients compared with the healthy controls (HCs) (P < 0.05). However, no significant difference was found in PD-1 + BCL-6 + or PD-1 + ICOS + Tfh cells. Furthermore, the percentages of PD-1 + Tfh and PD-1 + CD154 + Tfh cells were negatively correlated with the estimated glomerular filtration rate (eGFR), but positively correlated with the 24-h urinary protein concentration and serum IL-21 level. The percentages of PD-1 + Tfh and PD-1 + CD154 + Tfh cells were positively correlated with the percentages of CD38 + plasma cells and active CD38 + CD40 + plasma cells, respectively. After an 8-12-week treatment with prednisolone, the percentages of PD-1 + , PD-1 + CD154 + , and PD-1 + IL-21 + Tfh cells as well as the serum level of IL-21 were significantly reduced; in contrast, the serum levels of IL-4 and IL-10 were increased (P < 0.05). We conclude that increased PD-1 + CD154 + Tfh cells are possibly the most important functional subset of PD-1 + Tfh cells and may contribute towards the pathogenesis of MCD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tributyltin Exposure Alters Cytokine Levels in Mouse Serum

PubMed Central

Lawrence, Shanieek; Pellom, Samuel T.; Shanker, Anil; Whalen, Margaret M.

2016-01-01

Tributyltin (TBT), a toxic environmental contaminant, has been widely utilized for various industrial, agricultural and household purposes. Its usage has led to a global contamination and its bioaccumulation in aquatic organisms and terrestrial mammals. Previous studies suggest that TBT has debilitating effects on the overall immune function of animals, rendering them more vulnerable to diseases. TBT (at concentrations that have been detected in human blood) alters secretion of inflammatory cytokines from human lymphocytes ex vivo. Thus, it is important to determine if specified levels of TBT can alter levels of cytokines in an in vivo system. Mice were exposed to biologically relevant concentrations of TBT (200, 100 or 25 nM final concentrations). The quantitative determination of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL2, IL5, IL7, IL12βp40, IL13, IL15, KC, MIP1β, MIP2 and RANTES was performed in mouse sera by MAGPIX analysis and Western blot. Results indicated alterations (both decreases and increases) in several cytokines. The pro-inflammatory cytokines IFNγ, TNFα, IL-1β, IL-2, IL5, IL12βp40, and IL-15 were altered as were the chemokines MIP-1 and RANTES and the anti-inflammatory cytokine IL-13. Increases in IFNγ and TNFα were seen in serum of mice exposed to TBT for less than 24 hr. IL1-β, IL-12βp40, IL-5 and IL-15 were also modulated in mouse serum depending on the specific experiment and the exposure concentration. IL-2 was consistently decreased in mouse serum when animals were exposed to TBT. There were also TBT-induced increases in MIP-1β, RANTES, and IL-13. These results from human and murine samples clearly suggest that TBT exposures modulate the secretion inflammatory cytokines. PMID:27602597

Type I interferons modulate methotrexate resistance in gestational trophoblastic neoplasia.

PubMed

Elias, Kevin M; Harvey, Richard A; Hasselblatt, Kathleen T; Seckl, Michael J; Berkowitz, Ross S

2017-06-01

Resistance to methotrexate is a leading clinical problem in gestational trophoblastic neoplasia (GTN), but there are limited laboratory models for this condition. We created isogenic trophoblastic cell lines resistant to methotrexate and compared these to the parent cell lines using gene expression microarrays and qRT-PCR followed by mechanistic studies using recombinant cytokines, pathway inhibitors, and patient sera. Gene expression microarrays and focused analysis by qRT-PCR revealed methotrexate led to type I interferon upregulation, in particular interferon alpha 2 (IFNA2), and methotrexate resistance was associated with chronic low level increases in type I interferon expression. Recombinant IFNA2 imparted chemosensitive choriocarcinoma cells with partial resistance to methotrexate, while chemoresistant choriocarcinoma cells were uniquely sensitive to fludarabine, a STAT1 inhibitor. In pre-treatment patient sera, IFNA2 levels correlated with subsequent resistance to methotrexate chemotherapy. Methotrexate resistance is influenced by type I interferon signaling with prognostic and therapeutic implications for treating women with GTN. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Feasibility of commercial space manufacturing, production of pharmaceuticals. Volume 3: Product data

NASA Technical Reports Server (NTRS)

1978-01-01

The feasibility of commercial manufacturing of pharmaceuticals in space is analyzed and the study results are presented. The chronology of the study process is discussed. The separation of serum proteins by the continuous flow electrophoresis process is investigated. The production requirements of twelve candidate products including antihemophilic factor, beta cells, erythropoietin, epidermal growth factor, alpha-1-antitrypsin, and interferon are evaluated.

Growth hormone/IGF-1 axis longitudinal evaluation in clinically isolated syndrome patients on interferon β-1b therapy: stimulation tests and correlations with clinical and radiological conversion to multiple sclerosis.

PubMed

Lanzillo, R; Di Somma, C; Quarantelli, M; Carotenuto, A; Pivonello, C; Moccia, M; Cianflone, A; Marsili, A; Puorro, G; Saccà, F; Russo, C V; De Luca Picione, C; Ausiello, F; Colao, A; Brescia Morra, V

2017-02-01

Growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis abnormalities in multiple sclerosis (MS) suggest their role in its pathogenesis. Interferon β (IFN-β) efficacy could be mediated also by an increase of IGF-1 levels. A 2-year longitudinal study was performed to estimate the prevalence of GH and/or IGF-1 deficiency in clinically isolated syndrome (CIS) patients and their correlation with conversion to MS in IFN treated patients. Clinical and demographic features of CIS patients were collected before the start of IFN-β-1b. IGF-1 levels and GH response after arginine and GH releasing hormone + arginine stimulation tests were assessed. Clinical and magnetic resonance imaging evaluations were performed at baseline, 1 year and 2 years. Thirty CIS patients (24 female) were enrolled. At baseline, four patients (13%) showed a hypothalamic GH deficiency (GHD), whilst no one had a pituitary GHD. Baseline demographic, clinical and radiological data were not related to GHD, whilst IGF-1 levels were inversely related to age (P < 0.001) and GH levels (P = 0.03). GH and IGF-1 serum mean levels were not significantly modified after 1 and 2 years of treatment in the whole group, although 3/4 GHD patients experienced a normalization of GH levels, whilst one dropped out. After 2 years of treatment 13/28 (46%) patients converted to MS. The presence of GHD and GH and IGF-1 levels were not predictive of relapses, new T2 lesions or conversion occurrence. Growth hormone/IGF-1 axis function was found to be frequently altered in CIS patients, but this was not related to MS conversion. Patients experienced an improvement of GHD during IFN therapy. Longer follow-up is necessary to assess its impact on disease progression. © 2016 EAN.

Biomarkers of methylmercury exposure immunotoxicity among fish consumers in Amazonian Brazil.

PubMed

Nyland, Jennifer F; Fillion, Myriam; Barbosa, Fernando; Shirley, Devon L; Chine, Chiameka; Lemire, Melanie; Mergler, Donna; Silbergeld, Ellen K

2011-12-01

Mercury (Hg) is a ubiquitous environmental contaminant with neurodevelopmental and immune system effects. An informative biomarker of Hg-induced immunotoxicity could aid studies on the potential contribution to immune-related health effects. Our objectives were to test the hypothesis that methylmercury (MeHg) exposures affect levels of serum biomarkers and to examine interactions between Hg and selenium (Se) in terms of these responses. This cross-sectional epidemiological study assessed adults living along the Tapajós River, a system long affected by MeHg. We measured antinuclear (ANA) and antinucleolar (ANoA) autoantibody levels and eight cytokines in serum samples (n = 232). Total Hg (including MeHg) and Se were measured in blood, plasma, hair, and urine. The median (range) total Hg concentrations were 14.1 μg/g (1.1-62.4), 53.5 μg/L (4.3-288.9), 8.8 μg/L (0.2-40), and 3.0 μg/L (0.2-16.1) for hair, blood, plasma, and urine, respectively. Elevated titers of ANA (but not ANoA) were positively associated with MeHg exposure (log-transformed, for blood and plasma), unadjusted [odds ratio (OR) = 2.6; 95% confidence interval (CI): 1.1, 6.2] and adjusted for sex and age (OR = 2.9; 95% CI: 1.1, 7.5). Proinflammatory [interleukin (IL)-6 and interferon (IFN)-γ], anti-inflammatory (IL-4), and IL-17 cytokine levels were increased with MeHg exposure; however, in the subset of the population with elevated ANA, proinflammatory IL-1β, IL-6, IFN-γ, and tumor necrosis factor (TNF)-α and anti-inflammatory (IL-4) cytokine levels were decreased with MeHg exposure. Although Se status was associated with MeHg level (correlation coefficient = 0.86; 95% CI: 0.29, 1.43), Se status was not associated with any changes in ANA and did not modify associations between Hg and ANA titers. MeHg exposure was associated with an increased ANA and changes in serum cytokine profile. Moreover, alterations in serum cytokine profiles differed based on ANA response, suggesting a specific phenotype of MeHg susceptibility. Further research on the potential health implications of these observed immunological changes is warranted.

Interleukin-17A correlates with interleukin-6 production in human cystic echinococcosis: a possible involvement of IL-17A in immunoprotection against Echinococcus granulosus infection.

PubMed

Mezioug, Dalila; Touil-Boukoffa, Chafia

2012-01-01

Hydatidosis is a parasitic disease caused by the development, in humans and other mammals, of the larval form of Taenia, Echinococcus granulosus. It is one of the world's major zoonotic infections. This study aimed to examine interleukin-6 (IL-6), interferon-γ (IFN-γ) and interleukin-17A (IL-17A) production in patients with cystic echinococcosis (CE), and the role of IL-17A in the modulation of the immune response against the extracellular parasite, E. granulosus. A relationship between IL-6, IL-17A production and C reactive Protein (CRP) levels was also assessed. IL-6, IFN-γ, IL-17A and CRP production were determined in serum from Algerian hydatid patients. Cytokine production was also measured in supernatants from cultures of peripheral blood mononuclear cells (PBMCs) from hydatid patients stimulated by a major parasitic antigen (antigen-5). The increased activity of IL-6, IFN-γ and IL-17A were observed in most serum samples from patients. In contrast, healthy controls showed only minor levels. Similarly, high levels of CRP were detected. Our in vitro results indicate a positive correlation between IL-6, IFN-γ and IL-17A production in PBMC culture supernatants. However, IL-6, IFN-γ and IL-17A activity was low in serum and supernatants of PBMC cultures from relapsing patients, and there was no evidence of an immune response against parasitic antigen. Collectively, our results show that IL-17A was produced during human cystic echinococcosis, and was involved in the host defense mechanisms against the extracellular parasite E. granulosus. Our data suggest that IL-17A plays an immunoprotective role in this parasitic, helminth infection.

Ayanin, a non-selective phosphodiesterase 1-4 inhibitor, effectively suppresses ovalbumin-induced airway hyperresponsiveness without affecting xylazine/ketamine-induced anesthesia.

PubMed

Lee, Fei-Peng; Shih, Chwen-Ming; Shen, Hsin-Yi; Chen, Chien-Ming; Chen, Chi-Ming; Ko, Wun-Chang

2010-06-10

In recent in vitro reports, the IC(50) value of ayanin (quercetin-3,7,4'-O-trimethylether) was 2.2microM for inhibiting interleukin (IL)-4 production from purified basophils, and its therapeutic ratio was >19. Therefore, we were interested in investigating the effects on ovalbumin induced airway hyperresponsiveness in vivo, and to clarify its potential for treating asthma. Ayanin (30-100micromol/kg, orally (p.o.)) dose-dependently and significantly attenuated the enhanced pause (P(enh)) value induced by methacholine in sensitized and challenged mice. It also significantly suppressed the increases in total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils, and levels of cytokines, including IL-2, IL-4, IL-5, and tumor necrosis factor (TNF)-alpha in bronchoalveolar lavage fluid of these mice. However, at 100micromol/kg, it significantly enhanced the level of interferon (IFN)-gamma. In addition, ayanin (30-100micromol/kg, p.o.) dose-dependently and significantly suppressed total and OVA-specific immunoglobulin (Ig)E levels in the serum and bronchoalveolar lavage fluid, and enhanced the IgG(2a) level in serum of these mice. In the present results, ayanin did not affect xylazine/ketamine-induced anesthesia, suggesting that ayanin has few or no adverse effects, such as nausea, vomiting, and gastric hypersecretion. In conclusion, the above results suggest that ayanin may have the potential for use in treating allergic asthma.

Toxicological effect of TiO2 nanoparticle-induced myocarditis in mice

NASA Astrophysics Data System (ADS)

Hong, Fashui; Wang, Ling; Yu, Xiaohong; Zhou, Yingjun; Hong, Jie; Sheng, Lei

2015-08-01

Currently, impacts of exposure to TiO2 nanoparticles (NPs) on the cardiovascular system are not well understood. The aim of this study was to investigate whether TiO2 NPs induce myocarditis and its underlying molecular mechanism in the cardiac inflammation in mice. Mice were exposed to TiO2 NPs for 6 months; biochemical parameters of serum and expression of Th1-related and Th2-related cytokines in the heart were investigated. The results showed that TiO2 NP exposure resulted in cardiac lesions coupling with pulmonary inflammation; increases of aspartate aminotransferase (AST), creatine kinase (CK), C-reaction protein (CRP), lactate dehydrogenase (LDH), alpha-hydroxybutyrate dehydrogenase (HBDH), adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1) levels; and a reduction of nitric oxide (NOx) level in the serum. These were associated with increases of nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), interleukin (IL)-4, IL-6, transforming growth factor-β (TGF-β), creatine kinase, CRP, adhesion molecule-1, and monocyte chemoattractant protein-1, interferon-γ (IFN-γ), signal transducers and activators of transcription (STAT)1, STAT3, or STAT6, GATA-binding domain-3, GATA-binding domain-4, endothelin-1 expression levels, and T-box expressed in T cells expression level that is the master regulator of pro-inflammatory cytokines and transcription factors in the heart. These findings imply that TiO2 NP exposure may increase the occurrence and development of cardiovascular diseases.

Short-term effects of an anti-inflammatory treatment on clinical parameters and serum levels of C-reactive protein and proinflammatory cytokines in subjects with periodontitis.

PubMed

Renvert, Stefan; Lindahl, Christel; Roos-Jansåker, Ann-Marie; Lessem, Jan

2009-06-01

Periodontal disease is the most common multifactorial disease, afflicting a very large proportion of the adult population. Periodontal disease secondarily causes increases in the serum levels of C-reactive protein (CRP) and other markers of inflammation. An increased level of CRP reflects an increased risk for cardiovascular disease. The aim of the current randomized clinical trial was to evaluate the short-term effect of a combination of dipyridamole and prednisolone (CRx-102) on the levels of high-sensitivity (hs)-CRP, proinflammatory markers in blood, and clinical signs of periodontal disease. Fifty-seven patients with >/=10 pockets with probing depths >/=5 mm were randomized into two groups in this masked single-center placebo-controlled study: CRx-102 (n = 28) and placebo (n = 29). hs-CRP levels, inflammatory markers (interleukin [IL]-6, -1beta, -8, and -12, tumor necrosis factor-alpha, and interferon-gamma [IFN-gamma]), bleeding on probing (BOP), and changes in probing depths were evaluated. The subjects received mechanical non-surgical therapy after 42 days, and the study was completed after 49 days. At day 42, the differences in the hs-CRP, IFN-gamma, and IL-6 levels between the two groups were statistically significant (P <0.05), whereas no difference was found for the other inflammatory markers. There was no change in probing depth or BOP between the two groups. The administration of CRx-102 resulted in significant decreases in hs-CRP, IFN-gamma, and IL-6, but it did not significantly change BOP or probing depths.

(99) Tc-methylene diphosphonate improves rheumatoid arthritis disease activity by increasing the frequency of peripheral γδ T cells and CD4(+) CD25(+) Foxp3(+) Tregs.

PubMed

Su, Dinglei; Shen, Minning; Gu, Bingjie; Wang, Xiaoqin; Wang, Dandan; Li, Xia; Sun, Lingyun

2016-06-01

γδ T cells exhibit important functions in the pathogenesis of rheumatoid arthritis (RA). In recent years, numerous studies harnessed the γδ T cell-activating capacity of aminobiphosphonates for the treatment of malignant tumors. As (99) Tc-methylene diphosphonate ((99) Tc-MDP) has long been widely used for the treatment of RA in China with good efficacy, we are interested in whether this drug exerts its therapeutic effect on RA by modulating peripheral γδ T cells of RA patients. To investigate the effect of (99) Tc-MDP on the frequency of γδ T cells and CD4(+) CD25(+) Foxp3(+) Tregs in the peripheral blood of patients with active RA. Nineteen patients with active RA were treated with (99) Tc-MDP intravenously at a dose of 20 μg/day consecutively for 10-14 days. Before and after treatment, the main clinical and laboratory parameters for each patient were evaluated. The frequency of CD3(+) γδ(+) T cells and CD4(+) CD25(+) Foxp3(+) Tregs was detected by flow cytometry. Serum levels of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10 and transforming growth factor (TGF)-β were measured with enzyme-linked immunosorbent assay. After intravenous (99) Tc-MDP therapy, the frequency of peripheral CD3(+) γδ(+) T cells and CD4(+) CD25(+) Foxp3(+) Tregs were significantly elevated, paralleled with decreased serum levels of TNF-α and IL-6 and increased level of serum TGF-β. The elevation of peripheral CD3(+) γδ(+) T cells was positively correlated with increased serum TGF-β and decreased disease activity. (99) Tc-MDP may improve the activity of RA through upregulating the frequency of peripheral γδ T cells and CD4(+) CD25(+) Foxp3(+) Tregs as well as affecting the serum cytokine environment by increasing TGF-β and decreasing TNF-α and IL-6. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

INF-γ Enhances Nox2 Activity by Upregulating phox Proteins When Applied to Differentiating PLB-985 Cells but Does Not Induce Nox2 Activity by Itself.

PubMed

Ellison, Michael A; Thurman, Gail; Gearheart, Christy M; Seewald, Ryan H; Porter, Christopher C; Ambruso, Daniel R

2015-01-01

The cytokine and drug interferon-γ enhances superoxide anion production by the antimicrobicidal Nox2 enzyme of neutrophils. Because mature neutrophils have a short lifespan, we hypothesized that the effects of interferon-γ on these cells might be mediated by its prolonged exposure to differentiating neutrophil precursors in the bone marrow rather than its brief exposure to mature circulating neutrophils. Effects of INF-Γ on NOX2 activity: To address this possibility we exposed the myeloid PLB-985 cell line to interferon-γ for 3 days in the presence of dimethyl sulfoxide which induces terminal differentiation of these cells. Interferon-γ was found to enhance superoxide production by Nox2 in a concentration dependent manner. In contrast, application of interferon-γ alone for 3 days failed to induce detectible Nox2 activity. Additionally, application of interferon-γ for 3 hours to pre-differentiated PLB-985 cells, which models studies using isolated neutrophils, was much less effective at enhancing superoxide anion production. Effects of INF-Γ on phox protein levels: Addition of interferon-γ during differentiation was found to upregulate the Nox2 proteins gp91phox and p47phox in concert with elevated transcription of their genes. The p22phox protein was upregulated in the absence of increased transcription presumably reflecting stabilization resulting from binding to the elevated gp91phox. Thus, increased levels of gp91phox, p47phox and p22phox likely account for the interferon-γ mediated enhancement of dimethyl sulfoxide-induced Nox2 activity. In contrast, although interferon-γ alone also increased various phox proteins and their mRNAs, the pattern was very different to that seen with interferon-γ plus dimethyl sulfoxide. In particular, p47phox was not induced thus explaining the inability of interferon -γ alone to enhance Nox2 activity. Short application of interferon-γ to already differentiated cells failed to increase any phox proteins. Our findings indicate that interferon-γ has complex effects on phox protein expression and that these are different in cells undergoing terminal differentiation. Understanding these changes may indicate additional therapeutic uses for this cytokine in human disorders.

Host Defense against Viral Infection Involves Interferon Mediated Down-Regulation of Sterol Biosynthesis

PubMed Central

Blanc, Mathieu; Hsieh, Wei Yuan; Robertson, Kevin A.; Watterson, Steven; Shui, Guanghou; Lacaze, Paul; Khondoker, Mizanur; Dickinson, Paul; Sing, Garwin; Rodríguez-Martín, Sara; Phelan, Peter; Forster, Thorsten; Strobl, Birgit; Müller, Matthias; Riemersma, Rudolph; Osborne, Timothy; Wenk, Markus R.; Angulo, Ana; Ghazal, Peter

2011-01-01

Little is known about the protective role of inflammatory processes in modulating lipid metabolism in infection. Here we report an intimate link between the innate immune response to infection and regulation of the sterol metabolic network characterized by down-regulation of sterol biosynthesis by an interferon regulatory loop mechanism. In time-series experiments profiling genome-wide lipid-associated gene expression of macrophages, we show a selective and coordinated negative regulation of the complete sterol pathway upon viral infection or cytokine treatment with IFNγ or β but not TNF, IL1β, or IL6. Quantitative analysis at the protein level of selected sterol metabolic enzymes upon infection shows a similar level of suppression. Experimental testing of sterol metabolite levels using lipidomic-based measurements shows a reduction in metabolic output. On the basis of pharmacologic and RNAi inhibition of the sterol pathway we show augmented protection against viral infection, and in combination with metabolite rescue experiments, we identify the requirement of the mevalonate-isoprenoid branch of the sterol metabolic network in the protective response upon statin or IFNβ treatment. Conditioned media experiments from infected cells support an involvement of secreted type 1 interferon(s) to be sufficient for reducing the sterol pathway upon infection. Moreover, we show that infection of primary macrophages containing a genetic knockout of the major type I interferon, IFNβ, leads to only a partial suppression of the sterol pathway, while genetic knockout of the receptor for all type I interferon family members, ifnar1, or associated signaling component, tyk2, completely abolishes the reduction of the sterol biosynthetic activity upon infection. Levels of the proteolytically cleaved nuclear forms of SREBP2, a key transcriptional regulator of sterol biosynthesis, are reduced upon infection and IFNβ treatment at both the protein and de novo transcription level. The reduction in srebf2 gene transcription upon infection and IFN treatment is also found to be strictly dependent on ifnar1. Altogether these results show that type 1 IFN signaling is both necessary and sufficient for reducing the sterol metabolic network activity upon infection, thereby linking the regulation of the sterol pathway with interferon anti-viral defense responses. These findings bring a new link between sterol metabolism and interferon antiviral response and support the idea of using host metabolic modifiers of innate immunity as a potential antiviral strategy. PMID:21408089

Human endogenous retrovirus expression is inversely related with the up-regulation of interferon-inducible genes in the skin of patients with lichen planus.

PubMed

Nogueira, Marcelle Almeida de Sousa; Gavioli, Camila Fátima Biancardi; Pereira, Nátalli Zanete; de Carvalho, Gabriel Costa; Domingues, Rosana; Aoki, Valéria; Sato, Maria Notomi

2015-04-01

Lichen planus (LP) is a common inflammatory skin disease of unknown etiology. Reports of a common transactivation of quiescent human endogenous retroviruses (HERVs) support the connection of viruses to the disease. HERVs are ancient retroviral sequences in the human genome and their transcription is often deregulated in cancer and autoimmune diseases. We explored the transcriptional activity of HERV sequences as well as the antiviral restriction factor and interferon-inducible genes in the skin from LP patients and healthy control (HC) donors. The study included 13 skin biopsies from patients with LP and 12 controls. Real-time PCR assay identified significant decrease in the HERV-K gag and env mRNA expression levels in LP subjects, when compared to control group. The expressions of HERV-K18 and HERV-W env were also inhibited in the skin of LP patients. We observed a strong correlation between HERV-K gag with other HERV sequences, regardless the down-modulation of transcripts levels in LP group. In contrast, a significant up-regulation of the cytidine deaminase APOBEC 3G (apolipoprotein B mRNA-editing), and the GTPase MxA (Myxovirus resistance A) mRNA expression level was identified in the LP skin specimens. Other transcript expressions, such as the master regulator of type I interferon-dependent immune responses, STING (stimulator of interferon genes) and IRF-7 (interferon regulatory factor 7), IFN-β and the inflammassome NALP3, had increased levels in LP, when compared to HC group. Our study suggests that interferon-inducible factors, in addition to their role in innate immunity against exogenous pathogens, contribute to the immune control of HERVs. Evaluation of the balance between HERV and interferon-inducible factor expression could possibly contribute to surveillance of inflammatory/malignant status of skin diseases.

Chronic hepatitis C virus patients with breakthroughs during interferon treatment can successfully be retreated with consensus interferon. The Consensus Interferon Study Group.

PubMed

Heathcote, E J; James, S; Mullen, K D; Hauser, S C; Rosenblate, H; Albert, D G

1999-08-01

Patients with chronic hepatitis C who have not had a sustained hepatitis C virus (HCV)-RNA response or serum alanine transaminase (ALT) response to a 6-month course of interferon (IFN) may respond to higher dose retreatment with consensus interferon (CIFN). Some nonresponders to initial IFN treatment have a transient response defined as undetectable HCV RNA or normalization of ALT during treatment, but subsequently have a "breakthrough" while still on treatment. The aim of this study was to determine if nonresponders who had breakthroughs responded differently to CIFN retreatment than nonresponders without breakthroughs using data from a large, multicenter trial. ALT and HCV RNA were monitored frequently during initial IFN therapy (either 9 mcg CIFN or 3 MU IFN-alpha2b 3 times per week). HCV-RNA breakthroughs were observed in 86 of 467 (18%) of all treated patients, and ALT breakthroughs were observed in 90 of 467 (19%) of all treated patients. There was no association between breakthroughs and the presence of either binding or neutralizing anti-IFN antibodies. When the patients who were nonresponders to initial IFN treatment were retreated with CIFN (15 mcg) for 12 months, 27% of those with viral breakthroughs had a sustained viral response compared with 8% in prior nonresponders without breakthroughs (P =.102). Sustained ALT responses were observed in 39% with breakthroughs compared with 10% in those without breakthroughs (P =.014). The data suggest that prior nonresponders with breakthroughs have a greater chance of responding to retreatment than do nonresponders without breakthroughs. However, most breakthrough patients would be missed unless repeated HCV-RNA testing were conducted during therapy.

Interferon-related genetic markers of necroinflammatory activity in chronic hepatitis C.

PubMed

López-Rodríguez, Rosario; Hernández-Bartolomé, Ángel; Borque, María Jesús; Rodríguez-Muñoz, Yolanda; Martín-Vílchez, Samuel; García-Buey, Luisa; González-Moreno, Leticia; Real-Martínez, Yolanda; Muñoz de Rueda, Paloma; Salmerón, Javier; Vidal-Castiñeira, José Ramón; López-Larrea, Carlos; Rodrigo, Luis; Moreno-Otero, Ricardo; Sanz-Cameno, Paloma

2017-01-01

Chronic hepatitis C (CHC) is a major cause of liver disease worldwide which often leads to progressive liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). CHC displays heterogeneous progression depending on a broad set of factors, some of them intrinsic to each individual such as the patient's genetic profile. This study aims to evaluate the contribution of certain genetic variants of crucial interferon alpha and lambda signaling pathways to the hepatic necroinflammatory activity (NIA) grade of CHC patients. NIA was evaluated in 119 CHC patients by METAVIR scale and classified as low (NIA = 0-2, n = 80) or high grade (NIA = 3, n = 39). In a candidate gene approach, 64 SNPs located in 30 different genes related to interferon pathways (IL-28B, IFNAR1-2, JAK-STAT and OAS1-3, among others) were genotyped using the Illumina GoldenGate® Genotyping Assay. Statistical association was determined by logistic regression and expressed as OR and 95% CI. Those SNPs significantly associated were further adjusted by other covariates. Seven SNPs located in IL-28B (rs12979860), JAK1 (rs11576173 and rs1497056), TYK2 (rs280519), OAS1 (rs2057778), SOCS1 (rs33932899) and RNASEL (rs3738579) genes were significantly related to severe NIA grade (p<0.05). Regarding to clinical variables, elevated NIA was notably associated with aspartate aminotransferase (AST) serum levels >40 IU/L (p<0.05) but not with other clinical factors. Multivariate logistic regression analysis of these factors reflected that AST (>40 IU/L), TYK2 rs280519 (G allele) and RNASEL rs3738579 (G allele) were factors independently associated with elevated NIA (p<0.05). AST concentration showed a moderate AUC value (AUC = 0.63), similar to TYK2 (rs280519) and RNASEL (rs3738579) SNPs (AUC = 0.61, both) in the ROC_AUC analysis. Interestingly, the model including all significant variables reached a considerable predictive value (AUC = 0.74). The identified genetic variants in interferon signaling pathways may constitute useful prognostic markers of CHC progression. Further validation in larger cohorts of patients is needed.

New perspectives in occult hepatitis C virus infection

PubMed Central

Carreño, Vicente; Bartolomé, Javier; Castillo, Inmaculada; Quiroga, Juan Antonio

2012-01-01

Occult hepatitis C virus (HCV) infection, defined as the presence of HCV RNA in liver and in peripheral blood mononuclear cells (PBMCs) in the absence of detectable viral RNA in serum by standard assays, can be found in anti-HCV positive patients with normal serum levels of liver enzymes and in anti-HCV negative patients with persistently elevated liver enzymes of unknown etiology. Occult HCV infection is distributed worldwide and all HCV genotypes seem to be involved in this infection. Occult hepatitis C has been found not only in anti-HCV positive subjects with normal values of liver enzymes or in chronic hepatitis of unknown origin but also in several groups at risk for HCV infection such as hemodialysis patients or family members of patients with occult HCV. This occult infection has been reported also in healthy populations without evidence of liver disease. Occult HCV infection seems to be less aggressive than chronic hepatitis C although patients affected by occult HCV may develop liver cirrhosis and even hepatocellular carcinoma. Thus, anti-HCV negative patients with occult HCV may benefit from antiviral therapy with pegylated-interferon plus ribavirin. The persistence of very low levels of HCV RNA in serum and in PBMCs, along with the maintenance of specific T-cell responses against HCV-antigens observed during a long-term follow-up of patients with occult hepatitis C, indicate that occult HCV is a persistent infection that is not spontaneously eradicated. This is an updated report on diagnosis, epidemiology and clinical implications of occult HCV with special emphasis on anti-HCV negative cases. PMID:22736911

Prediagnostic serum levels of inflammatory biomarkers are correlated with future development of lung and esophageal cancer

PubMed Central

Keeley, Brieze R; Islami, Farhad; Pourshams, Akram; Poustchi, Hossein; Pak, Jamie S; Brennan, Paul; Khademi, Hooman; Genden, Eric M; Abnet, Christian C; Dawsey, Sanford M; Boffetta, Paolo; Malekzadeh, Reza; Sikora, Andrew G

2014-01-01

This study tests the hypothesis that prediagnostic serum levels of 20 cancer-associated inflammatory biomarkers correlate directly with future development of head and neck, esophageal, and lung cancers in a high-risk prospective cohort. This is a nested case–control pilot study of subjects enrolled in the Golestan Cohort Study, an ongoing epidemiologic project assessing cancer trends in Golestan, Iran. We measured a panel of 20 21cytokines, chemokines, and inflammatory molecules using Luminex technology in serum samples collected 2 or more years before cancer diagnosis in 78 aerodigestive cancer cases and 81 controls. Data was analyzed using Wilcoxon rank sum test, odds ratios, receiver operating characteristic areas of discrimination, and multivariate analysis. Biomarkers were profoundly and globally elevated in future esophageal and lung cancer patients compared to controls. Odds ratios were significant for association between several biomarkers and future development of esophageal cancer, including interleukin-1Rα (IL-1Ra; 35.9), interferon α2 (IFN-a2; 34.0), fibroblast growth factor-2 (FGF-2; 17.4), and granulocyte/macrophage colony-stimulating factor (GM-CSF; 17.4). The same pattern was observed among future lung cancer cases for G-CSF (27.7), GM-CSF (13.3), and tumor necrosis factor-α (TNF-a; 8.6). By contrast, the majority of biomarkers studied showed no significant correlation with future head and neck cancer development. This study provides the first direct evidence that multiple inflammatory biomarkers are coordinately elevated in future lung and esophageal cancer patients 2 or more years before cancer diagnosis. PMID:25040886

Food antigen-induced immune responses in Crohn's disease patients and experimental colitis mice.

PubMed

Kawaguchi, Takaaki; Mori, Maiko; Saito, Keiko; Suga, Yasuyo; Hashimoto, Masaki; Sako, Minako; Yoshimura, Naoki; Uo, Michihide; Danjo, Keiko; Ikenoue, Yuka; Oomura, Kaori; Shinozaki, Junko; Mitsui, Akira; Kajiura, Takayuki; Suzuki, Manabu; Takazoe, Masakazu

2015-04-01

In Crohn's disease (CD), the involvement of food antigens in immune responses remains unclear. The objective of this study was to detect immune responses against food antigens in CD patients and examine the mechanism in a mouse model of colitis. We enrolled 98 CD patients, 50 ulcerative colitis patients, and 52 healthy controls (HCs) to compare the levels of serum immunoglobulin (Ig)Gs against 88 foods. The presence of serum IgGs against foods was also examined in interleukin (IL)-10 knockout (KO) mice in which CD4(+) T cell activation by antigenic food protein was assessed. Mice transferred with IL-10 KO cells received diets with or without food antigens, and the development of colitis was evaluated. The prevalence of IgGs against various foods, especially vegetables, grains, and nuts, was significantly higher in CD patients than in HCs. Similarly, the prevalence of IgGs against food proteins was higher in IL-10 KO mice than in BALB/c mice. Beta-conglycinin, identified as an antigenic food proteins in IL-10 KO mice, induced CD4(+) T cell production of interferon-γ and IL-17 through dendritic cell antigen presentation. Elimination of the food antigens ameliorated the development of colitis in mice without altering the composition of their intestinal microbiota. In CD colitis mice, intestinal inflammation via CD4(+) T cell hyperactivation was induced by food antigens associated with high serum IgG levels and was ameliorated by the elimination of food antigens. This disrupted immunological tolerance to food antigen, which might act as an exacerbating factor, remains to be elucidated in CD patients.

Effects of lipopolysaccharide on interleukin-2-induced cytotoxic activity of murine splenocyte cultures: role of prostaglandin E2 and interferons.

PubMed

Vaillier, D; Daculsi, R; Gualde, N

1992-01-01

Splenocytes cultured for 24 h in the presence of interleukin-2 (IL-2), lipopolysaccharide (LPS) or both together expressed a cytotoxic activity against the YAC-1 lymphoma cell line and to a lesser extent against P815 mastocytoma cells. The association of IL-2 and LPS had an additive effect on induction of cytotoxicity. The IL-2-induced cytotoxic activity lasted for the whole of the culture; however, the addition of LPS at the initiation of the culture increased the cytotoxic activity during its the early phase, the increment being followed by a fall of lytic activity after 72 h of culture. Assessment of interferon (IFN) in the culture supernatants showed (a) a production of IFN gamma by IL-2-supplemented cultures, (b) a more potent IFN production by cultures treated with IL-2 plus LPS (including 20% IFN alpha/beta, (c) and that indomethacin (1 microM) potentiated the effect of either IL-2 or LPS used alone but did not significantly increase the cytotoxic activity of cultures treated with IL-2 plus LPS (the one that produced a high level of IFN). When cultures were treated by an anti-IFN gamma antibody we observed no change in the cytotoxic activity; however, in the presence of anti-IFN alpha/beta serum the cytotoxic activity of cultures treated with IL-2 plus LPS was inhibited after 24 h but stimulated after 72 h. When cultures treated with IL-2 plus LPS were supplemented with both indomethacin and anti-IFN alpha/beta the cytotoxic activity assessed after 72 h of culture was maintained at the same level as that of IL-2-treated cultures, hence the fall after 72 h of the cytotoxicity of cultures initiated in the presence of LPS alone was affected by both the immune serum and the cyclooxygenase inhibitor. Altogether these data show that when splenocytes are cultured for more than 72 h in the presence of IL-2 and LPS their cytotoxic activity decreases, and it is likely that this diminution is linked to the endogenous production of prostaglandin E2 and INF alpha/beta.

The effect of Base Transceiver Station waves on some immunological and hematological factors in exposed persons.

PubMed

Taheri, Mohammad; Roshanaei, Ghodratollah; Ghaffari, Jamileh; Rahimnejad, Samira; Khosroshahi, Behzad Nazel; Aliabadi, Mohsen; Eftekharian, Mohammad Mahdi

2017-01-01

Since the number of mobile subscribers has significantly increased in recent years, the installation and deployment of Base Transceiver Station (BTS) antennas sending and receiving signals has become common and inevitable in different regions. In this study, we have tried to evaluate the effect of the waves on some immunological and hematological parameters in exposed individuals. In this study, the exposed and non-exposed individuals were used as the test and control groups, respectively. The test group was healthy people who resided in the vicinity of the Base Transceiver Station (BTS) antenna and received the maximum of radiation. The control group was selected from the healthy individuals that were matched with the exposed group by age. They resided in a distance of Base Transceiver Station (BTS) antenna and received the minimum of radiation. After stating complete explanations and obtaining the consent, the venous blood samples were taken from them. Then, CBC and the level of cytokines including IL-4, IL-10 and interferon γ were performed on the samples and the results were analyzed by SPSS software. In the test group, the whole number of white blood cells, the level of hematocrit, percent of monocytes, eosinophils and basophils were significantly lower than the control group. The number of red blood cells, their average volume and the mean concentration of hemoglobin were notably higher than the controls. There was not observed a significant difference between the two groups in hemoglobin, its mean concentration, platelet count, percent of lymphocytes and neutrophils as well as serum levels of cytokines IL-4, IL-10 and interferon γ . It seems that radiation of mobile phone antennas influenced the blood and immune systems, but further study should be done to exactly determine the targets.

The alkylphenols 4-nonylphenol, 4-tert-octylphenol and 4-tert-butylphenol aggravate atopic dermatitis-like skin lesions in NC/Nga mice.

PubMed

Sadakane, Kaori; Ichinose, Takamichi; Takano, Hirohisa; Yanagisawa, Rie; Koike, Eiko; Inoue, Ken-ichiro

2014-08-01

Phthalate esters in plastics act as adjuvants for immunoglobulin production, which aggravates allergic disease. However, the effects of alkylphenols (used as plasticizers and surfactants) on atopic dermatitis have not been studied in detail. Therefore, the goal of the present study was to investigate the effects of the alkylphenols 4-nonylphenol (NP), 4-tert-octylphenol (OP) and 4-tert-butylphenol (BP) in a murine model of atopic dermatitis. NC/Nga mice were intraperitoneally administered NP, OP or BP and were subcutaneously injected with mite allergen in one ear to induce atopic dermatitis-like skin lesions (ADSLs). The condition of the skin was observed, and the levels of immunoglobulin in serum and inflammatory cytokines in lesions were determined. NP exacerbated mite allergen-induced ADSLs according to dose. OP and BP also significantly exacerbated skin lesions but not as a function of dose. Alkylphenols tended to increase the levels of IgE and antigen-specific IgG1 in serum. Further, the treatment of the alkylphenols increased the expression in lesions of inflammatory cytokines, interleukin-4 and monocyte chemotactic protein-3. Thymic stromal lymphopoietin levels increased according to ADSL severity. In contrast, the levels of the T-helper 1 cytokines (interleukin-18 and interferon-gamma) decreased. NP, OP or BP may enhance T-helper 2-type immune responses in NC/Nga mice, which aggravates mite allergen-induced ADSLs. Therefore, the uptake of very low levels of alkylphenols may contribute to the increase in the incidence of atopic dermatitis. Copyright © 2013 John Wiley & Sons, Ltd.

Intra-articular corticoid injection induces circulating glucocorticoid bioactivity and systemic immune activation in juvenile idiopathic arthritis.

PubMed

Rintamäki, H; Tamm, K; Vaarala, O; Sidoroff, M; Honkanen, V; Raivio, T; Jänne, Oa; Kolho, K-L

2011-01-01

To study the systemic effects of intra-articular (IA) glucocorticoid (GC) injections in juvenile idiopathic arthritis (JIA). The study group comprised 21 JIA patients being treated with IA methylprednisolone [MP (n = 15) or MP plus triamcinolone hexacetonide (THA) (n = 6)] prescribed on clinical indications. The systemic effect of MP was assessed by measuring circulating glucocorticoid bioactivity (GBA) with a recombinant cell transactivation assay 7 and 24 h after the IA injections, and after 2 months. The systemic immunological responses were studied with a novel assay for testing patient serum-induced changes in the secretion of interferon (IFN)-γ and interleukin (IL)-5 from target cells. Administration of IA GC induced serum GBA (p = 0.001) and suppressed circulating cortisol levels (p = 0.002) 7 h after the injection. Serum withdrawn 24 h after the IA injection induced less IL-5 secretion from mitogen-activated target cells when compared with pre-treatment sera (p = 0.036). This decrease in target cell T helper (Th)2 response (IL-5) was MP dose related (r = -0.550, p = 0.018). High IL-5 secretion from target cells prior to the IA injections was associated with good clinical outcome at 2 months, seen as a low number of active (p = 0.044) and restricted joints (p = 0.049). IA GC injections have systemic effects that are reflected in the serum as an immediate elevation of GBA, a decrease of endogenous cortisol as well as a suppressive effect of patient serum on target cell IL-5 secretion. These systemic effects may play a role in the attenuation of disease activity.

IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus

PubMed Central

Niewold, Timothy B; Kelly, Jennifer A; Kariuki, Silvia N; Franek, Beverly S; Kumar, Akaash A; Kaufman, Kenneth M; Thomas, Kenaz; Walker, Daniel; Kamp, Stan; Frost, Jacqueline M; Wong, Andrew K; Merrill, Joan T; Alarcón-Riquelme, Marta E; Tikly, Mohammed; Ramsey-Goldman, Rosalind; Reveille, John D; Petri, Michelle A; Edberg, Jeffrey C; Kimberly, Robert P; Alarcón, Graciela S; Kamen, Diane L; Gilkeson, Gary S; Vyse, Timothy J; James, Judith A; Gaffney, Patrick M; Moser, Kathy L; Crow, Mary K; Harley, John B

2012-01-01

Objective High serum interferon α (IFNα) activity is a heritable risk factor for systemic lupus erythematosus (SLE). Auto-antibodies found in SLE form immune complexes which can stimulate IFNα production by activating endosomal Toll-like receptors and interferon regulatory factors (IRFs), including IRF5. Genetic variation in IRF5 is associated with SLE susceptibility; however, it is unclear how IRF5 functional genetic elements contribute to human disease. Methods 1034 patients with SLE and 989 controls of European ancestry, 555 patients with SLE and 679 controls of African–American ancestry, and 73 patients with SLE of South African ancestry were genotyped at IRF5 polymorphisms, which define major haplotypes. Serum IFNα activity was measured using a functional assay. Results In European ancestry subjects, anti-double-stranded DNA (dsDNA) and anti-Ro antibodies were each associated with different haplotypes characterised by a different combination of functional genetic elements (OR > 2.56, p >003C; 1.9×10−14 for both). These IRF5 haplotype-auto-antibody associations strongly predicted higher serum IFNα in patients with SLE and explained > 70% of the genetic risk of SLE due to IRF5. In African–American patients with SLE a similar relationship between serology and IFNα was observed, although the previously described European ancestry-risk haplotype was present at admixture proportions in African–American subjects and absent in African patients with SLE. Conclusions The authors define a novel risk haplotype of IRF5 that is associated with anti-dsDNA antibodies and show that risk of SLE due to IRF5 genotype is largely dependent upon particular auto-antibodies. This suggests that auto-antibodies are directly pathogenic in human SLE, resulting in increased IFNα in cooperation with particular combinations of IRF5 functional genetic elements. SLE is a systemic autoimmune disorder affecting multiple organ systems including the skin, musculoskeletal, renal and haematopoietic systems. Humoral autoimmunity is a hallmark of SLE, and patients frequently have circulating auto-antibodies directed against dsDNA, as well as RNA binding proteins (RBP). Anti-RBP autoantibodies include antibodies which recognize Ro, La, Smith (anti-Sm), and ribonucleoprotein (anti-nRNP), collectively referred to as anti-retinol-binding protein). Anti-retinol-binding protein and anti-dsDNA auto-antibodies are rare in the healthy population.1 These auto-antibodies can be present in sera for years preceding the onset of clinical SLE illness2 and are likely pathogenic in SLE.34 PMID:22088620

Protective effects of sea cucumber (Holothuria atra) extract on testicular dysfunction induced by immune suppressant drugs in Wistar rats.

PubMed

Saad, D Y; Soliman, M M; Mohamed, A A; Youssef, G B

2018-04-23

The current study was aimed to evaluate the protective effect of Holothurian atra (HA) extract; naturally occurring marine resource, against methotrexate (MTX) induced testicular dysfunction. Mature rats received either MTX (20 mg/kg, intraperitoneally) or saline on the 7th day of experiment al design. Seven days prior and after MTX-injection, rats received HA at dose of 300 mg/kg intragastrically (HA + MTX group; HA group alone). Serum was extracted and testicular tissues were examined for the changes in serum biochemistry (liver & kidney biomarkers, testicular hormones and antioxidants), molecular and histopthological alterations using RT-PCR and immunohistochemistry. MTX-injected rats induced alteration in all testicular parameters. Prior administration of HA ameliorated the MTX-induced oxidative stress. HA administration normalised MTX-induced decrease in serum levels of interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ), reproductive hormones (FSH, LH and testosterone) and antioxidants GST, SOD and catalase. MTX-injected rats down-regulated mRNA expression of GST, SOD, steroidogenesis associated genes, IFN-γ, Bcl2 and NFKB. MTX up-regulated BAX expression and caspase 9 immunoreactivity that were ameliorated in HA + MTX group. Collectively, HA ameliorated and restored all altered genes. In conclusion, HA is a promising supplement that is helpful in protection against testicular cytotoxicity and dysfunction induced by methotrexate. © 2018 Blackwell Verlag GmbH.

Characterization of Serum Cytokine Profile in Predominantly Colonic Inflammatory Bowel Disease to Delineate Ulcerative and Crohn’s Colitides

PubMed Central

Korolkova, Olga Y; Myers, Jeremy N; Pellom, Samuel T; Wang, Li; M’Koma, Amosy E

2015-01-01

BACKGROUND As accessible diagnostic approaches fail to differentiate between ulcerative colitis (UC) and Crohn’s colitis (CC) in one-third of patients with predominantly colonic inflammatory bowel disease (IBD), leading to inappropriate therapy, we aim to investigate the serum cytokine levels in these patients in search of molecular biometric markers delineating UC from CC. METHODS We measured 38 cytokines, chemokines, and growth factors using magnetic-bead-based multiplex immunoassay in 25 UC patients, 28 CC patients, and 30 controls. Our results are compared with those from a review of current literature regarding advances in serum cytokine profiles and associated challenges preventing their use for diagnostic/prognostic purposes. RESULTS Univariate analysis showed statistically significant increases of eotaxin, GRO, and TNF-α in UC patients compared to controls (Ctrl); interferon γ, interleukin (IL)-6, and IL-7 in CC group compared to Ctrl; and IL-8 in both UC and CC versus Ctrl. No cytokines were found to be different between UC and CC. A generalized linear model identified combinations of cytokines, allowing the identification of UC and CC patients, with area under the curve (AUC) = 0.936, as determined with receiver operating characteristic (ROC) analysis. CONCLUSIONS The current knowledge available about circulating cytokines in IBD is often contradictory. The development of an evidence-based tool using cytokines for diagnostic accuracy is still preliminary. PMID:26078592

Inflammatory Cytokine Pattern Is Sex-Dependent in Mouse Cutaneous Melanoma Experimental Model

PubMed Central

Surcel, Mihaela

2017-01-01

We present the evaluation of inflammatory cytokines in mouse cutaneous melanoma experimental model, as markers of disease evolution. Moreover, to test our experimental model, we have used low doses of dacarbazine (DTIC). C57 BL/6J mouse of both sexes were subjected to experimental cutaneous melanoma and treated with low doses of DTIC. Clinical parameters and serum cytokines were followed during tumor evolution and during DTIC therapy. Cytokine/chemokine pattern was assessed using xMAP technology and the following molecules were quantified: interleukins (IL)-1-beta, IL-6, IL-10, IL-12 (p70), interferon (IFN)-gamma, granulocyte macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-1alpha, monocyte chemoattractant protein (MCP-1), and keratinocyte-derived chemokine (KC). Significant differences were found between normal females and males mice, female mice having a statistically higher serum concentration of IL-1-beta compared to male mice, while males have a significantly higher concentration of MIP-1-alpha. During melanoma evolution in the female group, IL-1-beta, MIP-1-alpha, and KC circulatory levels were found 10-fold increased, while other cytokines doubled their values. In the male mice group, only circulatory KC increased 4 times, while IL-1-beta and TNF-alpha doubled their circulatory values. Various serum cytokines correlated with the disease evolution in cutaneous melanoma mouse model. PMID:29318162

Relationship between serum interleukin-17 level and inflammatory bowel disease.

PubMed

Liu, Q L; Huang, L; Zhao, Q J; Li, Q; He, Z

2016-01-01

By detecting expression of interleukin (IL)-17A, IL-10 and interferon-γ (IFN-γ) in serum of inflammatory bowel disease (IBD) patients, this study aims to analyze the effects of these factors on the pathogenesis of IBD. According to illness status, selected patients were divided into Crohn’s disease (CD) group (28 patients), ulcerative colitis (UC) group (74 patients) and normal control group (36 patients); enzymelinked immunosorbent assay (ELISA) was used to detect IL-17A, IL-10 and IFN-γ levels in serum; immunohistochemical assay was used to detect local IL-17A expression in the colonic mucosa of each group. Clinical results showed that IL-17A content of the UC group and CD group was significantly higher than that of the normal control group (p less than 0.05); IL-17A content of the CD group was higher than that of the UC group (p>0.05). The UC group had the highest IL-10 content, and the difference between the UC group and other two groups had statistical significance (p less than 0.05); the difference of IL-10 content between UC group and normal control group had no statistical significance (p>0.05). There was no significant difference of IFN-γ level between the CD group and the UC group and normal control group (p>0.05), and no significant difference of IFN-γ level was shown between the CD group and the UC group (p>0.05). Both the CD and UC groups showed IL-17A positive staining in cytoplasm of lymphocyte, however no positive staining was found in any layer of intestinal mucosa of the normal control group. IL-17A was locally expressed in the colon of IBD patients in remission; furthermore, it also had high expression in serum; thus, there still existed high expression of pro-inflammatory factor, which might be related to relapse of IBD. Therefore, prevention of IL-17A may become a feasible therapy for IBD in the future.

Cervical cerclage placement decreases local levels of proinflammatory cytokines in patients with cervical insufficiency.

PubMed

Monsanto, Stephany P; Daher, Silvia; Ono, Erika; Pendeloski, Karen Priscilla Tezotto; Trainá, Évelyn; Mattar, Rosiane; Tayade, Chandrakant

2017-10-01

Cervical insufficiency is characterized by premature, progressive dilation and shortening of the cervix during pregnancy. If left unattended, this can lead to the prolapse and rupture of the amniotic membrane, which usually results in midtrimester pregnancy loss or preterm birth. Previous studies have shown that proinflammatory cytokines such as interleukin-1β, interleukin-6, interleukin-8, and tumor necrosis factor alpha are up-regulated in normal parturition but are also associated with preterm birth. Studies evaluating such markers in patients with cervical insufficiency have evaluated only their diagnostic potential. Even fewer studies have studied them within the context of cerclage surgery. The objective of the study was to evaluate the impact of local and systemic inflammatory markers on the pathogenesis of cervical insufficiency and the effect of cerclage surgery on the local immune microenvironment of women with cervical insufficiency. We recruited 28 pregnant women (12-20 weeks' gestation) diagnosed with insufficiency and referred for cerclage surgery and 19 gestational age-matched normal pregnant women as controls. Serum and cervicovaginal fluid samples were collected before and after cerclage surgery and during a routine checkup for normal women and analyzed using a targeted 13-plex proinflammatory cytokine assay. Before surgery, patients with cervical insufficiency had higher levels of interleukin-1β, interleukin-6, interleukin-12, monocyte chemoattractant protein-1 and tumor necrosis factor alpha in cervicovaginal fluid compared to controls, but after surgery, these differences disappeared. No differences were found in serum of insufficiency versus control women. In patients with insufficiency, the levels of interleukin-1β, interleukin-6, interleukin-8, monocyte chemoattractant protein-1, and interferon gamma in cervicovaginal fluid declined significantly after cerclage compared with before intervention, but these changes were not detected in serum. Compared with normal women, patients with cervical insufficiency have elevated levels of proinflammatory cytokines in cervicovaginal fluid but not in serum, suggesting a dysregulation of the local immune environment. Cerclage intervention led to a significant decline in these proinflammatory cytokines, suggesting that cerclage may help reduce local inflammation in cervical insufficiency. Copyright © 2017 Elsevier Inc. All rights reserved.

Consuming Lentinula edodes (Shiitake) Mushrooms Daily Improves Human Immunity: A Randomized Dietary Intervention in Healthy Young Adults.

PubMed

Dai, Xiaoshuang; Stanilka, Joy M; Rowe, Cheryl A; Esteves, Elizabethe A; Nieves, Carmelo; Spaiser, Samuel J; Christman, Mary C; Langkamp-Henken, Bobbi; Percival, Susan S

2015-01-01

Mushrooms are widely cited for their medicinal qualities, yet very few human intervention studies have been done using contemporary guidelines. The aim of this study was to determine whether consumption of whole, dried Lentinula edodes (shiitake) mushrooms could improve human immune function. Primary objectives were to ascertain whether L. edodes consumption would improve γδ-T cell proliferation and activation responses, quantify a dose response, and elicit cytokine secretion patterns. Secondary objectives included determining changes in natural killer T (NK-T) cell proliferation and activation, secretory immunoglobulin A (sIgA) in saliva, and C-reactive protein (CRP) in serum. Fifty-two healthy males and females, aged 21-41 years, participated in a 4-week parallel group study, consuming either 5 or 10 g of mushrooms daily. Each subject had blood drawn before and after 4 weeks of daily L. edodes consumption. Saliva and serum were also collected. Peripheral blood mononuclear cells were cultured in autologous serum for 24 hours or 6 days, stained, and examined by flow cytometry. Eating L. edodes for 4 weeks resulted in increased ex vivo proliferation of γδ-T (60% more, p < 0.0001) and NK-T (2-fold more, p < 0.0001) cells. Both cell types also demonstrated a greater ability to express activation receptors, suggesting that consuming mushrooms improved cell effector function. The increase in sIgA implied improved gut immunity. The reduction in CRP suggested lower inflammation. The pattern of cytokines secreted before and after mushroom consumption was significantly different; consumption resulted in increased interleukin (IL)-4, IL-10, tumor necrosis factor (TNF)-α, and IL-1α levels, a decreased macrophage inflammatory protein-1α/chemokine C-C ligand 3 (MIP-1α/CCL3) level, and no change to IL-6, IL-1β, MIP-1β, IL-17 and interferon (IFN)-γ levels. Regular L. edodes consumption resulted in improved immunity, as seen by improved cell proliferation and activation and increased sIgA production. The changes observed in cytokine and serum CRP levels suggest that these improvements occurred under conditions that were less inflammatory than those that existed before consumption.

Gut microbiota modulates type I interferon and antibody-mediated immune responses in chickens infected with influenza virus subtype H9N2.

PubMed

Yitbarek, A; Alkie, T; Taha-Abdelaziz, K; Astill, J; Rodriguez-Lecompte, J C; Parkinson, J; Nagy, É; Sharif, S

2018-04-25

Commensal gut microbes play a critical role in shaping host defences against pathogens, including influenza viruses. The current study was conducted to assess the role and mechanisms of action of commensal gut microbiota on the innate and antibody-mediated responses of layer chickens against influenza virus subtype H9N2. A total of 104 one-day-old specific pathogen free chickens were assigned to either of the four treatments, which included two levels of antibiotics treatment (ABX- and ABX+) and two levels of H9N2 virus infection (H9N2- and H9N2+). At day 17 of age, chickens in the H9N2+ group were infected via the oral-nasal route with 400 μl of 107 TCID 50 /ml (200 μl/each route). Oropharyngeal and cloacal swabs at days 1, 3, 5, 7 and 9 post-infection (p.i.) for virus shedding, tissue samples at 12 h, 24 h and 36 h p.i. for mRNA measurement, and serum samples at days 7 and 14 p.i. for hemagglutination inhibition (HI) assay and IgG antibodies were collected. Virus shedding analysis showed that antibiotic treated (depleted)-H9N2 virus infected chickens showed a significantly higher oropharyngeal virus shedding at all time points, and cloacal shedding at days 3 and 5 p.i. compared to control treated (undepleted)-H9N2 infected chickens. Analysis of mRNA expression showed that infection of depleted chickens with H9N2 virus resulted in significantly down-regulated type I interferon responses both in the respiratory and gastrointestinal tracts compared to undepleted-H9N2 infected chickens. However, antibody-mediated immune response analysis showed a significantly higher HI antibody titre and IgG levels in the serum of chickens depleted with antibiotics and infected with H9N2 virus compared to undepleted-H9N2 infected chickens. In conclusion, findings from the current study suggest that the gut microbiota of chickens plays an important role in the initiation of innate responses against influenza virus infection, while the antibody-mediated immune response remains unaffected.

TH1/TH2 cytokines and soluble CD30 levels in kidney allograft patients with donor bone marrow cell infusion.

PubMed

Solgi, G; Amirzagar, A A; Pourmand, G; Mehrsai, A R; Taherimahmoudi, M; Baradaran, N; Nicknam, M H; Ebrahimi Rad, M R; Saraji, A; Asadpoor, A A; Moheiydin, M; Nikbin, B

2009-09-01

We investigated the relevance of donor bone marrow cell infusion (DBMI) and serum levels of interferon-gamma (IFN-gamma), interleukin-10 (IL-10), and soluble CD30 (sCD30) in kidney recipients. We analyzed the allograft outcomes correlated with sCD30, IFN-gamma, and IL-10 levels using pre- and posttransplantation sera from 40 live donor renal transplants (20 patients with DBMI [2.1 x 10(9) +/- 1.3 x 10(9) mononuclear cells/body] and 20 controls). Patients with acute rejection episodes (ARE)-3/20 DBMI and 6/20 controls-showed increased sCD30 and IFN-gamma as well as decreased IL-10 posttransplantation compared with nonrejectors. Significant differences were observed for sCD30 and IFN-gamma levels: 59.54 vs 30.92 ng/mL (P = .02) and 11.91 vs 3.01 pg/mL (P = .01), respectively. Comparison of pre- and posttransplant levels of IFN-gamma, IL-10, and sCD30 in ARE patients showed higher levels in posttransplant sera except for IFN-gamma in controls (6.37 vs 11.93; P = .01). Increased IFN-gamma and IL-10 were correlated with rejection (r = .93; P = .008). sCD30 correlated with serum creatinine among ARE patients in control and DBMI groups (r = .89; P = .019; and r = 1.00; P < .0001, respectively). Higher levels of sCD30, IFN-gamma, and IL-10 posttransplantation in rejecting patients provided evidence for coexistence of cellular and humoral responses in ARE. There appeared to be a down-regulatory effect of infusion on alloresponses.

Interferon-γ-induced protein 10 in Lyme disease.

PubMed

Fallahi, P; Elia, G; Bonatti, A

2017-01-01

Lyme disease is an infectious disease caused by bacteria of the Borrelia type, that affects about 300,000 people a year in the USA and 65,000 people a year in Europe. Borrelia infection, and Lyme disease, following occupational exposure has been frequently reported in USA, Europe and Asia. The manifestations of Lyme disease include erythema migrans (EM), arthritis, neuroborrelliosis (NB), and others. Cytokines and chemokines primarily orchestrate leukocyte recruitment to the areas of Borrelia infection, and they are critical mediators of immune and inflammatory responses, in particular of the induction of interferon (IFN)-γ and IFN-γ dependent chemokines. In EM high levels of T helper (Th) 1 cells chemoattranctants [monokine induced by IFN-γ (MIG), IFN-γ-induced protein 10 (IP- 10), and IFN-inducible T cell alpha chemoattractant (I-TAC)] have been shown. Synovial tissues and fluids of patients with Lyme Arthritis (LA) (overall with antibiotic-refractory LA) contained exceptionally high levels of Th1 chemoattractants and cytokines, particularly MIG and IFN-γ. In NB concentrations of IP-10 and I-TAC in the cerebrospinal fluid (CSF) were significantly higher, suggesting that IP-10 and I-TAC create a chemokine gradient between the CSF and serum and recruite C-X-C chemokine receptor 3-expressing memory CD4+ T-cells into the CSF of these patients. A positive association between the disseminating capacity of B. burgdorferi and early type I IFN induction has also been shown. These results suggest that IFN-γ dependent chemokines are important biomarkers to monitor the progression and diffusion of the disease in patients with Borrelia infection; further larger studies are needed.

Human T-cell responses to oral streptococci in human PBMC-NOD/SCID mice.

PubMed

Salam, M A; Nakao, R; Yonezawa, H; Watanabe, H; Senpuku, H

2006-06-01

We investigated cellular and humoral immune responses to oral biofilm bacteria, including Streptococcus mutans, Streptococcus anginosus, Streptococcus sobrinus, and Streptococcus sanguinis, in NOD/SCID mice immunized with human peripheral blood mononuclear cells (hu-PBMC-NOD/SCID mice) to explore the pathogenicity of each of those organisms in dental and oral inflammatory diseases. hu-PBMC-NOD/SCID mice were immunized by intraperitoneal injections with the whole cells of the streptococci once a week for 3 weeks. FACS analyses were used to determine the percentages of various hu-T cell types, as well as intracellular cytokine production of interleukin-4 and interferon-gamma. Serum IgG and IgM antibody levels in response to the streptococci were also determined by enzyme-linked immunosorbent assay. S. anginosus induced a significant amount of the proinflammatory cytokine interferon-gamma in CD4(+) and CD8(+) T cells in comparison with the other streptococci. However, there was no significant differences between the streptococci in interleukin-4 production by CD4(+) and CD8(+) T cells after inoculation. Further, S. mutans significantly induced human anti-S. mutans IgG, IgG(1), IgG(2), and IgM antibodies in comparison with the other organisms. In conclusion, S. anginosus up-regulated Th1 and Tc1 cells, and S. mutans led to increasing levels of their antibodies, which was associated with the induction of Th2 cells. These results may contribute to a better understanding of human lymphocyte interactions to biofilm bacteria, along with their impact on dental and mucosal inflammatory diseases, as well as endocarditis.

Important role of interferon regulatory factor (IRF)-3 in the interferon response of mouse macrophages upon infection by Newcastle disease virus.

PubMed

Wilden, Holger; Schirrmacher, Volker; Fournier, Philippe

2011-08-01

Newcastle disease virus (NDV) is an interesting agent for activating innate immune activity in macrophages including secretion of TNF-α and IFN-α, upregulation of TRAIL and activation of NF-κB and iNOS. However, the molecular mechanism of such cellular activities remains largely unknown. Tumor selectivity of replication of NDV has been described to be linked to deviations in tumor cells of the type I interferon response. We therefore focused on the interferon response to NDV of macrophages as part of innate anti-viral and anti-tumor activity. In particular, we investigated the functional significance of the interferon regulatory factor genes (IRF)-3 and IRF-7. Deletion of the IRF-3 or IRF-7 gene was found to increase susceptibility of mouse macrophages to virus infection. Surprisingly, NDV replicated better in IRF-3 KO than in IRF-7 KO macrophages. Further analysis showed that IRF-3 KO macrophages have a lower basal and NDV-induced RIG-I expression in comparison to IRF-7 KO macrophages. This might explain why, in IRF-3 KO macrophages, the secretion of type I interferons after NDV infection is delayed, when compared to IRF-7 KO and wild-type macrophages. In addition, IRF-3 KO cells showed reduced NDV-induced levels of IRF-7. This effect could be prevented by priming the cells first by interferon-α. Further results indicated that an early production of type I interferon rather than high maximal levels at later time points are important for resistance to infection by NDV. In conclusion, these results demonstrate an important role of IRF-3 for the innate anti-viral response to NDV of mouse macrophages.

Enhancement of the Th1-phenotype immune system by the intake of Oyster mushroom (Tamogitake) extract in a double-blind, placebo-controlled study.

PubMed

Tanaka, Aiko; Nishimura, Mie; Sato, Yuji; Sato, Hiroki; Nishihira, Jun

2016-10-01

Pleurotus cornucopiae (Oyster mushroom, Tamogitake) has long been eaten as a functional food for enhancement of the immune system, but its effectiveness has not been well confirmed in humans. To this end, we set up a double-blind placebo-controlled human clinical trial to investigate the potential of Oyster mushrooms with respect to the up-regulation of the immune system. The subjects ingested Oyster mushroom extract for 8 weeks. We measured the serum cytokine levels involved in regulation of the immune system, including interferon (IFN)-γ, interleukin (IL)-4, IL-5, IL-10, IL-12, IL-13, and tumor-necrosis factor (TNF)-α. We found that intake of Oyster mushroom extract elevated IFN-γ ( P  = 0.013) and IL-12, whereas serum levels of IL-10 and IL-13 and other cytokines were minimally changed. We also measured natural killer (NK) cell activity, the levels of which tended to increase, but not significantly. Taken together, these facts suggest that Oyster mushrooms have the potential to enhance the immune system, through Th1 phenotype potentiation as the macrophage-IL-12 - IFN-γ pathway. This results in activation of the cell-mediated immune system as exemplified by up-regulation of NK cell activity. Oyster mushroom extract may be beneficial for the prevention of various diseases, including infectious diseases and cancer, due to its stimulation of the immune system.

Sensitivity of African swine fever virus to type I interferon is linked to genes within multigene families 360 and 505.

PubMed

Golding, Josephine P; Goatley, Lynnette; Goodbourn, Steve; Dixon, Linda K; Taylor, Geraldine; Netherton, Christopher L

2016-06-01

African swine fever virus (ASFV) causes a lethal haemorrhagic disease of pigs. There are conflicting reports on the role of interferon in ASFV infection. We therefore analysed the interaction of ASFV with porcine interferon, in vivo and in vitro. Virulent ASFV induced biologically active IFN in the circulation of pigs from day 3-post infection, whereas low virulent OUR T88/3, which lacks genes from multigene family (MGF) 360 and MGF505, did not. Infection of porcine leucocytes enriched for dendritic cells, with ASFV, in vitro, induced high levels of interferon, suggesting a potential source of interferon in animals undergoing acute ASF. Replication of OUR T88/3, but not virulent viruses, was reduced in interferon pretreated macrophages and a recombinant virus lacking similar genes to those absent in OUR T88/3 was also inhibited. These findings suggest that as well as inhibiting the induction of interferon, MGF360 and MGF505 genes also enable ASFV to overcome the antiviral state. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Chloroplast-derived vaccine antigens and biopharmaceuticals: expression, folding, assembly and functionality.

PubMed

Chebolu, S; Daniell, H

2009-01-01

Chloroplast genetic engineering offers several advantages, including high levels of transgene expression, transgene containment via maternal inheritance, and multi-gene expression in a single transformation event. Oral delivery is facilitated by hyperexpression of vaccine antigens against cholera, tetanus, anthrax, plague, or canine parvovirus (4%-31% of total soluble protein, TSP) in transgenic chloroplasts (leaves) or non-green plastids (carrots, tomato) as well as the availability of antibiotic free selectable markers or the ability to excise selectable marker genes. Hyperexpression of several therapeutic proteins, including human serum albumin (11.1% TSP), somatotropin (7% TSP), interferon-alpha (19% TSP), interferon-gamma (6% TSP), and antimicrobial peptide (21.5% TSP), facilitates efficient and economic purification. Also, the presence of chaperones and enzymes in chloroplasts facilitates assembly of complex multisubunit proteins and correct folding of human blood proteins with proper disulfide bonds. Functionality of chloroplast-derived vaccine antigens and therapeutic proteins has been demonstrated by several assays, including the macrophage lysis assay, GM1-ganglioside binding assay, protection of HeLA cells or human lung carcinoma cells against encephalomyocarditis virus, systemic immune response, protection against pathogen challenge, and growth or inhibition of cell cultures. Purification of human proinsulin has been achieved using novel purification strategies (inverse temperature transition property) that do not require expensive column chromatography techniques. Thus, transgenic chloroplasts are ideal bio-reactors for production of functional human and animal therapeutic proteins in an environmentally friendly manner.

Chloroplast-Derived Vaccine Antigens and Biopharmaceuticals: Expression, Folding, Assembly and Functionality

PubMed Central

Chebolu, S.; Daniell, H.

2009-01-01

Chloroplast genetic engineering offers several advantages, including high levels of transgene expression, transgene containment via maternal inheritance, and multi-gene expression in a single transformation event. Oral delivery is facilitated by hyperexpression of vaccine antigens against cholera, tetanus, anthrax, plague, or canine parvovirus (4%–31% of total soluble protein, TSP) in transgenic chloroplasts (leaves) or non-green plastids (carrots, tomato) as well as the availability of antibiotic free selectable markers or the ability to excise selectable marker genes. Hyperexpression of several therapeutic proteins, including human serum albumin (11.1% TSP), somatotropin (7% TSP), interferon-alpha (19% TSP), interferon-gamma (6% TSP), and antimicrobial peptide (21.5% TSP), facilitates efficient and economic purification. Also, the presence of chaperones and enzymes in chloroplasts facilitates assembly of complex multisubunit proteins and correct folding of human blood proteins with proper disulfide bonds. Functionality of chloroplast-derived vaccine antigens and therapeutic proteins has been demonstrated by several assays, including the macrophage lysis assay, GM1-ganglioside binding assay, protection of HeLA cells or human lung carcinoma cells against encephalomyocarditis virus, systemic immune response, protection against pathogen challenge, and growth or inhibition of cell cultures. Purification of human proinsulin has been achieved using novel purification strategies (inverse temperature transition property) that do not require expensive column chromatography techniques. Thus, transgenic chloroplasts are ideal bioreactors for production of functional human and animal therapeutic proteins in an environmentally friendly manner. PMID:19401820

Polymorphonuclear Neutrophils Are Necessary for the Recruitment of CD8+ T Cells in the Liver in a Pregnant Mouse Model of Chlamydophila abortus (Chlamydia psittaci Serotype 1) Infection

PubMed Central

de Oca, Roberto Montes; Buendía, Antonio J.; Del Río, Laura; Sánchez, Joaquín; Salinas, Jesús; Navarro, Jose A.

2000-01-01

The role of polymorphonuclear neutrophils (PMNs) in the development of the specific immune response against Chlamydophila abortus (Chlamydia psittaci serotype 1) infection was studied in a pregnant mouse model involving treatment with RB6-8C5 monoclonal antibody. PMN depletion significantly affected the immune response in the liver, in which the T-lymphocyte and F4/80+ cell populations decreased, particularly the CD8+ T-cell population. A Th1-like response, characterized by high levels of gamma interferon without detectable levels of interleukin 4 (IL-4) in serum, was observed in both depleted and nondepleted mice, although an increased production of IL-10 was detected in the depleted group. Our results suggest that PMNs play a very important role in the recruitment of other leukocyte populations to the inflammatory foci but have little influence in the polarization of the immune specific response toward a Th1-like response. PMID:10679002

Vitamin A supplementation leads to increases in regulatory CD4+Foxp3+LAP+ T cells in mice.

PubMed

Medeiros, Samara R; Pinheiro-Rosa, Natalia; Lemos, Luisa; Loli, Flavia G; Pereira, Alline G; Santiago, Andrezza F; Pinter, Ester C; Alves, Andrea C; Oliveira, Jamil S; Cara, Denise C; Maioli, Tatiani U; Faria, Ana Maria C

2015-10-01

Dietary compounds, including micronutrients such as vitamin A and its metabolite retinoic acid, directly influence the development and function of the immune system. In this study, we show that either dietary deficiency of or supplementation with vitamin A had immunologic effects in mice that were fed these diets during their development (for 8 wk during the postweaning period). Deficient mice presented higher levels of interferon-γ, interleukin (IL)-6, transforming growth factor-β, IL-17, and IL-10 in the gut-associated lymphoid tissues and draining lymph nodes, indicating a proinflammatory shift in the gut mucosa. Serum immunoglobulin G levels also were elevated in these mice. Conversely, supplemented mice showed higher frequencies of CD4+Foxp3+LAP+ regulatory T cells in gut lymphoid tissues and spleen, suggesting that vitamin A supplementation in the diet may be beneficial in pathologic situations such as inflammatory bowel diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

Clinical application of the Quantiplex HCV RNA 2.0 and Amplicor HCV Monitor assays for quantifying serum hepatitis C virus RNA.

PubMed

Yu, M L; Chuang, W L; Chen, S C; Lin, Z Y; Hsieh, M Y; Wang, L Y; Chang, W Y

1999-11-01

To compare the performance characteristics and clinical application of two different technologies for quantifying serum hepatitis C virus (HCV) RNA levels. HCV RNA was quantified by Amplicor HCV Monitor assay (Amplicor) and Quantiplex HCV RNA 2.0 assay (bDNA-2) in 119 sera from 107 HCV infected patients. Both assays had similar sensitivity (79.4% for Amplicor; 86.0% for bDNA-2), acceptable coefficients of variation (5.3% in Amplicor; 2.6% in bDNA-2), and good linearity (r2 > or = 0.98). There was a positive correlation between quantification values of both methods (r = 0.683, p < 0.001). The Amplicor values were on an average 1.76 log lower than bDNA-2 results. Male subjects and HCV genotype 1b were significantly associated with higher viral load determined by Amplicor, but not with viral load measured by bDNA-2. In 70 chronic HCV infected patients treated with interferon alfa, mean (SD) pretreatment viral load in 27 complete responders (3.47 (0.84) logs for Amplicor, 5.63 (0.58) for bDNA-2) was significantly lower than in non-responders (4.43 (1.01) logs for Amplicor, 6.10 (0.67) logs for bDNA-2; p < 0.001). Cut off points of 3.9 logs for Amplicor and 5.8 logs for bDNA-2 were determined to be the best for predicting response to interferon alfa, giving acceptable sensitivity (70.4%, 74.1%), specificity (72.1%, 65.1%), and accuracy (71.4%, 68.6%), respectively. Both the Amplicor and bDNA-2 assays are clinically useful methods for HCV RNA quantification and are reliable for predicting the outcome of treatment, despite differences in absolute quantification values and in the correlation between HCV genotypes and viral load.

Melatonin inhibits the development of 2,4-dinitrofluorobenzene-induced atopic dermatitis-like skin lesions in NC/Nga mice.

PubMed

Kim, Tae-Ho; Jung, Jung-A; Kim, Gun-Dong; Jang, An-Hee; Ahn, Hyun-Jong; Park, Yong Seek; Park, Cheung-Seog

2009-11-01

Atopic dermatitis (AD) is a common disease in children, and epicutaneous treatment with a chemical hapten such as 2,4-dinitrofluorobenzene (DNFB) evokes an AD-like reaction in NC/Nga mice under specific pathogen-free conditions. Melatonin (N-acetyl-5-methoxytryptamine) is synthesized by the pineal gland, has several different physiologic functions, which include seasonal reproduction control, immune system modulation, free radical scavenging, and inflammatory suppression. In the present study, we investigated whether melatonin suppresses DNFB-induced AD-like skin lesions in NC/Nga mice. The topical administration of melatonin to DNFB-treated NC/Nga mice was found to inhibit ear thickness increases and the skin lesions induced by DNFB. Furthermore, interleukin (IL)-4 and interferon (IFN)-gamma secretion by activated CD4(+) T cells from the draining lymph nodes of DNFB-treated NC/Nga mice were significantly inhibited by melatonin, and total IgE levels in serum were reduced. Our findings suggest that melatonin suppresses the development of AD-like dermatitis in DNFB-treated NC/Nga mice by reducing total IgE in serum, and IL-4 and IFN-gamma production by activated CD4(+) T cells.

Crosstalk Between Apoptosis and Autophagy: Environmental Genotoxins, Infection, and Innate Immunity.

PubMed

Kemp, Michael G

2017-01-01

Autoimmune disorders constitute a major and growing health concern. However, the genetic and environmental factors that contribute to or exacerbate disease symptoms remain unclear. Type I interferons (IFNs) are known to break immune tolerance and be elevated in the serum of patients with autoimmune diseases such as lupus. Extensive work over the past decade has characterized the role of a protein termed stimulator of interferon genes, or STING, in mediating IFN expression and activation in response to cytosolic DNA and cyclic dinucleotides. Interestingly, this STING-dependent innate immune pathway both utilizes and is targeted by the cell's autophagic machinery. Given that aberrant interplay between the apoptotic and autophagic machineries contributes to deregulation of the STING-dependent pathway, IFN-regulated autoimmune phenotypes may be influenced by the combined exposure to environmental carcinogens and pathogenic microorganisms and viruses. This review therefore summarizes recent data regarding these important issues in the field of autoimmunity.

Cytokine levels and histopathology in chronic hepatitis B and chronic hepatitis C.

PubMed

Akcam, Fusun Zeynep; Tigli, Arzu; Kaya, Onur; Ciris, Metin; Vural, Huseyin

2012-12-01

The changes in balance of cytokine profile may result in either recovery or persistence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. This study aims to reveal a possible correlation between cytokine levels, ie, tumor necrosis factor (TNF)-α; interferon-gamma (IFN-γ); interleukin (IL)-10, IL-18, and transforming growth factor-beta (TGF-β); and Ishak score or fibrosis in patients with chronic hepatitis B (CHB) or chronic hepatitis C (CHC). Fifty patients with CHB (n=25), CHC (n=25), and the control group of subjects with negative hepatitis B and C serology (n=30) were included in the study. Patients who did not agree to participate in the study were excluded. Serum cytokine levels were measured by ELISA. Liver biopsies from the patients were also taken for pathological analyses by the same pathologist. The serum levels of TNF-α, IL-10, and IL-18 in the hepatitis C group were significantly high compared with those of the control group (P=0.017, P=0.001, and P=0.004 respectively), but, only IL-10 levels in the hepatitis B group were significantly high (P=0.001). These groups did not show any significant difference with respect to IFN-γ or TGF-β levels. In patients with CHB or CHC, there was a significant correlation (P=0.000) between TNF-α and Ishak score or fibrosis; but no such correlation was found with IFN-γ, IL-10, IL-18, or TGF-β. Result of the current study indicated that cytokine activities were important indicators of clinical severity and progression of HBV- and HCV infections. Further investigations on possible effects of cytokines on hepatocellular damage and fibrosis should be done to arrange new immunopathological approaches to viral hepatitis.

Insulinotropic and Anti-Inflammatory Effects of Rosiglitazone in Experimental Autoimmune Diabetes

PubMed Central

Awara, Wageh M.; El-Sisi, Alaa E.; El-Refaei, Mohamed; El-Naa, Mona M.; El-Desoky, Karima

2005-01-01

Cytokines and nitric oxide (NO) are involved in the pathogenesis of autoimmune diabetes mellitus (DM). Rosiglitazone is an insulin-sensitizing drug that is a ligand for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-γ). The anti-inflammatory and immunomodulating properties of PPAR-γ have been documented. The aim of this study is to investigate the effectiveness of rosiglitazone in autoimmune DM and to clarify the possible mechanism(s) involved. Autoimmune DM was induced in adult male Balb/c mice by co-administration of cyclosporin A and multiple low doses of streptozotocin. Diabetic mice were treated daily with rosiglitazone (7 mg/kg, p.o.) for 21 days. Blood glucose level (BGL), serum insulin level and pancreatic levels of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and NO were measured. Histopathological examination and immunohistochemical determination of CD4 and CD8 T lymphocytes in the pancreatic islets were performed. In addition, analysis of pancreatic protein expression was carried out. The results showed that rosiglitazone treatment resulted in a significant decrease in the BGL and the pancreatic levels of TNF-α, IFN-γ and NO compared to diabetic mice. The serum insulin level was significantly increased after rosiglitazone treatment compared to diabetic mice. The destroyed pancreatic islets were regenerated and became free from both CD4 and CD8 T cells after treatment. Furthermore, many changes in pancreatic protein expression were observed. These results suggest that rosiglitazone has a beneficial effect in the treatment of autoimmune diabetes, an effect that seemed to be a secondary consequence of its anti-inflammatory and immunomodulating properties and might be reflected at the level of protein expression. PMID:17491689

Systemic Inflammatory Load in Young and Old Ringdoves Is Modulated by Consumption of a Jerte Valley Cherry-Based Product

PubMed Central

Delgado, Jonathan; Terrón, María del Pilar; Garrido, María; Barriga, Carmen; Paredes, Sergio Damián; Espino, Javier

2012-01-01

Abstract A chronic subclinical inflammatory status that coexists with immune dysfunction is commonly found in the elderly population. Consumption of foods rich in antioxidants (e.g., cherries) is an attractive strategy to reduce risk from chronic diseases. Based on previous studies showing the antioxidant effect of a Jerte Valley cherry derivative product in humans, the objective of this work was to evaluate the effect of the intake of a Jerte Valley cherry-based beverage on inflammatory load in both young and old ringdoves (Streptopelia risoria). To this purpose, circulating levels of pro-inflammatory and anti-inflammatory cytokines as well as serum levels of different acute-phase proteins were measured before and after a 10-day treatment with the Jerte Valley cherry-based beverage. Thus, the 10-day treatment with the cherry-based beverage modulated the balance of pro- and anti-inflammatory cytokines in both young and old ringdoves by down-regulating the levels of pro-inflammatory cytokines (interleukin [IL]-1β, tumor necrosis factor-α, and interferon-γ) and up-regulating the levels of anti-inflammatory cytokines (IL-4, IL-2, and IL-10). Moreover, the 10-day treatment with the Jerte Valley cherry-based product reduced the levels of several proteins involved in acute-phase responses, such as C-reactive protein, haptoglobin, α2-macroglobulin, and serum amyloid P component. On the other hand, old birds showed imbalanced levels of inflammatory markers toward a pro-inflammatory status, thereby underlining the fact that aging is usually accompanied by systemic inflammation and inflammation-related chronic diseases. To sum up, the data suggest a potential health benefit by consuming the cherry-based beverage, especially in aged populations, through their anti-inflammatory properties. PMID:22846077

Genetic Variation near IRF8 is Associated with Serologic and Cytokine Profiles in Systemic Lupus Erythematosus and Multiple Sclerosis

PubMed Central

Chrabot, Beverly S.; Kariuki, Silvia N.; Zervou, Maria I.; Feng, Xuan; Arrington, Jasmine; Jolly, Meenakshi; Boumpas, Dimitrios T.; Reder, Anthony T.; Goulielmos, George N.; Niewold, Timothy B.

2013-01-01

Alleles of IRF8 are associated with susceptibility to both systemic lupus erythematosus (SLE) and multiple sclerosis (MS). While high type I interferon (IFN) is thought to be causal in SLE, type I IFN is used as a therapy in MS. We investigated whether IRF8 alleles were associated with type I IFN levels or serologic profiles in SLE and MS. Alleles which have been previously associated with SLE or MS were genotyped in SLE and MS patients. The MS-associated rs17445836G allele was associated with anti-dsDNA autoantibodies in SLE patients (meta-analysis OR=1.92). The same allele was associated with decreased serum IFN activity in SLE patients with anti-dsDNA antibodies, and with decreased type I IFN-induced gene expression in PBMC from anti-dsDNA negative SLE patients. In secondary progressive MS patients, rs17445836G was associated with decreased serum type I IFN. Rs17445836G was associated with increased IRF8 expression in SLE patient B cells. In summary, IRF8 rs17445836G is associated with human autoimmune disease characterized by low type I IFN levels, and this may have pharmacogenetic relevance as type I IFN is modulated in SLE and MS. The association with autoantibodies and increased IRF8 expression in B cells supports a role for rs17445836G in humoral tolerance. PMID:23965942

Indirubin, a purple 3,2- bisindole, inhibited allergic contact dermatitis via regulating T helper (Th)-mediated immune system in DNCB-induced model.

PubMed

Kim, Mi Hye; Choi, You Yeon; Yang, Gabsik; Cho, Ik-Hyun; Nam, Dongwoo; Yang, Woong Mo

2013-01-09

Indirubin, isolated from Indigo naturalis (Apiaceae) is a purple 3,2- bisindole and a stable isomer of indigo. Although it is known to have anti-inflammatory activities, its mechanism of action has not been elucidated. Seven-week-old female BALB/c mice were sensitized with 1-chloro-2,4-dinitrobenzene (DNCB) to induce skin inflammation. Hematoxylin and eosin staining was performed to assess epidermal and dermal hyperplasia, which were determined by measuring the thicknesses of the epidermis and dermis, respectively. We also evaluated serum immunoglobulin E (IgE) levels and cytokines production, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-4, 6 and Interferon (IFN)-gamma. In addition, we investigated nuclear factor (NF)-κB, IκB-α and mitogen-activated protein (MAP) kinase activities for verifying the molecular mechanism of inflammation. Indirubin treatment suppressed skin inflammation in DNCB-exposed mice. The skin lesions were significantly thinner in the Indirubin-treated group than in untreated controls, and the hyperkeratosis disappeared. Indirubin reduced the total serum IgE level and cytokines production. In addition, it normalized NF-κB, IκB-α and MAP kinase expression. Indirubin might be a useful treatment for allergic contact dermatitis via regulating the co-expression of T helper (Th) 1 and 2 cell-mediated immune responses. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

α-Lipoic acid suppresses the development of DNFB-induced atopic dermatitis-like symptoms in NC/Nga mice.

PubMed

Kim, Gun-Dong; Kim, Tae-Ho; Jang, An-Hee; Ahn, Hyun-Jong; Park, Yong Seek; Park, Cheung-Seog

2011-02-01

Atopic dermatitis (AD) is a common skin disease that has complex pathogenic mechanisms. Under specific pathogen-free conditions, repeated epicutaneous treatment of 2-4-dinitrofluorobenzene (DNFB) evokes AD-like clinical symptoms in NC/Nga mice. α-Lipoic acid (α-LA; 1, 2-dithiolane-3-pentanoic acid) is a dietary component that is synthesized in bacteria, yeast, plants, and mammals. α-LA and its reduced form, dihydrolipoic acid, are powerful antioxidants that have many physiological functions, including free radical scavenging of reactive oxygen species, generation of cellular antioxidants, chelation of metal ions, and inflammatory suppression. In this study, we investigated whether α-LA suppresses AD-like skin lesions induced by repeated DNFB application in NC/Nga mice. α-LA significantly suppressed production of interferon (IFN)-γ and interleukin (IL)-4 by activated CD4(+) T cells. We found that the oral administration of α-LA reduced AD-like clinical symptoms and inhibited increases of epidermal thickness in DNFB-induced AD-like skin lesions of NC/Nga mice. Furthermore, total serum IgE levels were dramatically reduced by topical α-LA treatment. Our findings suggest that oral administration of α-LA suppresses the development of AD in DNFB-treated NC/Nga mice and reduces IFN-γ and IL-4 production from activated CD4(+) T cells as well as total serum IgE levels. © 2011 John Wiley & Sons A/S.

Genetically Modified Flax Expressing NAP-SsGT1 Transgene: Examination of Anti-Inflammatory Action

PubMed Central

Matusiewicz, Magdalena; Kosieradzka, Iwona; Zuk, Magdalena; Szopa, Jan

2014-01-01

The aim of the work was to define the influence of dietary supplementation with GM (genetically modified) GT#4 flaxseed cake enriched in polyphenols on inflammation development in mice liver. Mice were given ad libitum isoprotein diets: (1) standard diet; (2) high-fat diet rich in lard, high-fat diet enriched with 30% of (3) isogenic flax Linola seed cake; and (4) GM GT#4 flaxseed cake; for 96 days. Administration of transgenic and isogenic seed cake lowered body weight gain, of transgenic to the standard diet level. Serum total antioxidant status was statistically significantly improved in GT#4 flaxseed cake group and did not differ from Linola. Serum thiobarbituric acid reactive substances, lipid profile and the liver concentration of pro-inflammatory cytokine tumor necrosis factor-α were ameliorated by GM and isogenic flaxseed cake consumption. The level of pro-inflammatory cytokine interferon-γ did not differ between mice obtaining GM GT#4 and non-GM flaxseed cakes. The C-reactive protein concentration was reduced in animals fed GT#4 flaxseed cake and did not differ from those fed non-GM flaxseed cake-based diet. Similarly, the liver structure of mice consuming diets enriched in flaxseed cake was improved. Dietetic enrichment with GM GT#4 and non-GM flaxseed cakes may be a promising solution for health problems resulting from improper diet. PMID:25247574

Budesonide suppresses pulmonary antibacterial host defense by down-regulating cathelicidin-related antimicrobial peptide in allergic inflammation mice and in lung epithelial cells

PubMed Central

2013-01-01

Background Glucocorticoids are widely regarded as the most effective treatment for asthma. However, the direct impact of glucocorticoids on the innate immune system and antibacterial host defense during asthma remain unclear. Understanding the mechanisms underlying this process is critical to the clinical application of glucocorticoids for asthma therapy. After sensitization and challenge with ovalbumin (OVA), BALB/c mice were treated with inhaled budesonide and infected with Pseudomonas aeruginosa (P. aeruginosa). The number of viable bacteria in enflamed lungs was evaluated, and levels of interleukin-4 (IL-4) and interferon-γ (IFN-γ) in serum were measured. A lung epithelial cell line was pretreated with budesonide. Levels of cathelicidin-related antimicrobial peptide (CRAMP) were measured by immunohistochemistry and western blot analysis. Intracellular bacteria were observed in lung epithelial cells. Results Inhaled budesonide enhanced lung infection in allergic mice exposed to P. aeruginosa and increased the number of viable bacteria in lung tissue. Higher levels of IL-4 and lower levels of IFN-γ were observed in the serum. Budesonide decreased the expression of CRAMP, increased the number of internalized P. aeruginosa in OVA-challenged mice and in lung epithelial cell lines. These data indicate that inhaled budesonide can suppress pulmonary antibacterial host defense by down-regulating CRAMP in allergic inflammation mice and in cells in vitro. Conclusions Inhaled budesonide suppressed pulmonary antibacterial host defense in an asthmatic mouse model and in lung epithelium cells in vitro. This effect was dependent on the down-regulation of CRAMP. PMID:23387852

Human brucellosis is characterized by an intense Th1 profile associated with a defective monocyte function.

PubMed

Rodríguez-Zapata, Manuel; Matías, Marlene J; Prieto, Alfredo; Jonde, Marco A; Monserrat, Jorge; Sánchez, Lorenzo; Reyes, Eduardo; De la Hera, Antonio; Alvarez-Mon, Melchor

2010-07-01

In animal models, a defective Th1 response appears to be critical in the pathogenesis of brucellosis, but the Th1 response in human brucellosis patients remains partially undefined. Peripheral blood from 24 brucellosis patients was studied before and 45 days after antibiotherapy. Twenty-four sex- and age-matched healthy donors were analyzed in parallel. Significantly increased levels of interleukin 1beta (IL-1beta), IL-2, IL-4, IL-6, IL-12p40, gamma interferon (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha), but not of IL-10, in serum and/or significantly increased percentages of samples with detectable levels of these cytokines, measured by enzyme-linked immunosorbent assays (ELISA), were found for untreated brucellosis patients, but these levels were reduced and/or normalized after treatment. Flow cytometry studies showed that the intracytoplasmic expression of IFN-gamma, IL-2, and TNF-alpha, but not that of IL-4, by phorbol myristate-activated CD4(+) CD3(+) and CD8(+) CD3(+) T lymphocytes was significantly increased in untreated brucellosis patients and was also partially normalized after antibiotherapy. The percentage of phagocytic cells, the mean phagocytic activity per cell, and the phagocytic indices for monocytes at baseline were defective and had only partially reverted at follow-up. T lymphocytes from untreated brucellosis patients are activated in vivo and show Th1 cytokine production polarization, with strikingly high serum IFN-gamma levels. In spite of this Th1 environment, we found deficient effector phagocytic activity in peripheral blood monocytes.

Human Brucellosis Is Characterized by an Intense Th1 Profile Associated with a Defective Monocyte Function▿

PubMed Central

Rodríguez-Zapata, Manuel; Matías, Marlene J.; Prieto, Alfredo; Jonde, Marco A.; Monserrat, Jorge; Sánchez, Lorenzo; Reyes, Eduardo; De la Hera, Antonio; Alvarez-Mon, Melchor

2010-01-01

In animal models, a defective Th1 response appears to be critical in the pathogenesis of brucellosis, but the Th1 response in human brucellosis patients remains partially undefined. Peripheral blood from 24 brucellosis patients was studied before and 45 days after antibiotherapy. Twenty-four sex- and age-matched healthy donors were analyzed in parallel. Significantly increased levels of interleukin 1β (IL-1β), IL-2, IL-4, IL-6, IL-12p40, gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α), but not of IL-10, in serum and/or significantly increased percentages of samples with detectable levels of these cytokines, measured by enzyme-linked immunosorbent assays (ELISA), were found for untreated brucellosis patients, but these levels were reduced and/or normalized after treatment. Flow cytometry studies showed that the intracytoplasmic expression of IFN-γ, IL-2, and TNF-α, but not that of IL-4, by phorbol myristate-activated CD4+ CD3+ and CD8+ CD3+ T lymphocytes was significantly increased in untreated brucellosis patients and was also partially normalized after antibiotherapy. The percentage of phagocytic cells, the mean phagocytic activity per cell, and the phagocytic indices for monocytes at baseline were defective and had only partially reverted at follow-up. T lymphocytes from untreated brucellosis patients are activated in vivo and show Th1 cytokine production polarization, with strikingly high serum IFN-γ levels. In spite of this Th1 environment, we found deficient effector phagocytic activity in peripheral blood monocytes. PMID:20404074

Virological and immunological characteristics of human cytomegalovirus infection associated with Alzheimer disease.

PubMed

Lurain, Nell S; Hanson, Barbara A; Martinson, Jeffrey; Leurgans, Sue E; Landay, Alan L; Bennett, David A; Schneider, Julie A

2013-08-15

Serum, cerebrospinal fluid (CSF), and cryopreserved lymphocytes from subjects in the Rush Alzheimer's Disease Center Religious Orders Study were analyzed for associations between cytomegalovirus (CMV) infection and clinical and pathological markers of Alzheimer disease. CMV antibody levels were associated with neurofibrillary tangles (NFTs). CSF interferon γ was only detected in seropositive subjects and was significantly associated with NFTs. The percentage of senescent T cells (CD4+ or CD8+CD28-CD57+) was significantly higher for CMV-seropositive as compared to CMV-seronegative subjects and was marginally associated with the pathologic diagnosis of Alzheimer disease (CD4+) or amyloid-β (CD8+). Immunocytochemical analysis showed induction of amyloid-β in human foreskin fibroblasts (HFFs) infected with each of 3 clinical CMV strains. In the same subjects, there was no association of herpes simplex virus type 1 (HSV-1) antibody levels with CMV antibody levels or clinical or pathological markers of Alzheimer disease. HSV-1 infection of HFFs did not induce amyloid-β. These data support an association between CMV and the development of Alzheimer disease.

Prepatellar bursitis due to Brucella abortus: case report and analysis of the local immune response.

PubMed

Wallach, Jorge C; Delpino, M Victoria; Scian, Romina; Deodato, Bettina; Fossati, Carlos A; Baldi, Pablo C

2010-12-01

A case of prepatellar bursitis in a man with chronic brucellosis is presented. Brucella abortus biotype 1 was isolated from the abundant yellowish fluid obtained from the bursa. Clinical and epidemiological data did not suggest a direct inoculation of the agent in the bursa. However, the patient mentioned occasional local trauma due to recreational sports, which may have constituted a predisposing factor. As determined by ELISA, there were higher levels of IgG against Brucella LPS and cytosolic proteins detected in the patient's bursal synovial fluid when compared with serum. Levels of proinflammatory cytokines (tumour necrosis factor alpha, interleukin 1 beta, gamma interferon, interleukin 8 and MCP-1) were higher than in synovial fluids obtained from patients with rheumatoid arthritis and a patient with septic arthritis, and a zymographic analysis revealed a gelatinase of about 92 kDa. These findings indicate that it may be possible to diagnose brucellar bursitis by measuring specific antibodies in the bursal synovial fluid. In addition, our findings suggest a role of increased local levels of proinflammatory cytokines and gelatinases in the inflammatory manifestations of brucellar bursitis.

Virological and Immunological Characteristics of Human Cytomegalovirus Infection Associated With Alzheimer Disease

PubMed Central

Lurain, Nell S.; Hanson, Barbara A.; Martinson, Jeffrey; Leurgans, Sue E.; Landay, Alan L.; Bennett, David A.; Schneider, Julie A.

2013-01-01

Serum, cerebrospinal fluid (CSF), and cryopreserved lymphocytes from subjects in the Rush Alzheimer's Disease Center Religious Orders Study were analyzed for associations between cytomegalovirus (CMV) infection and clinical and pathological markers of Alzheimer disease. CMV antibody levels were associated with neurofibrillary tangles (NFTs). CSF interferon γ was only detected in seropositive subjects and was significantly associated with NFTs. The percentage of senescent T cells (CD4+ or CD8+CD28−CD57+) was significantly higher for CMV-seropositive as compared to CMV-seronegative subjects and was marginally associated with the pathologic diagnosis of Alzheimer disease (CD4+) or amyloid-β (CD8+). Immunocytochemical analysis showed induction of amyloid-β in human foreskin fibroblasts (HFFs) infected with each of 3 clinical CMV strains. In the same subjects, there was no association of herpes simplex virus type 1 (HSV-1) antibody levels with CMV antibody levels or clinical or pathological markers of Alzheimer disease. HSV-1 infection of HFFs did not induce amyloid-β. These data support an association between CMV and the development of Alzheimer disease. PMID:23661800

The ratios of pro-inflammatory to anti-inflammatory cytokines in the serum of chronic periodontitis patients with and without type 2 diabetes and/or smoking habit.

PubMed

Miranda, Tamires Szeremeske; Heluy, Sílvia Lacerda; Cruz, Daniele Ferreira; da Silva, Hélio Doyle Pereira; Feres, Magda; Figueiredo, Luciene Cristina; Duarte, Poliana Mendes

2018-05-08

This study assessed the impact of chronic periodontitis (CP) and CP associated with type 2 diabetes mellitus (DM) and/or smoking on the serum ratios of pro- to anti-inflammatory cytokines. Subjects were assigned into one of the following groups: control (n = 25, non-diabetic non-smokers with no history of periodontitis), CP (n = 26, non-diabetic non-smokers with CP), DMCP (n = 30, non-smokers with DM and CP), SCP (n = 27, non-diabetic smokers with CP), and SDMCP (n = 22, smokers with type 2 DM and CP). Serum levels of 18 cytokines were measured using multiplex immunoassays. Six ratios of pro-inflammatory to anti-inflammatory cytokines were significantly higher in the CP group than in the control group (p < 0.05). Eleven, seventeen and nine ratios of pro-inflammatory to anti-inflammatory cytokines were significantly higher in the DMCP, SCP and SDMCP groups than in the control group, respectively (p < 0.05). The SCP group presented higher serum ratios of tumor necrosis factor (TNF)-α/interleukin (IL)-4, TNF-α/IL-5, IL-17/IL-13 and IL-6/IL-13 (p < 0.05) than the CP group. Cluster analysis revealed a relevant cluster composed of ten cytokines (IL-17, IL-23, interferon-γ, IL-12, IL-1β, IL-2, IL-21, IL-6, IL-4 and granulocyte-macrophage colony-stimulating factor [GM-CSF]) in the serum of subjects from the DMCP group. The ratios of pro- to anti-inflammatory cytokines shift to favor a pro-inflammatory status in the serum of patients with CP and even more when CP is associated with one or both risk factors. CP and CP associated with hyperglycemia and/or smoking might contribute to a systemic inflammatory burden and increased risk of systemic complications.

Dysregulated expression of MIG/CXCL9, IP-10/CXCL10 and CXCL16 and their receptors in systemic sclerosis

PubMed Central

2011-01-01

Introduction Systemic sclerosis (SSc) is characterized by fibrosis and microvascular abnormalities including dysregulated angiogenesis. Chemokines, in addition to their chemoattractant properties, have the ability to modulate angiogenesis. Chemokines lacking the enzyme-linked receptor (ELR) motif, such as monokine induced by interferon-γ (IFN-γ) (MIG/CXCL9) and IFN-inducible protein 10 (IP-10/CXCL10), inhibit angiogenesis by binding CXCR3. In addition, CXCL16 promotes angiogenesis by binding its unique receptor CXCR6. In this study, we determined the expression of these chemokines and receptors in SSc skin and serum. Methods Immunohistology and enzyme-linked immunosorbent assays (ELISAs) were used to determine chemokine and chemokine receptor expression in the skin and serum, respectively, of SSc and normal patients. Endothelial cells (ECs) were isolated from SSc skin biopsies and chemokine and chemokine receptor expression was determined by quantitative PCR and immunofluorescence staining. Results Antiangiogenic IP-10/CXCL10 and MIG/CXCL9 were elevated in SSc serum and highly expressed in SSc skin. However, CXCR3, the receptor for these chemokines, was decreased on ECs in SSc vs. normal skin. CXCL16 was elevated in SSc serum and increased in SSc patients with early disease, pulmonary arterial hypertension, and those that died during the 36 months of the study. In addition, its receptor CXCR6 was overexpressed on ECs in SSc skin. At the mRNA and protein levels, CXCR3 was decreased while CXCR6 was increased on SSc ECs vs. human microvascular endothelial cells (HMVECs). Conclusions These results show that while the expression of MIG/CXCL9 and IP-10/CXCL10 are elevated in SSc serum, the expression of CXCR3 is downregulated on SSc dermal ECs. In contrast, CXCL16 and CXCR6 are elevated in SSc serum and on SSc dermal ECs, respectively. In all, these findings suggest angiogenic chemokine receptor expression is likely regulated in an effort to promote angiogenesis in SSc skin. PMID:21303517

Evaluation of the immune response induced by DNA vaccines expressing MIF and MCD-1 genes of Trichinella spiralis in BALB/c mice.

PubMed

Tang, F; Xu, L; Yan, R; Song, X; Li, X

2012-12-01

Plasmids expressing macrophage migration inhibitory factor (MIF) of Trichinella spiralis (TsMIF), multi-cystatin-like domain protein (MCD-1) of T. spiralis (TsMCD-1), or co-expressing TsMIF and TsMCD-1 were constructed with a pVAX1 vector. Their ability to generate a protective immune response against T. spiralis infection was evaluated in BALB/c mice. Groups of mice were immunized twice at 2-week intervals with 100 μg of recombinant plasmids pVAX1-Tsmif, pVAX1-Tsmcd-1 or pVAX1-Tsmif-Tsmcd-1. Control animals were immunized with phosphate-buffered saline (PBS) or blank vector plasmid. Specific antibody levels (IgG, IgG1, IgG2a, IgG2b, IgM, IgA, IgE) against the recombinant protein TsMIF-TsMCD-1, serum cytokines (interferon (IFN)-γ, interleukin (IL)-4, IL-5, transforming growth factor (TGF)-β1 and IL-17) and CD4+/CD8+ T cells were monitored. Challenge infection was performed 2 weeks following the second immunization and worm burden was assayed at 35 days post-challenge. Vaccination with pVAX1-Tsmif induced moderate serum IFN-γ and increases of CD4+ and CD8+ T cells, but no specific immunoglobulin antibody response. Vaccination with pVAX1-Tsmcd-1 induced a predominant Th1 antibody (IgG2a and IgG2b) response and strong levels of serum IFN-γ, and increases of CD4+ T cells. Importantly, co-expression of TsMIF and TsMCD-1 in DNA immunization produced more serum IFN-γ and markedly enhanced CD4+ and CD8+ T cells than the single DNA vaccine of the two genes. Challenge infection demonstrated that immunization with pVAX1-Tsmif-Tsmcd-1 reduced worm burdens (by 23.17%; P < 0.05).

Apolipoprotein E-knockout mice show increased titers of serum anti-nuclear and anti-dsDNA antibodies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Yuehai; Huang, Ziyang, E-mail: huangziyang666@126.com; Lu, Huixia

2012-07-13

Highlights: Black-Right-Pointing-Pointer Titers of ANA and anti-dsDNA antibodies were higher in ApoE{sup -/-} than C57B6/L mice. Black-Right-Pointing-Pointer Spleen was greater and splenocyte apoptosis lower in ApoE{sup -/-} than B6 mice. Black-Right-Pointing-Pointer Level of TLR4 was lower in spleen tissue of ApoE{sup -/-} than B6 mice. Black-Right-Pointing-Pointer The TLR4 pathway may participate in maintaining the balance of splenocyte apoptosis. Black-Right-Pointing-Pointer The TLR4 pathway may participate in antibody production in spleen tissue. -- Abstract: Apolipoprotein E-knockout (ApoE{sup -/-}) mice, atherosclerosis-prone mice, show an autoimmune response, but the pathogenesis is not fully understood. We investigated the pathogenesis in female and male ApoE{sup -/-}more » mice. The spleens of all ApoE{sup -/-} and C57BL/6 (B6) mice were weighed. The serum IgG level and titers of anti-nuclear antibody (ANA) and anti-double-stranded DNA (anti-dsDNA) antibody were assayed by ELISA. Apoptosis of spleen tissue was evaluated by TUNEL. TLR4 level in spleen tissue was tested by immunohistochemistry and Western blot analysis. Levels of MyD88, p38, phosphorylated p38 (pp38), interferon regulatory factor 3 (IRF3) and Bcl-2-associated X protein (Bax) in spleen tissue were detected by Western blot analysis. We also survey the changes of serum autoantibodies, spleen weight, splenocyte apoptosis and the expressions of TLR4, MyD88, pp38, IRF3 and Bax in spleen tissue in male ApoE{sup -/-} mice after 4 weeks of lipopolysaccharide (LPS), Toll-like receptor 4 ligand, administration. ApoE{sup -/-} mice showed splenomegaly and significantly increased serum level of IgG and titers of ANA and anti-dsDNA antibody as compared with B6 mice. Splenocyte apoptosis and the expression of TLR4, MyD88, pp38, IRF3 and Bax in spleen tissue were significantly lower in ApoE{sup -/-} than B6 mice. The expression of TLR4, MyD88, IRF3, pp38, and Bax differed by sex in ApoE{sup -/-} spleen tissue. The down-regulation of TLR4 signal molecules induced by LPS led to decreased expression of Bax and increased serum titers of ANA and anti-dsDNA antibody. Therefore, the TLR4 signal pathway may participate in maintaining the balance of splenocyte apoptosis and autoantibody production in ApoE{sup -/-} mice.« less

The effect of royal jelly on the growth of breast cancer in mice

PubMed Central

Zhang, Shuang; Shao, Qiqi; Geng, Haiyang; Su, Songkun

2017-01-01

Due to various pharmacological properties, including antioxidative, anti-inflammatory and antibiotic properties, royal jelly (RJ) has been widely consumed in daily diets in numerous countries. In the present study, the effect of RJ on 4T1-bearing mice was investigated. The study was performed by feeding 4T1-bearing mice with RJ using either the prophylactic-therapeutic (PTRJ) or therapeutic (TRJ) method. The experimental results for the PTRJ group demonstrated that the weight of tumor was significantly reduced (RJ 0.5 and 1.5 g/kg); and in the serum, the levels of interleukin (IL)-2 (RJ 0.5 and 1.5 g/kg), interferon (IFN)-α, superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) were significantly elevated, but the concentrations of IL-4 (RJ 0.5 and 1.5 g/kg) and IL-10 (RJ 1.0 g/kg) were significantly decreased. In addition, the activities of T-AOC and glutathione reductase (GR) were significantly improved in the liver, whereas in the kidney, the activities of T-AOC and GR were significantly increased only under the dose of 0.5 g/kg. For the TRJ group, the antitumor effect of RJ was not significant; the change in IL-2, IFN-α, SOD and T-AOC levels in the serum, and the change in T-AOC and GR in liver were similar to those observed in the PTRJ groups. RJ treatment was demonstrated to reduce the development of breast tumor in mice, and simultaneously improve the antioxidant capacity of the serum, liver and kidney, particularly using the prophylactic-therapeutic method. These results corroborated the efficacy of RJ supplementation in diets. The results of the present study suggest that the antioxidant and immunomodulatory activities of RJ serve an important role on antitumor growth. PMID:29344209

T cell cytokine polarity as a determinant of immunoglobulin A (IgA) glycosylation and the severity of experimental IgA nephropathy.

PubMed

Chintalacharuvu, S R; Yamashita, M; Bagheri, N; Blanchard, T G; Nedrud, J G; Lamm, M E; Tomino, Y; Emancipator, S N

2008-09-01

Immunoglobulin A (IgA) glycosylation, recognized as an important pathogenic factor in IgA nephropathy (IgAN), is apparently controlled by the polarity of T helper (Th) cytokine responses. To examine the role of cytokine polarity in IgAN, inbred mice were immunized by intraperitoneal priming with inactivated Sendai virus (SeV) emulsified in either complete Freund's adjuvant (CFA) or incomplete Freund's adjuvant (IFA), which promote Th1- or Th2-immune response, respectively, and then boosted identically twice orally with aqueous suspensions of inactivated virus. Next, some mice were challenged intranasally with infectious SeV. Mice primed with CFA or IFA had equal reductions in nasal viral titre relative to non-immune controls, and equally increased serum levels of SeV-specific IgA antibody. Mice primed with CFA showed higher SeV-specific IgG than those with IFA. Splenocytes from mice primed with IFA produced copious amounts of interleukin (IL)-4 and IL-5, but little interferon-gamma and IL-2; those primed with CFA had reciprocal cytokine recall responses. Total serum IgA and especially SeV-specific IgA from mice primed with IFA showed a selective defect in sialylation and galactosylation. Although the frequency and intensity of glomerular deposits and haematuria did not differ, glomerulonephritis in mice primed with IFA and challenged with infectious virus was more severe than in those given CFA, as judged by serum creatinine level. We conclude that the polarity of T cell cytokines controls the pattern of IgA glycosylation and exerts direct or indirect effects on functional glomerular responses to immune complex deposition.

The effect of royal jelly on the growth of breast cancer in mice.

PubMed

Zhang, Shuang; Shao, Qiqi; Geng, Haiyang; Su, Songkun

2017-12-01

Due to various pharmacological properties, including antioxidative, anti-inflammatory and antibiotic properties, royal jelly (RJ) has been widely consumed in daily diets in numerous countries. In the present study, the effect of RJ on 4T1-bearing mice was investigated. The study was performed by feeding 4T1-bearing mice with RJ using either the prophylactic-therapeutic (PTRJ) or therapeutic (TRJ) method. The experimental results for the PTRJ group demonstrated that the weight of tumor was significantly reduced (RJ 0.5 and 1.5 g/kg); and in the serum, the levels of interleukin (IL)-2 (RJ 0.5 and 1.5 g/kg), interferon (IFN)-α, superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) were significantly elevated, but the concentrations of IL-4 (RJ 0.5 and 1.5 g/kg) and IL-10 (RJ 1.0 g/kg) were significantly decreased. In addition, the activities of T-AOC and glutathione reductase (GR) were significantly improved in the liver, whereas in the kidney, the activities of T-AOC and GR were significantly increased only under the dose of 0.5 g/kg. For the TRJ group, the antitumor effect of RJ was not significant; the change in IL-2, IFN-α, SOD and T-AOC levels in the serum, and the change in T-AOC and GR in liver were similar to those observed in the PTRJ groups. RJ treatment was demonstrated to reduce the development of breast tumor in mice, and simultaneously improve the antioxidant capacity of the serum, liver and kidney, particularly using the prophylactic-therapeutic method. These results corroborated the efficacy of RJ supplementation in diets. The results of the present study suggest that the antioxidant and immunomodulatory activities of RJ serve an important role on antitumor growth.

Conjugates of ubiquitin cross-reactive protein distribute in a cytoskeletal pattern.

PubMed Central

Loeb, K R; Haas, A L

1994-01-01

Ubiquitin cross-reactive protein (UCRP), a 15-kDa interferon-induced protein, is a sequence homolog of ubiquitin that is covalently ligated to intracellular proteins in a parallel enzymatic reaction and is found at low levels within cultured cell lines and human tissues not exposed to interferon. Ubiquitin and UCRP ligation reactions apparently target distinct subsets of intracellular proteins, as judged from differences in the distributions of the respective adducts revealed on immunoblots. In this study, successive passages of the human lung carcinoma line A549 in the presence of neutralizing antibodies against alpha and beta interferons had no effect on the levels of either free or conjugated UCRP, indicating that these UCRP pools are constitutively present within uninduced cells and are thus not a consequence of autoinduction by low levels of secreted alpha/beta interferon. In an effort to identify potential targets for UCRP conjugation, the immunocytochemical distribution of UCRP was examined by using affinity-purified polyclonal antibodies against recombinant polypeptide. UCRP distributes in a punctate cytoskeletal pattern that is resistant to extraction by nonionic detergents (e.g., Triton X-100) in both uninduced and interferon-treated A549 cells. The cytoskeletal pattern colocalizes with the intermediate filament network of epithelial and mesothelial cell lines. Immunoblots of parallel Triton X-100-insoluble cell extracts suggest that the cytoskeletal association largely results from the noncovalent association of UCRP conjugates with the intermediate filaments rather than direct ligation of the polypeptide to structural components of the filaments. A significant increase in the sequestration of UCRP adducts on intermediate filaments accompanies interferon induction. These results suggest that UCRP may serve as a trans-acting binding factor directing the association of ligated target proteins to intermediate filaments. Images PMID:7526157

Biomarkers of Methylmercury Exposure Immunotoxicity among Fish Consumers in Amazonian Brazil

PubMed Central

Fillion, Myriam; Barbosa, Fernando; Shirley, Devon L.; Chine, Chiameka; Lemire, Melanie; Mergler, Donna; Silbergeld, Ellen K.

2011-01-01

Background: Mercury (Hg) is a ubiquitous environmental contaminant with neurodevelopmental and immune system effects. An informative biomarker of Hg-induced immunotoxicity could aid studies on the potential contribution to immune-related health effects. Objectives: Our objectives were to test the hypothesis that methylmercury (MeHg) exposures affect levels of serum biomarkers and to examine interactions between Hg and selenium (Se) in terms of these responses. Methods: This cross-sectional epidemiological study assessed adults living along the Tapajós River, a system long affected by MeHg. We measured antinuclear (ANA) and antinucleolar (ANoA) autoantibody levels and eight cytokines in serum samples (n = 232). Total Hg (including MeHg) and Se were measured in blood, plasma, hair, and urine. Results: The median (range) total Hg concentrations were 14.1 μg/g (1.1–62.4), 53.5 μg/L (4.3–288.9), 8.8 μg/L (0.2–40), and 3.0 μg/L (0.2–16.1) for hair, blood, plasma, and urine, respectively. Elevated titers of ANA (but not ANoA) were positively associated with MeHg exposure (log-transformed, for blood and plasma), unadjusted [odds ratio (OR) = 2.6; 95% confidence interval (CI): 1.1, 6.2] and adjusted for sex and age (OR = 2.9; 95% CI: 1.1, 7.5). Proinflammatory [interleukin (IL)-6 and interferon (IFN)-©], anti-inflammatory (IL-4), and IL-17 cytokine levels were increased with MeHg exposure; however, in the subset of the population with elevated ANA, proinflammatory IL-1®, IL-6, IFN-©, and tumor necrosis factor (TNF)-〈 and anti-inflammatory (IL-4) cytokine levels were decreased with MeHg exposure. Although Se status was associated with MeHg level (correlation coefficient = 0.86; 95% CI: 0.29, 1.43), Se status was not associated with any changes in ANA and did not modify associations between Hg and ANA titers. Conclusions: MeHg exposure was associated with an increased ANA and changes in serum cytokine profile. Moreover, alterations in serum cytokine profiles differed based on ANA response, suggesting a specific phenotype of MeHg susceptibility. Further research on the potential health implications of these observed immunological changes is warranted. PMID:21868305

Immunomodulatory efficacy of ethanol extract of propolis on tumor-bearing mice with disseminated candidiasis.

PubMed

Khosravi, A R; Shokri, H; Darvishi, S; Taghavi, M

2014-12-01

This study was aimed at investigating the effect of propolis on immunosurveillance by measuring the levels of serum interleukin (IL)-4, IL-10, IL-17, tumor necrosis factor (TNF)-α and interferon (IFN)-γ in tumor-bearing mice with disseminated candidiasis. The ethanol extract of propolis was selected for this study. Balb/C female mice were infected with Candida albicans (C. albicans) and inoculated with spontaneous mouse mammary tumor (SMMT). The serum levels of tissue inhibitor of metalloproteinase-1(TIMP-1) were assessed by enzyme- linked immunosorbent assay (ELISA). Mice were treated daily with propolis solution (100mg/kg, 0.1 mL, orally) for 3 days before IV challenge with C. albicans and SC challenge with SMMT and continued for 10 days. The rates of survival and tumor growth of understudy mice were investigated as well. The levels of TNF-α, IFN-γ, IL-4, IL-10 and IL-17 cytokines in culture supernatants were determined by ELISA. The mean tumor size was significantly increased in tumor-bearing mice infected with C. albicans (16.98 ± 0.49 mm(2)) as compared to other mice groups (P<0.05). The results showed a significant decline of IL-4 and IL-10 levels after propolis administration to tumor-bearing mice infected with C. albicans (53.41 pg/mL, 156.81 pg/mL and 63.45 pg/mL) (P < 0.05). The increment of TNF-α (433.85 pg/mL) and IFN-γ (120.43 pg/mL) levels were also observed. Data revealed that propolis has remarkable immunomodulatory effect, which provides a scientific validation for the popular use of this natural substance, and further investigation will help to understand propolis usefulness during immunosuppressive conditions. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Enhanced production of human influenza virus in PBS-12SF cells with a reduced interferon response.

PubMed

Carvajal-Yepes, Monica; Sporer, Kelly R B; Carter, Jenna L; Colvin, Christopher J; Coussens, Paul M

2015-01-01

Influenza is one of the most important infectious diseases in humans. The best way to prevent severe illness caused by influenza infection is vaccination. Cell culture-derived influenza vaccines are being considered in addition to the widely used egg-based system in order to support the increasing seasonal demand and to be prepared in case of a pandemic. Cell culture based systems offer increased safety, capacity, and flexibility with reduced downstream processing relative to embryonated eggs. We have previously reported a chick embryo cell line, termed PBS-12SF, that supports replication of human and avian influenza A viruses to high titers (>10(7) PFU/ml) without the need for exogenous proteases or serum proteins. Viral infections in cells are limited by the Interferon (IFN) response typified by production of type I IFNs that bind to the IFNα/β receptor and activate an antiviral state. In this study, we investigated how neutralizing the interferon (IFN) response in PBS-12SF cells, via shRNA-mediated knock-down of IFNAR1 mRNA expression, affects influenza virus production. We were successful in knocking down ∼90% of IFNAR1 protein expression by this method, resulting in a significant decrease in the response to recombinant chIFNα stimulation in PBS-12SF cells as shown by a reduction in expression of interferon-responsive genes when compared to control cells. Additionally; IFNAR1-knock-down cells displayed enhanced viral HA production and released more virus into cell culture supernatants than parental PBS-12SF cells.

Single dose of an adenovirus vectored mouse interferon-α protects mice from lethal EV71 challenge.

PubMed

Sun, Jialei; Ennis, Jane; Turner, Jeffrey D; Chu, Justin Jang Hann

2016-10-01

Enterovirus 71 (EV71) causes hand-foot-and-mouth diseases as well as neurological complications in young children. Interferon (IFN) can inhibit the replication of many viruses with low cytotoxic effects. Previously, an adenovirus vectored mouse interferon-α (DEF201), subtype 5, was generated by Wu et al, 2007. In this study, the antiviral effects of DEF201 against EV71 were evaluated in a murine model. 6-day-old BALB/c mice were administered a single dose of DEF201 before or after infection with lethal dose of EV71. The survival rate, clinical symptoms, tissue viral loads and histology pathogenesis were evaluated. IFN gene expression following a single dose of DEF201 maintained high concentrations of 100-9000 pg/mL for more than 7 days in mice serum. Pre-infection administration of a single dose of 10 6  PFU of DEF201 offered full protection of the mice against EV71 infection compared with the empty Ad5 vector control. In addition, virus load in DEF201-treated mice muscle tissue was significantly decreased as compared with empty vector control. Histopathology analysis revealed that DEF201 significantly prevented the development of severe tissue damage with reduction of viral antigen in the murine muscle tissue. Post-infection treatment at 6 h offered full protection and partial protection at 12 h, indicating that DEF201 could be used as an anti-EV71 therapeutic agent in early stage of EV71 infection. In addition, our study showed that DEF201 enhanced the neutralization ability of serum in EV71-vaccinated mice, implying that DEF201 could promote the production of specific anti-EV71 antibodies. In conclusion, single dose of DEF201 is highly efficacious as a prophylactic agent against EV71 infection in vivo. Copyright © 2016 Elsevier B.V. All rights reserved.

Importance of interferon alpha in the resistance of allogeneic C57B1/6 mice to the multiplication of Friend erythroleukemia cells in the liver.

PubMed

Gresser, I; Maury, C; Bandu, M T; Belardelli, F

1990-02-15

Friend erythroleukemia cells (FLC) (H-2d) injected intravenously multiply extensively in the livers of syngeneic DBA/2 mice and not at all in the livers of allogeneic C57B1/6 mice. Our results indicate that interferon alpha (IFN-alpha) is an important factor in the resistance of allogeneic mice to the multiplication of FLC in the liver. (a) After i.v. inoculation of FLC there was an inverse correlation between the presence of IFN-alpha in the serum and the capacity of FLC to multiply in the liver. Thus, all 44 FLC-injected adult C57B1/6 mice had circulating IFN-alpha and FLC did not multiply in the liver of any of the mice. Interferon was not detected in the serum of 83% of 41 FLC-injected DBA/2 mice (and was found only at a low titer in 17% of the mice) and FLC multiplied in the liver of all mice. (b) FLC did multiply in the livers of newborn C57B1/6 mice and in the livers of irradiated adult C57B1/6 mice, and IFN-alpha was not detected in their sera. In contrast, after i.v. inoculation of FLC, IFN-alpha was detected in the sera of 3-week-old and athymic nu/nu adult C57B1/6 mice while FLC failed to multiply in the liver. (c) FLC also induced IFN-alpha in congenic B10.D2 (H-2d) mice and FLC did not multiply in the liver. We suggest that, depending on the site of tumor implantation, different host mechanisms have various degrees of importance in controlling the growth and/or rejection of allogeneic tumor cells, and that IFN-alpha is particularly important when FLC are injected i.v.

Clearance of hepatitis C virus after living-donor liver transplantation in spite of residual viremia on end date of interferon therapy before transplantation

PubMed Central

Ichikawa, Tatsuki; Nakao, Kazuhiko; Hamasaki, Keisuke; Honda, Takuya; Shibata, Hidetaka; Akahoshi, Mana; Eguchi, Susumu; Takatsuki, Mitsuhisa; Kanematsu, Takashi; Eguchi, Katsumi

2007-01-01

Interferon (IFN) therapy is the only treatment strategy for hepatitis C virus (HCV) infection after liver transplantation (LT), but prophylactic and treatable IFN therapy after LT has been shown to be insufficient due to the adverse effects of IFN and rivabirin. In this paper, we describe the disappearance of HCV after LT without IFN therapy in the presence of residual viremia on the day of LT. We herein report our findings since this is considered an important case for the anti-HCV strategy of post LT. A 60-year old woman with LC and HCC was referred to Nagasaki University Hospital in August 2004. After she underwent LT on February 18, 2005, we injected peg-IFN-α-2a the 11th time at 18 wk and HCV-RNA was still positive in the serum at LT. The serum HCV-RNA was negative one month after operation and subsequently dissolved 15 mo after operation without IFN therapy. As a result, we speculate that if HCV-RNA is positive while HCV core antigen is negative before LT, then it may lead to clearance of HCV after LT. Therefore long acting peg-IFN-α-2a is thus considered a potentially effective agent for the treatment of HCV-related cirrhosis before LT. PMID:17696240

Interferon-gamma promotes the survival and Fc epsilon RI-mediated histamine release in cultured human mast cells.

PubMed Central

Yanagida, M; Fukamachi, H; Takei, M; Hagiwara, T; Uzumaki, H; Tokiwa, T; Saito, H; Iikura, Y; Nakahata, T

1996-01-01

We examined the effects of interferon-gamma (IFN-gamma) on 100% pure human mast cells generated in suspension cultures of umbilical cord blood mononuclear cells in the presence of stem cell factor (SCF) and interleukin-6 (IL-6). When mast cells were suspended in serum-free medium without any cytokine after the withdrawal of SCF and IL-6, they died over a period of 5 days because of apoptosis. IFN-gamma in the cultures suppressed apoptosis and prolonged their survival in a dose-dependent manner. This survival-promoting effect of IFN-gamma was blocked by neutralizing antibodies to IFN-gamma or to IFN-gamma receptor (IFN-gamma R). When mast cells were incubated with IFN-gamma in serum-free medium for more than 4 hr during sensitization, immunoglobulin E (IgE)/anti-IgE antibody-induced histamine release was effectively enhanced. Polymerase chain reaction (PCR) amplification of the alpha-chain of IFN-gamma R (IFN-gamma R alpha) yielded products of the correct size predicted from the sequence of the receptor. In addition, flow cytometry using anti-IFN-gamma R monoclonal antibodies (mAbs) indicated that these mast cells bear IFN-gamma R on their surface. These findings suggested that IFN-gamma activates human mast cells via specific receptors in certain aspects of inflammatory reactions. Images Figure 2 Figure 4 PMID:9014819

Effect of the bacillus of Calmette-Guérin, Propionibacter acnes and avridine as immunomodulators in antirabies vaccination of mice using the Fuenzalida-Palacios mouse brain vaccine.

PubMed

Megid, J; Peraçolli, M T; Curi, P R; Zanetti, C R; Cabrera, W H; Vassao, R; Ito, F H

1999-05-14

Using the laboratory mice, Fuenzalida-Palacios mouse brain human rabies vaccine was administered in groups of animals previously inoculated with rabies virus and then submitted to treatments with the immunomodulators onco-BCG, avridine and Propionibacterium acnes. Humoral and cellular immune responses were evaluated through the macrophage inhibition factor (MIF), intra-pad inoculation (IPI) and serum neutralization (SN) tests and by the detection of gamma-interferon (IFN-gamma). The IPI test was not effective in detecting the response of delayed-type hypersensitivity, contrary to MIF, which showed the immune cellular response. Higher levels of IFN-gamma were observed in the groups of mice vaccinated and treated with avridine and P. acnes. Although immunomodulating activities have been detected, the use of adjuvants with the Fuenzalida-Palacios type vaccine in mice did not reveal any encouraging results.

Viral interleukin-10 in chronic active Epstein-Barr virus infection.

PubMed

Kanegane, H; Wakiguchi, H; Kanegane, C; Kurashige, T; Tosato, G

1997-07-01

Viral interleukin-10 (IL-10), a product of the Epstein-Barr virus (EBV) replication gene BCRF1, shares extensive structural and functional similarity with the human cytokine IL-10. Both viral and human IL-10 inhibit T cell growth and interferon-gamma production. With two ELISAs, one that recognized both human and viral (total) IL-10 and the other specific for viral IL-10, IL-10 was measured in serum or plasma from 34 patients with chronic active EBV infection (CAEBV) and from 15 healthy controls. Of the patients, 56% had measurable total IL-10 and 29% had measurable viral IL-10. In contrast, total IL-10 was detectable in only 2 of 15 controls and viral IL-10 was undetectable. Thus, many patients with CAEBV have abnormally high levels of circulating IL-10 that may contribute to disease pathogenesis by inhibiting host immunity.

Evaluation of Oxidant/Antioxidant Status and Cytokine Levels in Patients with Cannabis Use Disorder.

PubMed

Bayazit, Huseyin; Selek, Salih; Karababa, Ibrahim Fatih; Cicek, Erdinc; Aksoy, Nurten

2017-08-31

Cannabis is the most commonly used illegal drug in the world and it has several adverse effects such as anxiety, panic reactions and psychotic symptoms. In this study, we aimed to evaluate oxidant, anti-oxidant status and cytokine levels in individuals with cannabis use disorder. Thirty-four patients with cannabis use disorder and 34 healthy controls were enrolled to the study. Serum total antioxidant status, total oxidant status and cytokine levels were investigated in patients with cannabis use disorder and healthy controls. We found increased levels of total oxidant status, oxidative stress index and interleukin (IL) 1β, IL-6, IL-8, and tumor necrosis factor (TNF) α in individuals with cannabis dependency compared to healthy people. When we compared total antioxidant status, IL-12, and interferon (IFN) γ levels, there were no differences in both groups. There was positive correlation between IL-6 and total oxidant status, oxidative stress index levels. The oxidative balance of individuals with cannabis use disorder was impaired and they had higher levels of IL-1β, IL-6, IL-8, and TNF-α, which is a pro-inflammatory cytokine and indicates increased inflammation compared to healthy controls. Thus, these findings suggest that cannabis increased inflammation and impaired the oxidative balance.

Vitamin D in addition to peg-interferon-alpha/ribavirin in chronic hepatitis C virus infection: ANRS-HC25-VITAVIC study.

PubMed

Terrier, Benjamin; Lapidus, Nathanael; Pol, Stanislas; Serfaty, Lawrence; Ratziu, Vlad; Asselah, Tarik; Thibault, Vincent; Souberbielle, Jean-Claude; Carrat, Fabrice; Cacoub, Patrice

2015-05-14

To investigate if correction of hypovitaminosis D before initiation of Peg-interferon-alpha/ribavirin (PegIFN/RBV) therapy could improve the efficacy of PegIFN/RBV in previously null-responder patients with chronic genotype 1 or 4 hepatitis C virus (HCV) infection. Genotype 1 or 4 HCV-infected patients with null response to previous PegIFN/RBV treatment and with hypovitaminosis D (< 30 ng/mL) prospectively received cholecalciferol 100000 IU per week for 4 wk [from week -4 (W-4) to W0], followed by 100000 IU per month in combination with PegIFN/RBV for 12 mo (from W0 to W48). The primary outcome was the rate of early virological response defined by an HCV RNA < 12 IU/mL after 12 wk PegIFN/RBV treatment. A total of 32 patients were included, 19 (59%) and 13 (41%) patients were HCV genotype 1 and 4, respectively. The median baseline vitamin D level was 15 ng/mL (range: 7-28). In modified intention-to-treat analysis, 29 patients who received at least one dose of PegIFN/RBV were included in the analysis. All patients except one normalized their vitamin D serum levels. The rate of early virologic response was 0/29 (0%). The rate of HCV RNA < 12 IU/mL after 24 wk of PegIFN/RBV was 1/27 (4%). The safety profile was favorable. Addition of vitamin D to PegIFN/RBV does not improve the rate of early virologic response in previously null-responders with chronic genotype 1 or 4 HCV infection.

Interferon-β Inhibits Neurotrophin 3 Signalling and Pro-Survival Activity by Upregulating the Expression of Truncated TrkC-T1 Receptor.

PubMed

Dedoni, Simona; Olianas, Maria C; Ingianni, Angela; Onali, Pierluigi

2017-04-01

Although clinically useful for the treatment of various diseases, type I interferons (IFNs) have been implicated as causative factors of a number of neuroinflammatory disorders characterized by neuronal damage and altered CNS functions. As neurotrophin 3 (NT3) plays a critical role in neuroprotection, we examined the effects of IFN-β on the signalling and functional activity of the NT3/TrkC system. We found that prolonged exposure of differentiated human SH-SY5Y neuroblastoma cells to IFN-β impaired the ability of NT3 to induce transphosphorylation of the full-length TrkC receptor (TrkC-FL) and the phosphorylation of downstream signalling molecules, including PLCγ1, Akt, GSK-3β and ERK1/2. NT3 was effective in protecting the cells against apoptosis triggered by serum withdrawal or thapsigargin but not IFN-β. Prolonged exposure to the cytokine had little effects on TrkC-FL levels but markedly enhanced the messenger RNA (mRNA) and protein levels of the truncated isoform TrkC-T1, a dominant-negative receptor that inhibits TrkC-FL activity. Cell depletion of TrkC-T1 by small interfering RNA (siRNA) treatment enhanced NT3 signalling through TrkC-FL and allowed the neurotrophin to counteract IFN-β-induced apoptosis. Furthermore, the upregulation of TrkC-T1 by IFN-β was associated with the inhibition of NT3-induced recruitment of the scaffold protein tamalin to TrkC-T1 and tamalin tyrosine phosphorylation. These data indicate that IFN-β exerts a negative control on NT3 pro-survival signalling through a novel mechanism involving the upregulation of TrkC-T1.

Interaction of interferon alpha therapy with thyroid function tests in the management of hepatitis C: a case report.

PubMed

Gill, Gurmit; Bajwa, Hammad; Strouhal, Peter; Buch, Harit N

2016-09-15

Interferon alpha is a widely used therapeutic agent in the treatment of hepatitis C virus infection. Clinical thyroid disease is seen in nearly 15 % of patients receiving interferon alpha for hepatitis C virus infection. The mechanism of thyroid dysfunction with interferon alpha is either autoimmune or inflammatory. We report a case of young woman who developed biphasic thyroid dysfunction posing a diagnostic challenge, while receiving interferon alpha treatment for hepatitis C virus infection. A 29-year-old, Caucasian woman with type 1 diabetes and hepatitis C virus infection was referred with hyperthyroidism, while she was at 17 weeks of a planned 24-week course of interferon alpha therapy. A laboratory investigation revealed a thyroid stimulation hormone level of 0.005 mU/L (0.350-4.94), free thyroxine of 45.6 pmol/L (9.0-19.0) and free tri-iodothyronine of 12.6 pmol/L (2.6-5.7). She had a mild neutropenia and alanine aminotransferase at double the reference value. Her thyroid peroxidase antibody level was 497 ku/L (<5.6) and thyroid inhibitory factor 7 IU/L (>1.8 iu/l is positive). Thyroid scintigraphy with technetium99 scan confirmed a normal-sized thyroid gland with diffuse but normal overall uptake. A diagnosis of interferon alpha-triggered autoimmune hyperthyroidism as opposed to an inflammatory thyroiditis was made. She was offered radioactive iodine therapy, as thionamides were considered inappropriate in view of her liver disease and mild neutropenia. Due to our patient's personal circumstances, radioactive iodine therapy was delayed by 8 weeks and her thyrotoxic symptoms were controlled with beta-blockers alone. A repeat thyroid function test, 4 weeks post treatment with interferon alpha, indicated spontaneous conversion to hypothyroidism with a thyroid stimulation hormone level of 100 mU/L, free thyroxine of 5.2 pmol/L and free tri-iodothyronine of 1.7 pmol/L. She subsequently received levothyroxine for 4 months only and had remained euthyroid for the last 3 months without any treatment. Initial investigations favored the autoimmune nature of hyperthyroidism but follow-up of the case, interestingly, was more consistent with inflammatory thyroiditis. We propose that this can be explained either on the basis of autoimmune subacute thyroiditis or a change in the nature of thyroid stimulation hormone receptor antibody production from stimulating-type to blocking-type antibodies, with disappearance of the latter on discontinuation of interferon alpha.

Improved viability and activity of neutrophils differentiated from HL-60 cells by co-culture with adipose tissue-derived mesenchymal stem cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Yoon Shin; Lim, Goh-Woon; Cho, Kyung-Ah

Highlights: Black-Right-Pointing-Pointer Neutropenia is a principal complication of cancer treatment. Black-Right-Pointing-Pointer Co-culture of neutrophils with AD-MSC retained cell survival and proliferation and inhibited neutrophil apoptosis under serum starved conditions. Black-Right-Pointing-Pointer AD-MSC increased functions of neutrophil. Black-Right-Pointing-Pointer AD-MSC promoted the viability of neutrophils by enhancing respiratory burst through the expression of IFN-{alpha}, G-CSF, and TGF-{beta}. Black-Right-Pointing-Pointer AD-MSC can be used to improve immunity for neutropenia treatment. -- Abstract: Neutropenia is a principal complication of cancer treatment. We investigated the supportive effect of adipose tissue-derived mesenchymal stem cells (AD-MSCs) on the viability and function of neutrophils. Neutrophils were derived from HL-60 cellsmore » by dimethylformamide stimulation and cultured with or without AD-MSCs under serum-starved conditions to evaluate neutrophil survival, proliferation, and function. Serum starvation resulted in the apoptosis of neutrophils and decreased cell survival. The co-culture of neutrophils and AD-MSCs resulted in cell survival and inhibited neutrophil apoptosis under serum-starved conditions. The survival rate of neutrophils was prolonged up to 72 h, and the expression levels of interferon (IFN)-{alpha}, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, and transforming growth factor (TGF)-{beta} in AD-MSCs were increased after co-culture with neutrophils. AD-MSCs promoted the viability of neutrophils by inhibiting apoptosis as well as enhancing respiratory burst, which could potentially be mediated by the increased expression of IFN-{alpha}, G-CSF, and TGF-{beta}. Thus, we conclude that the use of AD-MSCs may be a promising cell-based therapy for increasing immunity by accelerating neutrophil function.« less

Vitamin D deficiency is associated with an increased autoimmune response in healthy individuals and in patients with systemic lupus erythematosus

PubMed Central

Ritterhouse, Lauren L; Crowe, Sherry R; Niewold, Timothy B; Kamen, Diane L; Macwana, Susan R; Roberts, Virginia C; Dedeke, Amy B; Harley, John B; Scofield, R Hal; Guthridge, Joel M; James, Judith A

2011-01-01

Objectives Vitamin D deficiency is widespread and has been associated with many chronic diseases, including autoimmune disorders. A study was undertaken to explore the impact of low vitamin D levels on autoantibody production in healthy individuals, as well as B cell hyperactivity and interferon α (IFNα) activity in patients with systemic lupus erythematosus (SLE). Methods Serum samples from 32 European American female patients with SLE and 32 matched controls were tested for 25-hydroxyvitamin D (25(OH)D) levels, lupus-associated autoantibodies and serum IFNα activity. Isolated peripheral blood mononuclear cells were tested for intracellular phospho-ERK 1/2 as a measure of B cell activation status. Results Vitamin D deficiency (25(OH)D <20 ng/ml) was significantly more frequent among patients with SLE (n=32, 69%) and antinuclear antibody (ANA)-positive controls (n=14, 71%) compared with ANA-negative controls (n=18, 22%) (OR 7.7, 95% CI 2.0 to 29.4, p=0.003 and OR 8.8, 95% CI 1.8 to 43.6, p=0.011, respectively). Patients with high B cell activation had lower mean (SD) 25(OH)D levels than patients with low B cell activation (17.2 (5.1) vs 24.2 (3.9) ng/ml; p=0.009). Patients with vitamin D deficiency also had higher mean (SD) serum IFNα activity than patients without vitamin D deficiency (3.5 (6.6) vs 0.3 (0.3); p=0.02). Conclusions The observation that ANA-positive healthy controls are significantly more likely to be deficient in vitamin D than ANA-negative healthy controls, together with the finding that vitamin D deficiency is associated with certain immune abnormalities in SLE, suggests that vitamin D plays an important role in autoantibody production and SLE pathogenesis. PMID:21586442

Role of CTA1R7K-COL-DD as a novel therapeutic mucosal tolerance-inducing vector for treatment of collagen-induced arthritis.

PubMed

Hasselberg, Annemarie; Schön, Karin; Tarkowski, Andrej; Lycke, Nils

2009-06-01

To determine whether a cholera toxin-derived, novel immunomodulating fusion protein, CTA1R7K-COL-DD, carrying the class II major histocompatibility complex H-2q-restricted type II collagen peptide aa 259-274, can induce therapeutic tolerance and prevent collagen-induced arthritis (CIA) when administered intranasally in DBA/1 mice, and to assess whether ADP-ribosylation at the mucosal membranes exerts a regulatory function such that the outcome of tolerance or immune enhancement can be controlled. DBA/1 mice with CIA were treated intranasally with CTA1R7K-COL-DD. The therapeutic effect was monitored for 46 days after the onset of disease. Clinical scoring of disease, histologic examination of inflammation, and bone erosion were assessed, and cytokine levels were determined in the serum or supernatants from splenocytes stimulated with recall antigen. The protective effect of CTA1R7K-COL-DD resulted in roughly 60% of the mice having no clinical signs or histologic evidence of disease after treatment, and those with CIA had significantly milder disease with less bone erosion. The protective status was associated with lower serum titers of IgG1, IgG2a, IgG2b, and IgG3 anticollagen and a substantial decrease in the production of interleukin-6 (IL-6), IL-17, and interferon-gamma, while levels of IL-10 were markedly up-regulated both in the serum and at the T cell level. The enzymatically inactive mutant fusion protein CTA1R7K-COL-DD provided substantial therapeutic protection against CIA following intranasal administration. The mechanism behind the effect appears to be mediated by peptide-specific regulatory T cells induced by mucosal exposure to the peptide containing CTA1R7K-COL-DD vector. In addition, ADP-ribosylation at the mucosal membranes acts as a key regulator controlling mucosal tolerance or immunity.

Polysaccharides from Tricholoma matsutake and Lentinus edodes enhance 5-fluorouracil-mediated H22 cell growth inhibition.

PubMed

Ren, Ming; Ye, Lingyan; Hao, Xiaoshi; Ren, Zhixing; Ren, Shuping; Xu, Kun; Li, Juan

2014-06-01

Few studies have investigated the effects produced by combinations of polysaccharides and chemotherapeutic drugs in cancer treatment. We hypothesized that a combination of polysaccharides (COP) from Lentinus edodes and Tricholoma matsutake would improve the efficacy of 5-fluorouracil (5-FU)-mediated inhibition of H22 cell growth. Mice were injected H22 cells and then treated with either 5-FU, polysaccharides from Tricholoma matsutake (PTM), polysaccharides from Lentinus edodes (PL), PTM+PL, 5-FU+PTM, 5-FU+ PL, or 5-FU + COP. The tumor weight and volume, and splenic CD4 + and CD8 + T cell frequencies, were determined. Additionally, splenic natural killer (NK) cell and cytotoxic T lymphocyte (CTL) activities were assessed and the serum levels of tumor necrosis factor-alpha (TNF-alpha), Interleukin-2 (IL-2), and Interferon-gamma (IFN-gamma) were measured. Compared with mice from the control, 5-FU, PL, PTM, PTM + PL, 5-FU + PL, and 5-FU + PTM groups, mice treated with 5-FU + COP showed: (a) significantly reduced tumor weight and volume (P < 0.05); (b) significantly higher serum levels of TNF-alpha, IL-2, and IFN-gamma (P < 0.05); (c) significantly increased CD4+ and CD8+ T cell frequencies in the spleen (P < 0.05); and (d) significantly increased splenic NK cell and CTL activities (P < 0.05). The tumor weight and volume in mice treated with 5-FU+PL or 5-FU+PTM were significantly reduced compared with mice treated with 5-FU alone (P < 0.05). Serum levels of TNF-alpha, IL-2, and IFN-gamma, frequencies of CD4 + and CD8+ T cells in the spleen, and splenic NK and CTL activities were also significantly increased in mice treated with 5-FU+PL or 5-FU+PTM compared with mice treated with 5-FU alone (P < 0.05). Polysaccharides from Lentinus edodes and Tricholoma matsutake could enhance the efficacy of 5-FU-mediated H22 cell growth inhibition.

Dendrobium candidum Wall. ex Lindl. attenuates CCl4-induced hepatic damage in imprinting control region mice.

PubMed

Li, Gui-Jie; Sun, Peng; Wang, Qiang; Qian, Yu; Zhu, Kai; Zhao, Xin

2014-09-01

The aim of the present study was to determine the preventive effect of the traditional Chinese medicine, Dendrobium candidum Wall ex Lindl. ( D. candidum ), on CCl 4 -induced hepatic damage in mice. The CCl 4 -induced hepatic damage mice were treated with D. candidum, and the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), triglyceride (TG) and total cholesterol (TC) were determined. In addition, serum cytokine levels of interleukin (IL)-6, IL-12, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were analyzed with kits, while liver tissues were analyzed using hematoxylin and eosin staining and reverse transcription polymerase chain reaction (RT-PCR). Furthermore, the contents of D. candidum were determined by nuclear magnetic resonance (NMR). D. candidum was demonstrated to successfully prevent hepatic damage in mice. The serum levels of AST, ALT and LDH were significantly decreased when the mice were treated with 200 and 400 mg/kg D. candidum, as compared with the control mice (P<0.05). The lowest enzymatic activities were exhibited in the 400 mg/kg D. candidum group, which produced similar results to the positive control drug, silymarin. In addition, in the 400 mg/kg D. candidum group, the highest levels of TG and TC were observed among the treated groups. D. candidum -treated groups also demonstrated reduced levels of the serum proinflammatory cytokines, IL-6, IL-12, TNF-α and IFN-γ. The sections of liver tissue examined during histopathology in the high concentration 400 mg/kg D. candidum group recovered well from CCl 4 damage; however, the sections in the 200 mg/kg D. candidum group revealed necrosis to a more serious degree. RT-PCR analysis was conducted on inflammation-associated genes, including nuclear factor (NF)-κB, IκB-α, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, in the livers of the mice. The 400 mg/kg D. candidum group demonstrated significantly decreased mRNA expression levels of NF-κB, iNOS and COX-2, but an increased expression level of IκB-α when compared with the CCl 4 -treated control group. Furthermore, using NMR, 11 compounds were identified in the D. candidum leaf, whose functional contents may aid the preventive effect observed in the current study. Therefore, D. candidum may potentially contribute to the prevention of CCl 4 -induced hepatic damage in vivo .

Cytokine and neuropeptide levels are associated with pain relief in patients with chronically painful total knee arthroplasty: a pilot study.

PubMed

Singh, Jasvinder A; Noorbaloochi, Siamak; Knutson, Keith L

2017-01-14

There are few studies with an assessment of the levels of cytokines or neuropeptides as correlates of pain and pain relief in patients with painful joint diseases. Our objective was to assess whether improvements from baseline to 2-months in serum cytokine, chemokine and substance P levels were associated with clinically meaningful pain relief at 2-months post-injection in patients with painful total knee arthroplasty (TKA). Using data from randomized trial of 60 TKAs, we assessed the association of change in cytokine/chemokine/Substance P levels with primary study outcome, clinically important improvement in Western Ontario McMaster Osteoarthritis Index (WOMAC) pain subscale at 2-months post-injection using Student's t-tests and Spearman's correlation coefficient (non-parametric). Patients were categorized as pain responders (20-point reduction or more on 0-100 WOMAC pain) vs. pain non-responders. Sensitivity analysis used 0-10 daytime pain numeric rating scale (NRS) instead of WOMAC pain subscale. In a pilot study, compared to non-responders (n = 23) on WOMAC pain scale at 2-months, pain responders (n = 12) had significantly greater increase in serum levels of IL-7, IL-10, IL-12, eotaxin, interferon gamma and TNF-α from baseline to 2-months post-injection (p < 0.05 for all). Change in several cytokine/chemokine and substance P levels from pre-injection to 2-month follow-up correlated significantly with change in WOMAC pain with correlation coefficients ranging -0.37 to -0.51: IL-2, IL-7, IL-8, IL-9, IL-16, IL-12p, GCSF, IFN gamma, IP-10, MCP, MIP1b, TNF-α and VEGF (n = 35). Sensitivity analysis showed that substance P decreased significantly more from baseline to 2-months in the pain responders (0.54 ± 0.53; n = 10) than in the pain non-responders (0.48 ± 1.18; n = 9; p = 0.023) and that this change in serum substance P correlated significantly with change in daytime NRS pain, correlation coefficient was 0.53 (p = 0.021; n = 19). Findings should be interpreted with caution, since cytokine analyses were performed for a sub-group of the entire trial population. Serum cytokine, chemokine and Substance P levels correlated with pain response in patients with painful TKA after an intra-articular injection in a randomized trial.

Immunomodulatory Effects of Balneotherapy with Hae-Un-Dae Thermal Water on Imiquimod-Induced Psoriasis-Like Murine Model

PubMed Central

Lee, Young Bok; Lee, Jun Young; Lee, Hye Jin; Yun, Seong Taek; Lee, Jong Tae; Kim, Hong Jig; Yu, Dong Soo

2014-01-01

Background Balneotherapy, although not a well-established dermatological treatment, is thought to have therapeutic properties for psoriasis and is used as an alternative treatment modality throughout the world. Objective To evaluate the mechanism underlying the therapeutic immunologic effects of thermomineral water. Methods A murine model of imiquimod-induced psoriasis-like skin inflammation was used for evaluating the therapeutic effects of balneotherapy with Hae-Un-Dae hot spring mineral water. The clinical improvements were evaluated by a dermatologist. Lesional cytokines, including interleukin (IL)-17A, IL-23, and IL-22, were quantitatively measured by real-time reverse transcriptase polymerase chain reaction. Serum levels of interferon-γ, IL-4, IL-5, and IL-17A were measured by enzyme-linked immunosorbent assay. T cell proportions in the spleen were evaluated by flow cytometry, and histopathological evaluation of the skin was also performed. Results The mineral water balneotherapy group showed faster improvement in skin erythema and scales than the distilled water bathing group. A substantial reduction was observed in the lesional mRNA levels of IL-17A and IL-23 in the mineral water group. Serum levels of IL-4 and IL-5 were significantly decreased in the mineral water group but not in the distilled water group. Normalized T cell proportions were observed after bathing. Conclusion Balneotherapy showed immunomodulatory effects in a psoriasis-like murine model. Balneotherapy suppressed lesional IL-23 and IL-17A, which are important cytokines in the pathogenesis of psoriasis. These results suggest that balneotherapy can be used as an effective and safe treatment for psoriasis. PMID:24882978

Immunomodulatory effects of balneotherapy with hae-un-dae thermal water on imiquimod-induced psoriasis-like murine model.

PubMed

Lee, Young Bok; Lee, Jun Young; Lee, Hye Jin; Yun, Seong Taek; Lee, Jong Tae; Kim, Hong Jig; Yu, Dong Soo; Woo, So Youn; Kim, Jin-Wou

2014-04-01

Balneotherapy, although not a well-established dermatological treatment, is thought to have therapeutic properties for psoriasis and is used as an alternative treatment modality throughout the world. To evaluate the mechanism underlying the therapeutic immunologic effects of thermomineral water. A murine model of imiquimod-induced psoriasis-like skin inflammation was used for evaluating the therapeutic effects of balneotherapy with Hae-Un-Dae hot spring mineral water. The clinical improvements were evaluated by a dermatologist. Lesional cytokines, including interleukin (IL)-17A, IL-23, and IL-22, were quantitatively measured by real-time reverse transcriptase polymerase chain reaction. Serum levels of interferon-γ, IL-4, IL-5, and IL-17A were measured by enzyme-linked immunosorbent assay. T cell proportions in the spleen were evaluated by flow cytometry, and histopathological evaluation of the skin was also performed. The mineral water balneotherapy group showed faster improvement in skin erythema and scales than the distilled water bathing group. A substantial reduction was observed in the lesional mRNA levels of IL-17A and IL-23 in the mineral water group. Serum levels of IL-4 and IL-5 were significantly decreased in the mineral water group but not in the distilled water group. Normalized T cell proportions were observed after bathing. Balneotherapy showed immunomodulatory effects in a psoriasis-like murine model. Balneotherapy suppressed lesional IL-23 and IL-17A, which are important cytokines in the pathogenesis of psoriasis. These results suggest that balneotherapy can be used as an effective and safe treatment for psoriasis.

Extracts from Lentinula edodes (Shiitake) Edible Mushrooms Enriched with Vitamin D Exert an Anti-Inflammatory Hepatoprotective Effect.

PubMed

Drori, Ariel; Shabat, Yehudit; Ben Ya'acov, Ami; Danay, Ofer; Levanon, Dan; Zolotarov, Lidya; Ilan, Yaron

2016-04-01

Vitamin D has been known for its anti-inflammatory properties. Extracts derived from Lentinula edodes (Shiitake) edible mushroom exert an anti-inflammatory effect. These extracts contain high levels of ergosterol, which converts into ergocalciferol (vitamin D2) following exposure to ultraviolet light, followed by absorption and hydroxylation into the active form 25-hydroxyvitamin D [25(OH)D]. To determine the anti-inflammatory effect of overexpression of vitamin D in edible mushrooms, L. edodes mushrooms were exposed to ultraviolet-B light, freeze-dried, followed by measurement of vitamin D2 contents, in their dry weight. C57B1/6 mice were orally treated with vitamin D2-enriched or nonenriched mushroom extract prior and during concanavalin A-immune-mediated liver injury. Exposure to ultraviolet light increased vitamin D2 content in Shiitake edible mushrooms. Following feeding of vitamin D-enriched mushroom extracts to mice with immune-mediated hepatitis, a significant decrease in liver damage was noted. This was shown by a decrease in alanine aminotransferase and aspartate aminotransferase serum levels, a decrease in proportion of mice with severe liver injury, and by improvement in liver histology. These effects were associated with a decrease in serum interferon gamma levels. A synergistic effect was noted between the anti-inflammatory effect of the mushroom extracts and that of vitamin D. Oral administration of vitamin D-enriched L. edodes edible mushroom exerts a synergistic anti-inflammatory effect in the immune-mediated hepatitis. The data support its potential use as safe immunomodulatory adjuvant for the treatment of HCV and nonalcoholic steatohepatitis.

Genetic variants of interferon-gamma and its mRNA expression and inflammatory parameters in the pathogenesis of vitiligo.

PubMed

Karam, Rehab A; Zidan, Haidy E; Khater, Mohamed H

2017-08-01

Although genetics plays an essential role in the pathogenesis of vitiligo, vitiligo pathogenesis is still unclear. Our aim was to investigate the role of IFN-γ expression and polymorphism in vitiligo susceptibility and whether intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor (TNF)-α, and TNF-β play a role in vitiligo pathogenesis as important inflammatory parameters. Eighty-five patients with vitiligo and 90 controls were investigated for IFN-γ gene expression by quantitative real-time PCR and genotyped for IFN-γ +874T/A (rs2430561) and IFN-γ +2109A/G (rs1861494) gene polymorphisms by sequence-specific primer (SSP)-PCR and PCR-restriction fragment length polymorphism (RFLP), respectively. Serum levels of inflammatory parameters were measured using ELISA. Frequencies of the +874 TT genotype and T allele were significantly higher in patients with active vitiligo than in stable patients (P = 0.01 and 0.03, respectively). Calculation of odds ratio suggested a 1.7-fold increased risk of vitiligo in individuals having the TA haplotype. We observed overexpression of IFN-γ mRNA with elevated serum levels of IFN-γ, ICAM-1, TNF-α, and TNF-β in patients with vitiligo when compared with the control group (P = 0.001, for all). In addition, these levels were elevated in patients with active vitiligo compared with stable patients with vitiligo (P = 0.008, 0.006, 0.01, 0.01, and 0.03, respectively), which suggests the involvement of these cytokines in disease activity. In conclusion, IFN-γ is a promising immunological marker in vitiligo pathogenesis.

Feasibility of commercial space manufacturing, production of pharmaceuticals. Volume 1: Executive summary

NASA Technical Reports Server (NTRS)

1978-01-01

The feasibility of the commercial manufacturing of pharmaceuticals in space is examined. The method of obtaining pharmaceutical company involvement, laboratory results of the separation of serum proteins by the continuous flow electrophoresis process, the selection and study of candidate products, and their production requirements is presented. Antihemophilic factor, beta cells, erythropoietin, epidermal growth factor, alpha-1-antitrypsin and interferon were studied. Production mass balances for antihemophilic factor, beta cells, and erythropoietin were compared for space verus ground operation.

Stanniocalcin-1 Protects a Mouse Model from Renal Ischemia-Reperfusion Injury by Affecting ROS-Mediated Multiple Signaling Pathways.

PubMed

Liu, Dajun; Shang, Huiping; Liu, Ying

2016-07-12

Stanniocalcin-1 (STC-1) protects against renal ischemia-reperfusion injury (RIRI). However, the molecular mechanisms remain widely unknown. STC-1 inhibits reactive oxygen species (ROS), whereas most ROS-mediated pathways are associated with ischemic injury. Therefore, to explore the mechanism, the effects of STC-1 on ROS-medicated pathways were studied. Non-traumatic vascular clamps were used to establish RIRI mouse models. The serum levels of STC-1, interleukin-6 (IL-6), interferon (IFN) γ, P53, and capase-3 were measured by ELISA kits. Superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by fluorescence spectrofluorometer. All these molecules changed significantly in a RIRI model mouse when compared with those in a sham control. Kidney cells were isolated from sham and model mice. STC-1 was overexpressed or knockout in these kidney cells. The molecules in ROS-medicated pathways were measured by real-time quantitative PCR and Western blot. The results showed that STC-1 is an effective ROS scavenger. The serum levels of STC-1, MDA and SOD activity were increased while the serum levels of IL-6, iIFN-γ, P53, and capase-3 were decreased in a model group when compared with a sham control (p < 0.05). Furthermore, the levels of STC-1,p53, phosphorylated mitogen-activated protein kinase kinase (p-MEKK-1), c-Jun N-terminal kinase (p-JNK), extracellular signal-regulated kinase (p-ERK), IkB kinase (p-IKK), nuclear factor (NF) κB, apoptosis signal-regulating kinase 1 (ASK-1) and caspase-3 changed significantly in kidney cells isolated from a RIRI model when compared to those isolated from a sham control (p < 0.05). Meanwhile, STC-1 overexpression or silence caused significant changes of the levels of these ROS-mediated molecules. Therefore, STC-1 maybe improve anti-inflammation, anti-oxidant and anti-apoptosis activities by affecting ROS-mediated pathways, especially the phospho-modifications of the respective proteins, resulting in the increase of SOD and reduce of capase-3, p53, IL-6 and IFN-γ.

T-614, a novel immunomodulator, attenuates joint inflammation and articular damage in collagen-induced arthritis

PubMed Central

Du, Fang; Lü, Liang-jing; Fu, Qiong; Dai, Min; Teng, Jia-lin; Fan, Wei; Chen, Shun-le; Ye, Ping; Shen, Nan; Huang, Xin-fang; Qian, Jie; Bao, Chun-de

2008-01-01

Introduction T-614 is a novel oral antirheumatic agent for the treatment of rheumatoid arthritis. Whether it has immunomodulatory or disease-modifying properties and its mechanism of action are largely undetermined. Methods Rats with collagen-induced arthritis (CIA) were treated with T-614 (5 and 20 mg/kg) daily. Animals receiving methotrexate (1 mg/kg every 3 days) and the nonsteroidal anti-inflammatory agent nimesulide (10 mg/kg per day) were used as controls. A combination therapy group was treated with both T-614(10 mg/kg per day) and methotrexate (1 mg/kg every 3 days). Hind paw swelling was evaluated and radiographic scores calculated. Serum cytokine levels were assessed by Bio-plex analysis. Quantitative PCR was used to evaluate expression of mRNA for interferon-γ, IL-4 and IL-17. Serum IL-17 and anti-type II collagen antibodies (total IgG, IgG1, IgG2a, IgG2b and IgM) were measured using ELISA. Results Oral T-614 inhibited paw swelling and offered significant protection against arthritis-induced cartilage and bone erosion, comparable to the effects of methotrexate. CIA rats treated with T-614 exhibited decreases in both mRNA expression of IL-17 in peripheral blood mononuclear cells and lymph node cells, and circulating IL-17 in a dose-dependent manner. T-614 also reduced serum levels of tumor necrosis factor-α, IL-1β and IL-6. A synergistic effect was observed for the combination of methotrexate and T-614. In addition, T-614 (20 mg/kg per day) depressed production of anti-type II collagen antibodies and differentially affected levels of IgG2a subclasses in vivo, whereas IgM level was decreased without any change in the IgG1 level. Together, the findings presented here indicate that the novel agent T-614 has disease-modifying effects against experimental arthritis, as opposed to nimesulide. Conclusions Our data suggested that T-614 is an effective disease-modifying agent that can prevent bone/cartilage destruction and inflammation in in CIA rats. Combination with methotrexate markedly enhances the therapeutic effect of T-614. PMID:19019215

The improving effects on hepatic fibrosis of interferon-γ liposomes targeted to hepatic stellate cells

NASA Astrophysics Data System (ADS)

Li, Qinghua; Yan, Zhiqiang; Li, Feng; Lu, Weiyue; Wang, Jiyao; Guo, Chuanyong

2012-07-01

No satisfactory anti-fibrotic therapies have yet been applied clinically. One of the main reasons is the inability to specifically target the responsible cells to produce an available drug concentration and the side-effects. Exploiting the key role of the activated hepatic stellate cells (HSCs) in both hepatic fibrogenesis and over-expression of platelet-derived growth factor receptor-β (PDGFR-β), we constructed targeted sterically stable liposomes (SSLs) modified by a cyclic peptide (pPB) with affinity for the PDGFR-β to deliver interferon (IFN)-γ to HSCs. The pPB-SSL-IFN-γ showed satisfactory size distribution. In vitro pPB-SSL could be taken up by activated HSCs. The study of tissue distribution via living-body animal imaging showed that the pPB-SSL-IFN-γ mostly accumulated in the liver until 24 h. Furthermore, the pPB-SSL-IFN-γ showed more significant remission of hepatic fibrosis. In vivo the histological Ishak stage, the semiquantitative score for collagen in fibrotic liver and the serum levels of collagen type IV-C in fibrotic rats treated with pPB-SSL-IFN-γ were less than those treated with SSL-IFN-γ, IFN-γ and the control group. In vitro pPB-SSL-IFN-γ was also more effective in suppressing activated HSC proliferation and inducing apoptosis of activated HSCs. Thus the data suggest that pPB-SSL-IFN-γ might be a more effective anti-fibrotic agent and a new opportunity for clinical therapy of hepatic fibrosis.

Silymarin reduces profibrogenic cytokines and reverses hepatic fibrosis in chronic murine schistosomiasis.

PubMed

Mata-Santos, Hílton Antônio; Dutra, Fabianno Ferreira; Rocha, Carolina Carneiro; Lino, Fabiana Gonçalves; Xavier, Fabiola Ramos; Chinalia, Leandro Andrade; Hossy, Bryan Hudson; Castelo-Branco, Morgana Teixeira Lima; Teodoro, Anderson Junger; Paiva, Claudia N; dos Santos Pyrrho, Alexandre

2014-01-01

In chronic schistosomiasis, hepatic fibrosis is linked to the portal hypertension that causes morbidity in Schistosoma mansoni infection. Silymarin (SIL) is a hepatoprotective and antioxidant medicament largely prescribed against liver diseases that has previously been shown to prevent fibrosis during acute murine schistosomiasis. Here we employed silymarin to try to reverse established hepatic fibrosis in chronic schistosomiasis. Silymarin or vehicle was administered to BALB/c mice every 48 h, starting on the 40th (80 days of treatment), 70th (50 days), or 110th (10 days) day postinfection (dpi). All mice were sacrificed and analyzed at 120 dpi. Treatment with silymarin reduced liver weight and granuloma sizes, reduced the increase in alanine aminotransferase and aspartate aminotransferase levels, and reduced the established hepatic fibrosis (assessed by hydroxyproline contents and picrosirius staining). Treatment with silymarin also reduced the levels of interleukin-13 (IL-13) in serum and increased the gamma interferon (IFN-γ)/IL-13 ratio. There was a linear correlation between IL-13 levels in serum and hydroxyproline hepatic content in both infected untreated and SIL-treated mice, with decreased IL-13 levels corresponding to decreased hydroxyproline hepatic contents. Treatment with either SIL or N-acetylcysteine reduced both proliferation of fibroblast cell lines and basal/IL-13-induced production of collagen I, indicating that besides inhibiting IL-13 production during infection, SIL antioxidant properties most likely contribute to inhibition of collagen production downstream of IL-13. These results show that silymarin interferes with fibrogenic cytokines, reduces established fibrosis, and inhibits downstream effects of IL-13 on fibrogenesis, indicating the drug as a safe and cheap treatment to liver fibrotic disease in schistosomiasis.

Silymarin Reduces Profibrogenic Cytokines and Reverses Hepatic Fibrosis in Chronic Murine Schistosomiasis

PubMed Central

Mata-Santos, Hílton Antônio; Dutra, Fabianno Ferreira; Rocha, Carolina Carneiro; Lino, Fabiana Gonçalves; Xavier, Fabiola Ramos; Chinalia, Leandro Andrade; Hossy, Bryan Hudson; Castelo-Branco, Morgana Teixeira Lima; Teodoro, Anderson Junger; Paiva, Claudia N.

2014-01-01

In chronic schistosomiasis, hepatic fibrosis is linked to the portal hypertension that causes morbidity in Schistosoma mansoni infection. Silymarin (SIL) is a hepatoprotective and antioxidant medicament largely prescribed against liver diseases that has previously been shown to prevent fibrosis during acute murine schistosomiasis. Here we employed silymarin to try to reverse established hepatic fibrosis in chronic schistosomiasis. Silymarin or vehicle was administered to BALB/c mice every 48 h, starting on the 40th (80 days of treatment), 70th (50 days), or 110th (10 days) day postinfection (dpi). All mice were sacrificed and analyzed at 120 dpi. Treatment with silymarin reduced liver weight and granuloma sizes, reduced the increase in alanine aminotransferase and aspartate aminotransferase levels, and reduced the established hepatic fibrosis (assessed by hydroxyproline contents and picrosirius staining). Treatment with silymarin also reduced the levels of interleukin-13 (IL-13) in serum and increased the gamma interferon (IFN-γ)/IL-13 ratio. There was a linear correlation between IL-13 levels in serum and hydroxyproline hepatic content in both infected untreated and SIL-treated mice, with decreased IL-13 levels corresponding to decreased hydroxyproline hepatic contents. Treatment with either SIL or N-acetylcysteine reduced both proliferation of fibroblast cell lines and basal/IL-13-induced production of collagen I, indicating that besides inhibiting IL-13 production during infection, SIL antioxidant properties most likely contribute to inhibition of collagen production downstream of IL-13. These results show that silymarin interferes with fibrogenic cytokines, reduces established fibrosis, and inhibits downstream effects of IL-13 on fibrogenesis, indicating the drug as a safe and cheap treatment to liver fibrotic disease in schistosomiasis. PMID:24449779

Administration of Lactobacillus salivarius LI01 or Pediococcus pentosaceus LI05 improves acute liver injury induced by D-galactosamine in rats.

PubMed

Lv, Long-Xian; Hu, Xin-Jun; Qian, Gui-Rong; Zhang, Hua; Lu, Hai-Feng; Zheng, Bei-Wen; Jiang, Li; Li, Lan-Juan

2014-06-01

This work investigated the effect of the intragastric administration of five lactic acid bacteria from healthy people on acute liver failure in rats. Sprague-Dawley rats were given intragastric supplements of Lactobacillus salivarius LI01, Lactobacillus salivarius LI02, Lactobacillus paracasei LI03, Lactobacillus plantarum LI04, or Pediococcus pentosaceus LI05 for 8 days. Acute liver injury was induced on the eighth day by intraperitoneal injection of 1.1 g/kg body weight D-galactosamine (D-GalN). After 24 h, samples were collected to determine the level of liver enzymes, liver function, histology of the terminal ileum and liver, serum levels of inflammatory cytokines, bacterial translocation, and composition of the gut microbiome. The results indicated that pretreatment with L. salivarius LI01 or P. pentosaceus LI05 significantly reduced elevated alanine aminotransferase and aspartate aminotransferase levels, prevented the increase in total bilirubin, reduced the histological abnormalities of both the liver and the terminal ileum, decreased bacterial translocation, increased the serum level of interleukin 10 and/or interferon-γ, and resulted in a cecal microbiome that differed from that of the liver injury control. Pretreatment with L. plantarum LI04 or L. salivarius LI02 demonstrated no significant effects during this process, and pretreatment with L. paracasei LI03 aggravated liver injury. To the best of our knowledge, the effects of the three species-L. paracasei, L. salivarius, and P. pentosaceus-on D-GalN-induced liver injury have not been previously studied. The excellent characteristics of L. salivarius LI01 and P. pentosaceus LI05 enable them to serve as potential probiotics in the prevention or treatment of acute liver failure.

Effect on HBs antigen clearance of addition of pegylated interferon alfa-2a to nucleos(t)ide analogue therapy versus nucleos(t)ide analogue therapy alone in patients with HBe antigen-negative chronic hepatitis B and sustained undetectable plasma hepatitis B virus DNA: a randomised, controlled, open-label trial.

PubMed

Bourlière, Marc; Rabiega, Pascaline; Ganne-Carrie, Nathalie; Serfaty, Lawrence; Marcellin, Patrick; Barthe, Yoann; Thabut, Dominique; Guyader, Dominique; Hezode, Christophe; Picon, Magali; Causse, Xavier; Leroy, Vincent; Bronowicki, Jean Pierre; Carrieri, Patrizia; Riachi, Ghassan; Rosa, Isabelle; Attali, Pierre; Molina, Jean Michel; Bacq, Yannick; Tran, Albert; Grangé, Jean Didier; Zoulim, Fabien; Fontaine, Hélène; Alric, Laurent; Bertucci, Inga; Bouvier-Alias, Magali; Carrat, Fabrice

2017-03-01

Findings from uncontrolled studies suggest that addition of pegylated interferon in patients with HBe antigen (HBeAg)-negative chronic hepatitis B receiving nucleos(t)ide analogues with undetectable plasma hepatitis B virus (HBV) DNA might increase HBs antigen (HBsAg) clearance. We aimed to assess this strategy. In this randomised, controlled, open-label trial, we enrolled patients aged 18-75 years with HBeAg-negative chronic hepatitis B and documented negative HBV DNA while on stable nucleos(t)ide analogue regimens for at least 1 year from 30 hepatology tertiary care wards in France. Patients had to have an alanine aminotransferase concentration of less than or equal to five times the upper normal range, no hepatocellular carcinoma, and a serum α fetoprotein concentration of less than 50 ng/mL, normal dilated fundus oculi examination, and a negative pregnancy test in women. Patients with contraindications to pegylated interferon were not eligible. A centralised randomisation used computer-generated lists of random permuted blocks of four with stratification by HBsAg titres (< or ≥2·25 log 10 IU/mL) to allocate patients (1:1) to receive a 48 week course of subcutaneous injections of 180 μg per week of pegylated interferon alfa-2a in addition to the nucleos(t)ide analogue regimen or to continue to receive nucleos(t)ide analogues only. The primary endpoint was HBsAg loss at week 96 by intention-to-treat analysis. This trial is closed and registered with ClinicalTrials.gov, number NCT01172392. Between Jan 20, 2011, and July 18, 2012, we randomly allocated 185 patients (92 [50%] to pegylated interferon and nucleos(t)ide analogues and 93 [50%] to nucleos(t)ide analogues alone). We excluded two patients from the pegylated interferon plus nucleos(t)ide analogues group from analyses because of withdrawal of consent (one patient) or violation of inclusion criteria (one patient). At week 96, loss of HBsAg was reported in seven (7·8%) of 90 patients in the pegylated interferon plus nucleos(t)ide analogues group versus three (3·2%) of 93 in the nucleos(t)ide analogues-alone group (difference 4·6% [95% CI -2·6 to 12·5]; p=0·15). 85 (94%) of 90 patients started pegylated interferon, three (4%) of whom had a dose reduction and 17 (20%) had an early discontinuation of pegylated interferon (seven [41%] for serious adverse events). Grade 3 and 4 adverse events were more frequent in the pegylated interferon plus nucleos(t)ide analogues group (26 [29%] grade 3 adverse events; 19 [21%] grade 4 adverse events) than in the nucleos(t)ide analogues-alone group (three [3%] grade 3; six [6%] grade 4). Addition of a 48 week course of pegylated interferon to nucleos(t)ide analogue therapy in patients with HBeAg-negative chronic hepatitis B with undetectable HBV DNA for a least 1 year was poorly tolerated and did not result in a significant increase of HBsAg clearance. Institut national de la santé et de la recherche médicale-Agence nationale de recherches sur le sida et les hépatites virales (France Recherche Nord&sud Sida-vih Hepatites). Copyright © 2017 Elsevier Ltd. All rights reserved.

Modulatory effects of levamisole and garlic oil on the immune response of Wistar rats: Biochemical, immunohistochemical, molecular and immunological study.

PubMed

Mohamed, Essam Hassan; Baiomy, Ahmed Abdel-Aziz; Ibrahim, Zein Shaban; Soliman, Mohamed Mohamed

2016-09-01

Levamisole (LEVA) and garlic are prevalent immunomodulators in humans and animals. Therefore, the present study aimed to examine the immunomodulatory effects of LEVA and garlic oil (GO) alone or in combination on the immune response of Wistar rats. A total of 24 male Wistar rats were allocated into four equal groups: Control group, which was given ad libitum access to food and water; and groups 2‑4, which were orally administered LEVA [2.5 mg/kg body weight (BW) every 2 days], GO, (5 ml/kg BW daily), or LEVA plus GO, respectively for 4 consecutive weeks. Serum immunoglobulin (Ig)G and IgM levels were measured using a radial immunodiffusion assay. Serum cytokine levels, including interferon (IFN)-γ, interleukin (IL)-5 and tumor necrosis factor (TNF)-α, were measured using enzyme‑linked immunosorbent assay kits. Total blood counts were measured automatically using a cell counter. Serum lysozyme enzymatic activity was determined by measuring the diameters of the zones of clearance relative to lysozyme. Immunohistochemical detection of CD4 and CD8 was carried out using the streptavidin-biotin-peroxidase method. Furthermore, the mRNA expression levels of IL‑4, IL‑5 and IL‑12 were measured in the leukocytes and thymus gland by semi-quantitative polymerase chain reaction. The results revealed that LEVA increased serum levels of IFN‑γ, IL‑5 and TNF‑α cytokines, whereas co‑administration of LEVA and GO decreased the stimulatory action of LEVA alone. LEVA and GO alone increased the serum levels of IgG, IgM and total blood cell counts, and co‑administration of GO and LEVA inhibited the effects of LEVA. At the cellular level, in the spleen, LEVA increased immunoreactivity of CD4 and CD8, whereas co‑administration of GO with LEVA decreased this strong expression. At the molecular level, in leukocytes, LEVA upregulated the mRNA expression levels of IL‑2, IL‑4 and IL‑5, whereas GO alone downregulated mRNA expression. Co‑administration of GO with LEVA inhibited the LEVA‑induced upregulation of IL‑2, IL‑4 and IL‑5 mRNA expression. In the thymus, both LEVA and GO upregulated the mRNA expression levels of IL‑4 and IL‑5, whereas LEVA alone did not affect IL‑12 mRNA expression. Co‑administration of GO with LEVA inhibited LEVA‑induced upregulation of IL‑4 and GO‑induced upregulation of IL‑12 expression, and had an additive upregulatory effect on IL‑5 expression. In conclusion, LEVA stimulated T‑helper (Th)1 cytokines, whereas GO stimulated a Th2 response, and co‑administration of GO with LEVA inhibited the stimulatory effects of LEVA and balanced the Th1/Th2 response.

Induction of interferon lambda in influenza a virus infected cells treated with shRNAs against M1 transcript.

PubMed

Švančarová, P; Svetlíková, D; Betáková, T

2015-06-01

RNA interference (RNAi) represents a form of post-transcriptional gene silencing mediated by small interfering RNAs (siRNA) and provides a powerful tool to specifically inhibit viral infection. To investigate therapeutic capacity of siRNAs targeting M gene, six vectors with U1-short hairpin RNA (shRNA) expression system were prepared and tested in infected cells and animals. In infected cells, three of six shRNAs targeting M1 gene significantly (P <0,01) reduced the virus titer to 66%, 45% or 21%, respectively. Replication of IAV and levels of M1 RNAs were significantly reduced in the cells transfected with shRNAs, which decreased the virus titer. IFN-α/β altered in shRNAs-treated cells. The level of IFN-λ (type III interferon) mRNA was significantly increased in the infected cells treated with shM22, shM349, shM522, and (type I interferon) as well as IP-10 (type II interferon) mRNAs were not significantly their mixtures. The increased level of IFN-λ mRNA corresponded to significantly increased level of RIG-1 mRNA. shRNAs inhibited influenza virus infection in a gene-specific manner in co-operation with IFN-λ. Some constructs targeting the M1 transcript prolonged the survival of infected mice.

Tofacitinib ameliorates murine lupus and its associated vascular dysfunction

PubMed Central

Furumoto, Yasuko; Smith, Carolyne K.; Blanco, Luz; Zhao, Wenpu; Brooks, Stephen R.; Thacker, Seth G; Abdalrahman, Zarzour; Sciumè, Giuseppe; Tsai, Wanxia L.; Trier, Anna M.; Nunez, Leti; Mast, Laurel; Hoffmann, Victoria; Remaley, Alan T.; O'Shea, John J.

2016-01-01

Objectives Dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated premature vascular damage. To date, no drug targets both systemic inflammatory disease and the cardiovascular complications of SLE. Tofacitinib is a Janus kinase (JAK) inhibitor that blocks signaling downstream of multiple cytokines implicated in lupus pathogenesis. While clinical trials have shown that tofacitinib exhibits significant clinical efficacy in various autoimmune diseases, its role in SLE and on its associated vascular pathology remains to be characterized. Methods MRL/lpr lupus-prone mice received tofacitinib or vehicle by gavage for 6 weeks (therapeutic arm) or 8 weeks (preventive arm). Nephritis, skin inflammation, serum autoantibody levels and cytokines, mononuclear cell phenotype and gene expression, neutrophil extracellular trap (NET) release, endothelium-dependent vasorelaxation and endothelial differentiation were compared in treated and untreated mice. Results Treatment with tofacitinib led to significant improvement in measures of disease activity including nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment reduced serum levels of pro-inflammatory cytokines and interferon responses in splenocytes and kidney tissue. Tofacitinib also modulated NET formation and significantly increased endothelium-dependent vasorelaxation and endothelial differentiation. The drug was effective as both preventive and therapeutic strategies. Conclusions Tofacitinib modulates the innate and adaptive immune responses, ameliorates murine lupus and improves vascular function. These results indicate that JAK inhibitors have the potential to be beneficial in SLE and its associated vascular damage. PMID:27429362

Tofacitinib Ameliorates Murine Lupus and Its Associated Vascular Dysfunction.

PubMed

Furumoto, Yasuko; Smith, Carolyne K; Blanco, Luz; Zhao, Wenpu; Brooks, Stephen R; Thacker, Seth G; Abdalrahman, Zarzour; Sciumè, Giuseppe; Tsai, Wanxia L; Trier, Anna M; Nunez, Leti; Mast, Laurel; Hoffmann, Victoria; Remaley, Alan T; O'Shea, John J; Kaplan, Mariana J; Gadina, Massimo

2017-01-01

Dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated premature vascular damage. No drug to date targets both systemic inflammatory disease and the cardiovascular complications of SLE. Tofacitinib is a JAK inhibitor that blocks signaling downstream of multiple cytokines implicated in lupus pathogenesis. While clinical trials have shown that tofacitinib exhibits significant clinical efficacy in various autoimmune diseases, its role in SLE and the associated vascular pathology remains to be characterized. MRL/lpr lupus-prone mice were administered tofacitinib or vehicle by gavage for 6 weeks (therapeutic arm) or 8 weeks (preventive arm). Nephritis, skin inflammation, serum levels of autoantibodies and cytokines, mononuclear cell phenotype and gene expression, neutrophil extracellular traps (NETs) release, endothelium-dependent vasorelaxation, and endothelial differentiation were compared in treated and untreated mice. Treatment with tofacitinib led to significant improvement in measures of disease activity, including nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment reduced serum levels of proinflammatory cytokines and interferon responses in splenocytes and kidney tissue. Tofacitinib also modulated the formation of NETs and significantly increased endothelium-dependent vasorelaxation and endothelial differentiation. The drug was effective in both preventive and therapeutic strategies. Tofacitinib modulates the innate and adaptive immune responses, ameliorates murine lupus, and improves vascular function. These results indicate that JAK inhibitors have the potential to be beneficial in SLE and its associated vascular damage. © 2016, American College of Rheumatology.

Cytokine secretion from human peripheral blood mononuclear cells cultured in vitro with metal particles.

PubMed

Cachinho, Sandra C P; Pu, Fanrong; Hunt, John A

2013-04-01

The failure of implanted medical devices can be associated with changes in the production of cytokines by cells of the immune system. Cytokines released by peripheral blood mononuclear cells upon contact with metal particles were quantified to understand their role in implantation intergration and their importance as messengers in the recruitment of T-lymphocytes at the implantation site. Opsonization was utilised to understand the influence of serum proteins on particle-induced cytokine production and release. Different metal compositions were used in the particulate format, Titanium (Ti), Titanium alloy (Ti6Al4V), and Stainless Steel 316L (SS), and were cultured in vitro with a mixed population of monocytes/macrophages and lymphocytes. The cells were also exposed to an exogenous stimulant mixture of phytohemagglutinin-P and interferon-gamma (IFN-γ) and opsonized particles with human serum. Interleukins, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IFN-γ, and tumor necrosis factor-alpha (TNF-α) were investigated using enzyme-linked immunosorbent assay as they are an indicator of the inflammation evoked by particulate metals. It has been experimentally evidenced that metal particles induced higher amounts of IL-6 and IL-1 but very low amounts of TNF-α. T-lymphocyte activation was evaluated by the quantification of IL-2 and IFN-γ levels. The results showed that nonopsonized and opsonized metal particles did not induce the release of increased levels of IL-2 and IFN-γ. Copyright © 2013 Wiley Periodicals, Inc.

Anti-Colitic Effects of Kanjangs (Fermented Soy Sauce and Sesame Sauce) in Dextran Sulfate Sodium-Induced Colitis in Mice

PubMed Central

Song, Jia-Le; Choi, Jung-Ho; Seo, Jae-Hoon; Lim, Yaung-Iee

2014-01-01

Abstract This study was conducted to investigate the preventive effects of different kanjangs (Korean soy sauces), including acid-hydrolyzed soy sauce (AHSS), fermented soy sauce (FSS), and fermented sesame sauce (FSeS), on 2% dextran sulfate sodium (DSS)-induced ulcerative colitis in C57BL/6J mice. The fermented sauces, particularly FSeS, significantly suppressed DSS-induced body weight loss, increased colon length, and decreased colon weight/length ratios. Histological observations suggested that the fermented sauces prevented edema, mucosal damage, and the loss of crypts induced by DSS compared to the control mice and animals fed AHSS. FSeS and FSS decreased the serum levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin (IL)-6, and IL-17α. mRNA expression of these cytokines as well as that of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in colon mucosa was also inhibited by the two sauces. Our results suggest that fermented sauces, especially FSeS, exert an anticolitic effect partially by reducing the serum levels of proinflammatory cytokines and inhibiting the mRNA expression of these factors in the colon tissue of mice treated with DSS. However, AHSS did not protect against DSS-induced colitis. In addition, low-dose treatment (4 mL/kg) with the fermented sauces resulted in greater anticolitic effects than consumption of a high quantity (8 mL/kg) of the sauces. PMID:25188463

Anti-colitic effects of kanjangs (fermented soy sauce and sesame sauce) in dextran sulfate sodium-induced colitis in mice.

PubMed

Song, Jia-Le; Choi, Jung-Ho; Seo, Jae-Hoon; Lim, Yaung-Iee; Park, Kun-Young

2014-09-01

This study was conducted to investigate the preventive effects of different kanjangs (Korean soy sauces), including acid-hydrolyzed soy sauce (AHSS), fermented soy sauce (FSS), and fermented sesame sauce (FSeS), on 2% dextran sulfate sodium (DSS)-induced ulcerative colitis in C57BL/6J mice. The fermented sauces, particularly FSeS, significantly suppressed DSS-induced body weight loss, increased colon length, and decreased colon weight/length ratios. Histological observations suggested that the fermented sauces prevented edema, mucosal damage, and the loss of crypts induced by DSS compared to the control mice and animals fed AHSS. FSeS and FSS decreased the serum levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin (IL)-6, and IL-17α. mRNA expression of these cytokines as well as that of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in colon mucosa was also inhibited by the two sauces. Our results suggest that fermented sauces, especially FSeS, exert an anticolitic effect partially by reducing the serum levels of proinflammatory cytokines and inhibiting the mRNA expression of these factors in the colon tissue of mice treated with DSS. However, AHSS did not protect against DSS-induced colitis. In addition, low-dose treatment (4 mL/kg) with the fermented sauces resulted in greater anticolitic effects than consumption of a high quantity (8 mL/kg) of the sauces.

Brazilian nut consumption by healthy volunteers improves inflammatory parameters.

PubMed

Colpo, Elisângela; Dalton D A Vilanova, Carlos; Reetz, Luiz Gustavo B; Duarte, Marta M M F; Farias, Iria Luiza G; Meinerz, Daiane F; Mariano, Douglas O C; Vendrusculo, Raquel G; Boligon, Aline A; Dalla Corte, Cristiane L; Wagner, Roger; Athayde, Margareth L; da Rocha, João Batista T

2014-04-01

The aim of this study was to investigate the effect of a single dose of Brazil nuts on the inflammatory markers of healthy individuals. A randomized crossover study was conducted with 10 healthy individuals (mean age 24.7 ± 3.4 y). Each individual was tested four times regarding intake of different portions of Brazil nuts: 0, 5, 20 and 50 g. At each testing period, peripheral blood was collected before and at 1, 3, 6, 9, 24, and 48 h after intake of nuts, as well as at 5 and 30 d after intake of various Brazil nut portions. Blood samples were tested for high-sensitivity to C-reactive protein, interleukin (IL)-1, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ, aspartate and alanine aminotransferases, albumin, total protein, alkaline phosphatase, gamma-glutamyltransferase, urea, and creatinine. Consumption of nuts did not affect biochemical parameters for liver and kidney function, indicating absence of hepatic and renal toxicity. A single intake of Brazil nuts (20 or 50 g) caused a significant decrease in serum IL-1, IL-6, TNF-α, and IFN-γ levels (P < 0.05), whereas serum levels of IL-10 were significantly increased (P < 0.05). The results indicate a long-term decrease in inflammatory markers after a single intake of large portions of Brazil nuts in healthy volunteers. Therefore, the long-term effect of regular Brazil nut consumption on inflammatory markers should be better investigated. Copyright © 2014 Elsevier Inc. All rights reserved.

Tannic acid modulates NFκB signaling pathway and skin inflammation in NC/Nga mice through PPARγ expression.

PubMed

Karuppagounder, Vengadeshprabhu; Arumugam, Somasundaram; Thandavarayan, Rajarajan Amirthalingam; Pitchaimani, Vigneshwaran; Sreedhar, Remya; Afrin, Rejina; Harima, Meilei; Suzuki, Hiroshi; Nomoto, Mayumi; Miyashita, Shizuka; Suzuki, Kenji; Nakamura, Masahiko; Ueno, Kazuyuki; Watanabe, Kenichi

2015-12-01

Polyphenolic compound tannic acid, which is mainly found in grapes and green tea, is a potent antioxidant with anticarcinogenic activities. In this present study, we hypothesized that tannic acid could inhibit nuclear factor (NF)κB signaling and inflammation in atopic dermatitis (AD) NC/Nga mice. We have analyzed the effects of tannic acid on dermatitis severity, histopathology and expression of inflammatory signaling proteins in house dust mite extract induced AD mouse skin. In addition, serum levels of T helper (Th) cytokines (interferon (IFN)γ, interleukin (IL)-4) were measured by enzyme-linked immunosorbent assay. Treatment with tannic acid ameliorated the development of AD-like clinical symptoms and effectively inhibited hyperkeratosis, parakeratosis, acanthosis, mast cells and infiltration of inflammatory cells in the AD mouse skin. Serum levels of IFNγ and IL-4 were significantly down-regulated by tannic acid. Furthermore, tannic acid treatment inhibited DfE induced tumor necrosis factor (TNF)α, high mobility group protein (HMG)B1, receptor for advanced glycation end products (RAGE), extracellular signal-regulated kinase (ERK)1/2, NFκB, cyclooxygenase (COX)2, IL-1β and increased the protein expression of peroxisome proliferator-activated receptor (PPAR)γ. Taken together, our results demonstrate that, DfE induced skin inflammation might be mediated through NFκB signaling and tannic acid may be a potential therapeutic agent for AD, which may possibly act via induction of PPARγ protein. Copyright © 2015 Elsevier Ltd. All rights reserved.

Rosmarinic acid attenuates 2,4-dinitrofluorobenzene-induced atopic dermatitis in NC/Nga mice.

PubMed

Jang, An-Hee; Kim, Tae-Ho; Kim, Gun-Dong; Kim, Jeong Eun; Kim, Ha Jin; Kim, Sung Soo; Jin, Young-Ho; Park, Yong Seek; Park, Cheung-Seog

2011-09-01

Atopic dermatitis (AD) is one of the most common skin diseases, and its incidence is increasing in industrialized countries. Furthermore, the epicutaneous application of a hapten, such as 2,4-dinitrofluorobenzene (DNFB), evokes an AD-like lesion in NC/Nga mice under specific pathogen-free (SPF) conditions. Rosmarinic acid (RA) is a secondary metabolite that is frequently found in herbs, and has anti-inflammatory, anti-oxidant, and anti-microbial effects. In this study, we studied whether RA is an effective treatment against DNFB-induced AD-like skin lesions in NC/Nga mice. RA at 1 or 5 μM was found to suppress the productions of interferon (IFN)-γ and interleukin (IL)-4 significantly by activated CD4(+) T cells. Furthermore, an intraperitoneal injection of RA at 10 or 50 mg/kg significantly inhibited skin lesion development and ear thickness and total serum IgE level increases in DNFB-treated NC/Nga mice. In addition, intraperitoneal administered RA at 10 or 50 mg/kg significantly inhibited the infiltrations of CD4(+) T, CD8(+) T, and mast cells into DNFB-induced skin lesions in NC/Nga mice. This study suggests that RA suppresses the development of AD-like dermatitis in DNFB-treated NC/Nga mice by reducing IFN-γ and IL-4 production by activated T cells and total serum IgE levels. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

CD40 dependent exacerbation of immune mediated hepatitis by hepatic CD11b+ Gr-1+ myeloid derived suppressor cells in tumor bearing mice

PubMed Central

Kapanadze, Tamar; Medina-Echeverz, José; Gamrekelashvili, Jaba; Weiss, Jonathan M.; Wiltrout, Robert H.; Kapoor, Veena; Hawk, Nga; Terabe, Masaki; Berzofsky, Jay A.; Manns, Michael P.; Wang, Ena; Marincola, Francesco M.; Korangy, Firouzeh; Greten, Tim F.

2015-01-01

Immunosuppressive CD11b+Gr-1+ myeloid-derived suppressor cells (MDSC) accumulate in the livers of tumor-bearing mice. We studied hepatic MDSC in two murine models of immune mediated hepatitis. Unexpectedly, treatment of tumor bearing mice with Concanavalin A or α-Galactosylceramide resulted in increased ALT and AST serum levels in comparison to tumor free mice. Adoptive transfer of hepatic MDSC into naïve mice exacerbated Concanavalin A induced liver damage. Hepatic CD11b+Gr-1+ cells revealed a polarized pro-inflammatory gene signature after Concanavalin A treatment. An interferon gamma- dependent up-regulation of CD40 on hepatic CD11b+Gr-1+ cells along with an up-regulation of CD80, CD86, and CD1d after Concanavalin A treatment was observed. Concanavalin A treatment resulted in a loss of suppressor function by tumor-induced CD11b+Gr-1+ MDSC as well as enhanced reactive oxygen species-mediated hepatotoxicity. CD40 knockdown in hepatic MDSC led to increased arginase activity upon Concanavalin A treatment and lower ALT/AST serum levels. Finally, blockade of arginase activity in Cd40−/− tumor-induced myeloid cells resulted in exacerbation of hepatitis and increased reactive oxygen species production in vivo. Our findings indicate that in a setting of acute hepatitis, tumor-induced hepatic MDSC act as pro-inflammatory immune effector cells capable of killing hepatocytes in a CD40-dependent manner. PMID:25616156

Leukocyte Bim deficiency does not impact atherogenesis in ldlr -/- mice, despite a pronounced induction of autoimmune inflammation.

PubMed

Temmerman, Lieve; Westra, Marijke M; Bot, Ilze; van Vlijmen, Bart J M; van Bree, Niek; Bot, Martine; Habets, Kim L L; Keulers, Tom G H; van der Vlag, Johan; Cotter, Thomas G; van Berkel, Theo J C; Biessen, Erik A L

2017-06-08

Proapoptotic Bcl-2 family member Bim is particularly relevant for deletion of autoreactive and activated T and B cells, implicating Bim in autoimmunity. As atherosclerosis is a chronic inflammatory process with features of autoimmune disease, we investigated the impact of hematopoietic Bim deficiency on plaque formation and parameters of plaque stability. Bim -/- or wild type bone marrow transplanted ldlr -/- mice were fed a Western type diet (WTD) for 5 or 10 weeks, after which they were immunophenotyped and atherosclerotic lesions were analyzed. Bim -/- transplanted mice displayed splenomegaly and overt lymphocytosis. CD4 + and CD8 + T cells were more activated (increased CD69 and CD71 expression, increased interferon gamma production). B cells were elevated by 147%, with a shift towards the pro-atherogenic IgG-producing B2 cell phenotype, resulting in a doubling of anti-oxLDL IgG1 antibody titers in serum of bim -/- mice. Bim -/- mice displayed massive intraplaque accumulation of Ig complexes and of lesional T cells, although this did not translate in changes in plaque size or stability features (apoptotic cell and macrophage content). The surprising lack in plaque phenotype despite the profound pro-atherogenic immune effects may be attributable to the sharp reduction of serum cholesterol levels in WTD fed bim -/- mice.

Hepatic flares in chronic hepatitis C: spontaneous exacerbation vs hepatotropic viruses superinfection.

PubMed

Sagnelli, Evangelista; Sagnelli, Caterina; Pisaturo, Mariantonietta; Coppola, Nicola

2014-06-14

The hepatitis C virus (HCV) causes an acute infection that is frequently asymptomatic, but a spontaneous eradication of HCV infection occurs only in one-third of patients. The remaining two-thirds develop a chronic infection that, in most cases, shows an indolent course and a slow progression to the more advanced stages of the illness. Nearly a quarter of cases with chronic hepatitis C (CHC) develop liver cirrhosis with or without hepatocellular carcinoma. The indolent course of the illness may be troubled by the occurrence of a hepatic flare, i.e., a spontaneous acute exacerbation of CHC due to changes in the immune response, immunosuppression and subsequent restoration, and is characterized by an increase in serum aminotransferase values, a frequent deterioration in liver fibrosis and necroinflammation but also a high frequency of sustained viral response to pegylated interferon plus ribavirin treatment. A substantial increase in serum aminotransferase values during the clinical course of CHC may also be a consequence of a superinfection by other hepatotropic viruses, namely hepatitis B virus (HBV), HBV plus hepatitis D virus, hepatitis E virus, cytomegalovirus, particularly in geographical areas with high endemicity levels. The etiology of a hepatic flare in patients with CHC should always be defined to optimize follow-up procedures and clinical and therapeutic decisions.

Protective role of curcumin on renal ischemia reperfusion injury via attenuating the inflammatory mediators and Caspase-3.

PubMed

Liu, F-H; Ni, W-J; Wang, G-K; Zhang, J-J

2016-09-30

Renal ischemia/reperfusion (I/R) damage may arise due to nephron sparing surgery in patient with a solitary kidney of restricted renal parenchymas. Apoptosis, inflammation and oxidative stress play a significant role in the expansion of renal dysfunction following renal I/R. The aim of the current investigation was to particularize the potential effect of curcumin against hypoxia induced renal injury. The albino Wistar rats divided into groups and each group contains six rats. They groups are normal control; disease control; curcumin (5 mg/kg per day) and another group orally treated with curcumin (10 mg/kg per day) for two weeks before induction of renal I/R. The renal and serum samples were collected and used for the biochemical estimation. The renal tissue was further used for the histopathological estimation. The result of the current investigation demonstrated that the curcumin significantly (P<0.01) attenuated I/R induced renal injury in a dose-dependent way. It also causes significant (P<0.01) reduction in the serum creatinine, blood urea nitrogen level and also suppressed the kidney injury molecules-1. Additionally, it also causes significant inhibition of the malonaldehyde, caspase-3, myeloperoxide, lactose dehydrogenase and interferon-gamma together with enhanced interlukin-10 content.

Severe Unresponsive Hypoglycemia Associated with Neuroendocrine Tumor of Unknown Primary Site - 18 Years after Rectal Cancer Surgery. Case Report.

PubMed

Rusu, Octavia Cristina; Costea, Radu Virgil; Popa, Cristian Constantin; Iliesiu, Andreea; Dumitru, Adrian; Becheanu, Gabriel; Neagu, Stefan Ilie

2015-09-01

Neuroendocrine tumors are derived from cells that have the unique ability to synthesize, store and secrete a variety of metabolically active substances, peptides and amines, characteristic of the tissue of origin, which can cause distinct clinical syndromes. We present the case of a 58-year-old patient diagnosed and surgically treated in January 1996 for stage III inferior rectal cancer, who was readmitted after 18 years presenting persistent diarrheic syndrome and asthenia. Investigations performed (abdominal CT) showed multiple liver metastases, initially suspected as being related to the rectal cancer. Biopsy of liver metastases and pathological and immunohistochemical analysis demonstrated the neuroendocrine origin (moderately differentiated neuroendocrine tumor). Seven months after the identification of liver metastases and after initiation of oncological therapy with Interferon and Somatostatin, the patient presented severe hypoglycemia (serum glucose 13-70 mg/dl) proved to be due to insulin-like factors (serum insulin level 64.9 ìU/ml) secreted by metastases. Due to the aggressive evolution of neuroendocrine tumor, with multiple episodes of severe hypoglycemia, resistant to treatment, the patient died approximately one month after the occurrence of hypoglycemic episodes. Despite comprehensive tests (abdominal CT scan, colonoscopy, bone scintigraphy and PET/CT), the primary site of the neuroendocrine tumors remained unknown.

Flaxseed and cardiovascular health.

PubMed

Prasad, Kailash

2009-11-01

Flaxseed and its components may improve cardiovascular health because of their numerous attributes. Flaxseed contains 35% of its mass as oil, of which 55% is alpha-linolenic acid (ALA). Flax meal, which is devoid of oil, contains the lignan secoisolariciresinol diglucoside (SDG). Flaxseed, flaxseed with very low ALA, flaxseed oil, flax lignan complex (FLC), and SDG reduce the development of hypercholesterolemic atherosclerosis by 46%, 69%, 0%, 73%, and 34%, respectively, in the rabbit model. FLC and SDG slow the progression of atherosclerosis but have no effect in regression of atherosclerosis. Suppression of atherosclerosis by flaxseed is the result of its lignan content and not the result of ALA content. Suppression of atherosclerosis is associated with lowering of serum lipids and antioxidant activity. Effects of flaxseed on serum lipids in experimental animals are variable from no change to slight reduction. Flaxseed oil does not affect serum lipids, except for a slight reduction in serum triglycerides. Lignan in general reduces serum total cholesterol and low-density lipoprotein cholesterol and raises serum high-density lipoprotein cholesterol. SDG and its metabolites have antioxidant activity. Flaxseed and flaxseed oil do not have antioxidant activity except they suppress oxygen radical production by white blood cells. Flaxseed oil/ALA has variable effects on inflammatory mediators/markers (interleukin [IL]-1beta, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor-alpha, interferon-gamma, C-reactive protein, and serum amyloid A). Doses of ALA less than 14 g/d do not affect inflammatory mediators/markers, but 14 g/d or greater reduce inflammatory mediators/markers. Flaxseed oil decreases soluble vascular cell adhesion molecule-1 but has no effect on soluble intracellular adhesion molecule-1, soluble E-selectin, and monocyte colony-stimulating factor. Flaxseed has variable effects on IL-6, high-sensitivity C-reactive protein, and soluble vascular cell adhesion molecule-1. FLC reduces plasma levels of C-reactive protein but has no effects on IL-6, tumor necrosis factor-alpha, soluble intracellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, or monocyte chemoattractant protein. Flaxseed has a very small hypotensive effect, but flaxseed oil does not lower blood pressure. However, SDG is a very potent hypotensive agent. Flaxseed oil decreases platelet aggregation and increases platelet activating inhibitor-1 and bleeding time. Flaxseed and FLC have no effect on the hemopoietic system. SDG is a potent angiogenic and antiapoptotic agent that may have a role in cardioprotection in ischemic heart disease. In conclusion, flaxseed, FLC, and SDG, but not flaxseed oil, suppress atherosclerosis, and FLC and SDG slow progression of atherosclerosis but have no effect on regression. Flaxseed oil suppresses oxygen radical production by white blood cells, prolongs bleeding time, and in higher doses suppresses serum levels of inflammatory mediators and does not lower serum lipids.

Coeliac disease and C virus-related chronic hepatitis: a non association.

PubMed

Gravina, Antonietta Gerarda; Federico, Alessandro; Masarone, Mario; Cuomo, Antonio; Tuccillo, Concetta; Loguercio, Carmelina; Persico, Marcello; Romano, Marco

2012-09-26

A higher prevalence of coeliac disease has recently been reported among patients with HCV-related chronic hepatitis. Moreover, development of clinically overt coeliac disease has been described in a number of HCV-related chronic hepatitis patients during α-interferon therapy. This prospective study was designed to evaluate 1) the prevalence of coeliac disease in patients with HCV-related chronic hepatitis; 2) the prevalence of HCV infection in patients with coeliac disease; 3) whether PEG interferon-α treatment might favour the development of coeliac disease in patients with chronic hepatitis C. Two hundred-ten consecutive patients (M/F = 140/70, range of age 35-58 years, median age 46.5 years) with biopsy proven chronic hepatitis C underwent serological screening for antiendomysial and tissue transglutaminase IgA antibodies. One hundred ninety-four coeliac patients (M/F = 52/142, range of age 18-74 years, median age 34 years) were screened for HCV antibodies. Positivity for HCV antibodies in coeliac disease patients was confirmed by detection of serum HCV-RNA by RT-PCR. This work was carried out in accordance to ethical guidelines of Declaration of Helsinki and was approved by Institutional Ethics Committee of the Second University of Naples. All patients gave informed written consent. 1) none of the 210 HCV-related chronic hepatitis patients were positive for coeliac disease serologic screening; 2) prevalence of HCV infection among coeliac patients was 1.54% (3/194) which is comparable to that reported in the Southern Italy population; 3) PEG interferon-α treatment was not associated with development of coeliac disease either clinical or serological. 1) coeliac disease is not associated with HCV infection; 2) PEG interferon-α does not trigger celiac disease.

Peginterferon alfa‐2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy

PubMed Central

Sherman, M; Yoshida, E M; Deschenes, M; Krajden, M; Bain, V G; Peltekian, K; Anderson, F; Kaita, K; Simonyi, S; Balshaw, R; Lee, S S

2006-01-01

Background The management of patients with chronic hepatitis C who have relapsed or failed to respond to interferon based therapies is an important issue facing hepatologists. Aims We evaluated the efficacy and safety of peginterferon alfa‐2a (40KD) plus ribavirin in this population by conducting a multicentre open label study. Patients Data from adults with detectable serum hepatitis C virus (HCV) RNA who had not responded or had relapsed after previous conventional interferon or conventional interferon/ribavirin combination therapy were analysed. Methods Patients were retreated with peginterferon alfa‐2a (40KD) 180 µg/week plus ribavirin 800 mg/day for 24 or 48 weeks at the investigators' discretion. The study was conceived before the optimal dose of ribavirin (1000/1200 mg/day) for patients with genotype 1 was known. The primary endpoint was sustained virological response (SVR), defined as undetectable HCV RNA (<50 IU/ml) after 24 weeks of follow up. The analysis was conducted by intention to treat. Results A total of 312 patients (212 non‐responders, 100 relapsers) were included. Of these, 28 patients were treated for 24 weeks and 284 for 48 weeks. Baseline characteristics between non‐responders and relapsers were similar although more non‐responders had genotype 1 infection (87% v 69%). Overall SVR rates were 23% (48/212) for non‐responders and 41% (41/100) for relapsers. When data were analysed by genotype, SVR rates were 24% (61/253) in genotype 1 and 47% (28/59) in genotype 2/3. Conclusions These results in a large patient cohort demonstrate that it is possible to cure a proportion of previous non‐responders and relapsers by retreating with peginterferon alfa‐2a (40KD) plus ribavirin. PMID:16709661

Effects of a single dose of enrofloxacin on body temperature and tracheobronchial neutrophil count in healthy Thoroughbreds premedicated with interferon-α and undergoing long-distance transportation.

PubMed

Tsuchiya, Takeru; Hobo, Seiji; Endo, Yoshiro; Narita, Shoichi; Sakamoto, Koji

2012-07-01

To evaluate effects of a single dose of enrofloxacin (5 mg/kg, IV) on body temperature and tracheobronchial neutrophil count in healthy Thoroughbreds premedicated with interferon-α and undergoing long-distance transportation. 32 healthy Thoroughbreds. All horses received interferon-α (0.5 U/kg, sublingually, q 24 h) as an immunologic stimulant for 2 days before transportation and on the day of transportation. Horses were randomly assigned to receive enrofloxacin (5 mg/kg, IV, once; enrofloxacin group) or saline (0.9% NaCl) solution (50 mL, IV, once; control group) ≤ 1 hour before being transported 1,210 km via commercial vans (duration, approx 26 hours). Before and after transportation, clinical examination, measurement of temperature per rectum, and hematologic analysis were performed for all horses; a tracheobronchial aspirate was collected for neutrophil quantification in 12 horses (6/group). Horses received antimicrobial treatment after transportation if deemed necessary by the attending clinician. No adverse effects were associated with treatment. After transportation, WBC count and serum amyloid A concentration in peripheral blood samples and neutrophil counts in tracheobronchial aspirates were significantly lower in horses of the enrofloxacin group than in untreated control horses. Fever (rectal temperature, ≥ 38.5°C) after transportation was detected in 3 of 16 enrofloxacin group horses and 9 of 16 control horses; additional antimicrobial treatment was required in 2 horses in the enrofloxacin group and 7 horses in the control group. In horses premedicated with interferon-α, enrofloxacin appeared to provide better protection against fever and lower respiratory tract inflammation than did saline solution.

Post-Traumatic Hypoxia Is Associated with Prolonged Cerebral Cytokine Production, Higher Serum Biomarker Levels, and Poor Outcome in Patients with Severe Traumatic Brain Injury

PubMed Central

Yan, Edwin B.; Satgunaseelan, Laveniya; Paul, Eldho; Bye, Nicole; Nguyen, Phuong; Agyapomaa, Doreen; Kossmann, Thomas; Rosenfeld, Jeffrey V.

2014-01-01

Abstract Secondary hypoxia is a known contributor to adverse outcomes in patients with traumatic brain injury (TBI). Based on the evidence that hypoxia and TBI in isolation induce neuroinflammation, we investigated whether TBI combined with hypoxia enhances cerebral cytokine production. We also explored whether increased concentrations of injury biomarkers discriminate between hypoxic (Hx) and normoxic (Nx) patients, correlate to worse outcome, and depend on blood–brain barrier (BBB) dysfunction. Forty-two TBI patients with Glasgow Coma Scale ≤8 were recruited. Cerebrospinal fluid (CSF) and serum were collected over 6 days. Patients were divided into Hx (n=22) and Nx (n=20) groups. Eight cytokines were measured in the CSF; albumin, S100, myelin basic protein (MBP) and neuronal specific enolase (NSE) were quantified in serum. CSF/serum albumin quotient was calculated for BBB function. Glasgow Outcome Scale Extended (GOSE) was assessed at 6 months post-TBI. Production of granulocye macrophage-colony stimulating factor (GM-CSF) was higher, and profiles of GM-CSF, interferon (IFN)-γ and, to a lesser extent, tumor necrosis factor (TNF), were prolonged in the CSF of Hx but not Nx patients at 4–5 days post-TBI. Interleukin (IL)-2, IL-4, IL-6, and IL-10 increased similarly in both Hx and Nx groups. S100, MBP, and NSE were significantly higher in Hx patients with unfavorable outcome. Among these three biomarkers, S100 showed the strongest correlations to GOSE after TBI-Hx. Elevated CSF/serum albumin quotients lasted for 5 days post-TBI and displayed similar profiles in Hx and Nx patients. We demonstrate for the first time that post-TBI hypoxia is associated with prolonged neuroinflammation, amplified extravasation of biomarkers, and poor outcome. S100 and MBP could be implemented to track the occurrence of post-TBI hypoxia, and prompt adequate treatment. PMID:24279428

Safety, pharmacokinetics, and pharmacodynamics of RSLV-132, an RNase-Fc fusion protein in systemic lupus erythematosus: a randomized, double-blind, placebo-controlled study.

PubMed

Burge, D J; Eisenman, J; Byrnes-Blake, K; Smolak, P; Lau, K; Cohen, S B; Kivitz, A J; Levin, R; Martin, R W; Sherrer, Y; Posada, J A

2017-07-01

Blood-borne RNA circulating in association with autoantibodies is a potent stimulator of interferon production and immune system activation. RSLV-132 is a novel fully human biologic Fc fusion protein that is comprised of human RNase fused to the Fc domain of human IgG1. The drug is designed to remain in circulation and digest extracellular RNA with the aim of preventing activation of the immune system via Toll-like receptors and the interferon pathway. The present study describes the first clinical study of nuclease therapy in 32 subjects with systemic lupus erythematosus. The drug was well tolerated with a very favorable safety profile. The approximately 19-day serum half-life potentially supports once monthly dosing. There were no subjects in the study that developed anti-RSLV-132 antibodies. Decreases in B-cell activating factor correlated with decreases in disease activity in a subset of patients.

Enhancing effects of gamma interferon on phagocytic cell association with and killing of Trypanosoma cruzi

NASA Technical Reports Server (NTRS)

Wirth, J. J.; Kierszenbaum, F.; Sonnenfeld, G.; Zlotnik, A.

1985-01-01

Results are reported from a study of the influence gamma interferon (GIFN) and interleukin 2 (IL2) have on the capability of P388D1 cells and mouse resident peritoneal macrophages (MPM) to attach to the blood-resident parasites Trypanosoma cruzi and kill them. Cultures of trypomastigote forms of the Tulahuen strain of T. cruzi grown in bovine serum were introduced into peritoneal cells of mice, along with P388D1 cells incubated with GIFN, IL2 and both. Control cells were also maintained. Statistical analysis were then performed on data on counts of the number of dead T. Cruzi cells. The GIFN enhanced the interaction of MPM and P388D1 cells with the surface of T. Cruzi, provided the interaction was given over 12 hr to take place. A depression of the cytotoxicity of P388D1 cells was attributed to mediation by H2O2, an effect partially offset by incubation with the lymphokine GIFN.

Antiviral Activity of Chlorite-Oxidized Oxyamylose, a Polyacetal Carboxylic Acid

PubMed Central

Billiau, A.; Desmyter, J.; De Somer, P.

1970-01-01

Intraperitoneal injection of chlorite-oxidized oxyamylose (COAM) protected mice against mengo, vaccinia, Semliki Forest, and influenza APR8 viruses. Topical administration in the eye of rabbits partially inhibited the development of experimental herpetic keratoconjunctivitis. COAM resembled polyacrylic acid in many aspects, but it was markedly less toxic. For systemic administration, the therapeutic index was on the order of magnitude of 1:300 to 1:500. Although the in vivo antiviral effect of COAM wore off faster than that of polyacrylic acid, protection lasted for several weeks. Against mengovirus, such prolonged protection was achieved only when polymer and virus were injected intraperitoneally. Protection against intravenous vaccinia virus was not dependent on the injection route of COAM. Experiments on the mode of action of COAM pointed to macrophages as possible mediators of the antiviral effect. The fact that small amounts of interferon appeared in the serum after administration of high doses of COAM suggests that interferon may play a role in the induction of antiviral resistance by COAM. PMID:4314554

[Association between Fok I vitamin D receptor (VDR) gene polymorphism and plasmatic concentrations of transforming growth factor-beta1 and interferon gamma in type 1 diabetes mellitus].

PubMed

López, Tatiana; García, Diego; Angel, Bárbara; Carrasco, Elena; Codner, Ethel; Ugarte, Francisca; Pérez-Bravo, Francisco

2008-02-02

In order to assess whether Fok I vitamin D receptor gene (VDR) polymorphism is involved in the genetic susceptibility of type 1 diabetes, a case-control study was conducted and VDR genotypes were related to serum concentrations of 25(OH) vitamin D and cytokines transforming growth factor beta1 (TGF-beta1) and interferon gamma (INF-gamma). 151 incident cases of type 1 diabetes and 182 non related healthy controls from Santiago were studied for VDR polymorphisms in peripheral blood DNA. Exon 2 (Fok I) segments were amplified by polimerase chain reaction and analyzed by means of restriction fragment length polymorphism to determine each corresponding genotype. Differences for allele, genotype and serological markers as 25(OH) vitamin D, TGF-beta1 and INF-gamma levels distribution between patients and controls were analyzed. Fok I polymorphism distribution analysis showed no differences between patients and controls. Among diabetics, higher levels of TGF-beta1 (median, 282.6 pg/ml; range, 131.8-3,031.4) were observed compared with healthy children (median, 232.2 pg/ml; range, 135.7-506.5) (p < 0.0038). Similar results were observed for INF-gamma concentrations (median, 121.1 pg/ml, and range, 5.3-228.8, in cases, and median, 89.6 pg/ml, and range, 10.9-117.2 in controls) (p < 0.0004). The diabetic carriers of the ff genotype showed low levels of 25(OH) vitamin D compared with the carriers of the F allele: mean (standard deviation), 23.1 (5.9) versus 27.9 (10.3) ng/ml (p < 0.03). A similar result was observed for TGF-beta1 concentrations in diabetic carriers of ff genotype and patients carriers of the F allele (298.5 versus 276.6; p < 0.05). Fok I polymorphism of VDR could have a marginal role in the immunologic disturbance in type 1 diabetes.

Hepatitis C Virus-Related Lymphomagenesis in a Mouse Model

PubMed Central

Tsukiyama-Kohara, Kyoko; Sekiguchi, Satoshi; Kasama, Yuri; Salem, Nagla Elwy; Machida, Keigo; Kohara, Michinori

2011-01-01

B cell non-Hodgkin lymphoma is a typical extrahepatic manifestation frequently associated with hepatitis C virus (HCV) infection. The mechanism by which HCV infection leads to lymphoproliferative disorder remains unclear. Our group established HCV transgenic mice that expressed the full HCV genome in B cells (RzCD19Cre mice). We observed a 25.0% incidence of diffuse large B cell non-Hodgkin lymphomas (22.2% in male and 29.6% in female mice) within 600 days of birth. Interestingly, RzCD19Cre mice with substantially elevated serum-soluble interleukin-2 receptor α-subunit (sIL-2Rα) levels (>1000 pg/mL) developed B cell lymphomas. Another mouse model of lymphoproliferative disorder was established by persistent expression of HCV structural proteins through disruption of interferon regulatory factor-1 (irf-1_/_/CN2 mice). Irf-1_/_/CN2 mice showed extremely high incidences of lymphomas and lymphoproliferative disorders. Moreover, these mice showed increased levels of interleukin (IL)-2, IL-10, and Bcl-2 as well as increased Bcl-2 expression, which promoted oncogenic transformation of lymphocytes. PMID:22084693

Effect of Interferon, Polyacrylic Acid, and Polymethacrylic Acid on Tail Lesions in Mice Infected with Vaccinia Virus

PubMed Central

De Clercq, E.; De Somer, P.

1968-01-01

Intravenous inoculation of mice with vaccinia virus produced characteristic lesions of the tail surface which were suppressed by intraperitoneal administration of interferon and polyacrylic acid (PAA). Polymethacrylic acid (PMAA) stimulated the formation of vaccinia virus lesions. For full activity, both interferon and PAA must be given prior to infection. PAA was still significantly effective at small dose levels (3 mg/kg) and achieved protection for at least 4 weeks. Protection increased with increasing molecular weight of the polymer. The mode of action of PAA is discussed. PMID:5676405

[Acute outbreak of hepatitis C in human immunodeficiency virus-infected patients].

PubMed

Martínez-Rebollar, Maria; Mallolas, Josep; Pérez, Iñaki; González-Cordón, Ana; Loncà, Montserrat; Torres, Berta; Rojas, Jhon-Fredy; Monteiro, Polyana; Blanco, José-Luis; Martínez, Esteban; Gatell, José-María; Laguno, Montserrat

2015-01-01

Recent studies suggest an increased incidence of acute infection with hepatitisC virus (AHC) in men who have sex with men (MSM) co-infected with HIV. Early treatment with interferon-alpha, alone or in combination with ribavirin, significantly reduces the risk of chronic evolution. This retrospective study includes all HIV patients with AHC in our centre from 2003 to March 2013. AHC was defined by seroconversion of HCV antibodies and detection of serum HCV RNA. 93 episodes of AHC were diagnosed in 89 patients. All but three were MSM with a history of unprotected sex. Thirty-seven (40%) patients had other associated sexually transmitted disease. The 29% (27) had any symptoms suggestive of AHC. HCV genotype 4 was the most common (41%), followed by genotype1. Seventy patients started treatment with interferon-alfa and weight-adjusted ribavirin. Currently 46 have completed treatment and follow-up, reaching 26 of them (56.5%) sustained viral response. The incidence of AHC in HIV MSM patients from our centre has increased exponentially in recent years; sexual transmission remains the main route of infection. Early treatment with interferon-alpha and ribavirin achieved a moderate response in these patients. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Single-Dose Intranasal Treatment with DEF201 (Adenovirus Vectored Consensus Interferon) Prevents Lethal Disease Due to Rift Valley Fever Virus Challenge

PubMed Central

Gowen, Brian B.; Ennis, Jane; Bailey, Kevin W.; Vest, Zachary; Scharton, Dionna; Sefing, Eric J.; Turner, Jeffrey D.

2014-01-01

Rift Valley fever virus (RVFV) causes severe disease in humans and ungulates. The virus can be transmitted by mosquitoes, direct contact with infected tissues or fluids, or aerosol, making it a significant biological threat for which there is no approved vaccine or therapeutic. Herein we describe the evaluation of DEF201, an adenovirus-vectored interferon alpha which addresses the limitations of recombinant interferon alpha protein (cost, short half-life), as a pre- and post-exposure treatment in a lethal hamster RVFV challenge model. DEF201 was delivered intranasally to stimulate mucosal immunity and effectively bypass any pre-existing immunity to the vector. Complete protection against RVFV infection was observed from a single dose of DEF201 administered one or seven days prior to challenge while all control animals succumbed within three days of infection. Efficacy of treatment administered two weeks prior to challenge was limited. Post‑exposure, DEF201 was able to confer significant protection when dosed at 30 min or 6 h, but not at 24 h post-RVFV challenge. Protection was associated with reductions in serum and tissue viral loads. Our findings suggest that DEF201 may be a useful countermeasure against RVFV infection and further demonstrates its broad-spectrum capacity to stimulate single dose protective immunity. PMID:24662673

Beneficial effects of cytokine induced hyperlipidemia.

PubMed

Feingold, K R; Hardardóttir, I; Grunfeld, C

1998-01-01

Infection, inflammation and trauma induce marked changes in the plasma levels of a wide variety of proteins (acute phase response), and these changes are mediated by cytokines. The acute phase response is thought to be beneficial to the host. The host's response to injury also results in dramatic alterations in lipid metabolism and circulating lipoprotein levels which are mediated by cytokines. A large number of cytokines including TNF, the interleukins, and the interferons increase serum triglyceride levels. This rapid increase (1-2 h) is predominantly due to an increase in hepatic VLDL secretion while the late increase may be due to a variety of factors including increased hepatic production of VLDL or delayed clearance secondary to a decrease in lipoprotein lipase activity and/or apolipoprotein E levels on VLDL. In animals other than primates, cytokines also increase serum cholesterol levels, most likely by increasing hepatic cholesterol. Cytokines increase hepatic cholesterol synthesis by stimulating HMG CoA reductase gene expression and decrease hepatic cholesterol catabolism by inhibiting cholesterol 7 alpha-hydroxylase, the key enzyme in bile acid synthesis. Injury and/or cytokines also decrease HDL cholesterol levels and induce alterations in the composition of HDL. The content of SAA and apolipoprotein J increase, apolipoprotein A1 may decrease, and the cholesterol ester content decreases while free cholesterol increases. Additionally, key proteins involved in HDL metabolism are altered by cytokines; LCAT activity, hepatic lipase activity, and CETP levels decrease. These changes in lipid and lipoprotein metabolism may be beneficial in a number of ways including: lipoproteins competing with viruses for cellular receptors, apolipoproteins neutralizing viruses, lipoproteins binding and targeting parasites for destruction, apolipoproteins lysing parasites, redistribution of nutrients to cells involved in the immune response and/or tissue repair, and lipoproteins binding toxic agents and neutralizing their harmful effects. Thus, cytokines induce marked changes in lipid metabolism that lead to hyperlipidemia which represents part of the innate immune response and may be beneficial to the host.

Effects of interferon-gamma and tumor necrosis factor-alpha on macrophage enzyme levels

NASA Technical Reports Server (NTRS)

Pierangeli, Silvia S.; Sonnenfeld, Gerald

1989-01-01

Murine peritoneal macrophages were treated with interferon-gamma (IFN-gamma) or tumor necrosis factor-alpha (TNF). Measurements of changes in acid phosphatase and beta-glucuronidase levels were made as an indication of activation by cytokine treatment. IFN-gamma or TNF-gamma treatment resulted in a significant increase in the activities of both enzymes measured in the cell lysates. This increase was observable after 6 h of incubation, but reached its maximum level after 24 h of incubation. The effect of the treatment of the cell with both cytokines together was additive. No synergistic effect of addition of both cytokines on the enzyme levels was observed.

Post-treatment levels of α-fetoprotein predict incidence of hepatocellular carcinoma after interferon therapy.

PubMed

Oze, Tsugiko; Hiramatsu, Naoki; Yakushijin, Takayuki; Miyazaki, Masanori; Yamada, Akira; Oshita, Masahide; Hagiwara, Hideki; Mita, Eiji; Ito, Toshifumi; Fukui, Hiroyuki; Inui, Yoshiaki; Hijioka, Taizo; Inada, Masami; Katayama, Kazuhiro; Tamura, Shinji; Yoshihara, Harumasa; Inoue, Atsuo; Imai, Yasuharu; Hayashi, Eijiro; Kato, Michio; Miyagi, Takuya; Yoshida, Yuichi; Tatsumi, Tomohide; Kasahara, Akinori; Hamasaki, Toshimitsu; Hayashi, Norio; Takehara, Tetsuo

2014-07-01

In patients with chronic hepatitis C virus (HCV) infection, lack of sustained virologic response (SVR) 24 weeks after the end of interferon therapy is a significant risk factor for hepatocellular carcinoma (HCC). Although many pretreatment factors are known to affect HCC incidence, less is known about post-treatment factors-many change during the course of interferon therapy. We performed a prospective study, collecting data from 2659 patients with chronic hepatitis C without a history of HCC who had been treated with pegylated interferon (Peg-IFN) plus ribavirin from 2002 through 2008 at hospitals in Japan. Biopsy specimens were collected before treatment; all patients received Peg-IFN plus ribavirin for 48 to 72 weeks (HCV genotype 1) or 24 weeks (HCV genotype 2). Hematologic, biochemical, and virologic data were collected every 4 weeks during treatment and every 6 months after treatment. HCC was diagnosed based on angiography, computed tomography, and/or magnetic resonance imaging findings. HCC developed in 104 patients during a mean observation period of 40 months. Older age, male sex, lower platelet counts and higher levels of α-fetoprotein at baseline, and lack of an SVR were significant risk factors for HCC. The cumulative incidence of HCC was significantly lower in patients without SVRs who relapsed than those with no response to treatment. Levels of α-fetoprotein 24 weeks after the end of treatment (AFP24) were significantly lower than levels of α-fetoprotein at baseline in patients with SVRs and those who relapsed, but not in nonresponders. Post-treatment risk factors for HCC among patients with SVRs included higher AFP24 level and older age; among those without SVRs, risk factors included higher AFP24 level, integrated level of alanine aminotransferase, older age, and male sex. AFP24 (≥10 ng/mL, 10-5 ng/mL, and then <5 ng/mL) was a better predictor of HCC incidence than pretreatment level of AFP among patients with and without SVRs. In patients with chronic HCV infection, levels of α-fetoprotein decrease during interferon therapy. High post-treatment levels of α-fetoprotein predict HCC, regardless of whether patients achieve an SVR. University Hospital Medical Information Network Clinical Trials Registry: C000000196, C000000197. Copyright © 2014. Published by Elsevier Inc.

Altered cytokine production by specific human peripheral blood cell subsets immediately following space flight

NASA Technical Reports Server (NTRS)

Crucian, B. E.; Cubbage, M. L.; Sams, C. F.

2000-01-01

In this study, flow cytometry was used to positively identify the specific lymphocyte subsets exhibiting space flight-induced alterations in cytokine production. Whole blood samples were collected from 27 astronauts at three points (one preflight, two postflight) surrounding four space shuttle missions. Assays performed included serum/urine stress hormones, white blood cell (WBC) phenotyping, and intracellular cytokine production following mitogenic stimulation. Absolute levels of peripheral granulocytes were significantly elevated following space flight, but the levels of circulating lymphocytes and monocytes were unchanged. Lymphocyte subset analysis demonstrated a decreased percentage of T cells, whereas percentages of B cells and natural killer (NK) cells remained unchanged after flight. Nearly all the astronauts exhibited an increased CD4/CD8 T cell ratio. Assessment of naive (CD45RA+) vs. memory (CD45RO+) CD4+ T cell subsets was ambiguous, and subjects tended to group within specific missions. Although no significant trend was seen in absolute monocyte levels, a significant decrease in the percentage of the CD14+ CD16+ monocytes was seen following space flight in all subjects tested. T cell (CD3+) production of interleukin-2 (IL-2) was significantly decreased after space flight, as was IL-2 production by both CD4+ and CD8+ T cell subsets. Production of interferon-gamma (IFN-gamma) was not altered by space flight for the CD8+ cell subset, but there was a significant decrease in IFN-gamma production for the CD4+ T cell subset. Serum and urine stress hormone analysis indicated significant physiologic stresses in astronauts following space flight. Altered peripheral leukocyte subsets, altered serum and urine stress hormone levels, and altered T cell cytokine secretion profiles were all observed postflight. In addition, there appeared to be differential susceptibility to space flight regarding cytokine secretion by T cell subsets. These alterations may be the result of either microgravity exposure or the physiologic stresses of landing and readaptation to unit gravity. Future studies, including in-flight analysis or sampling, will be necessary to determine the cause of these alterations.

Protective effects of a traditional Chinese herbal formula Jiang-Xian HuGan on Concanavalin A-induced mouse hepatitis via NF-κB and Nrf2 signaling pathways.

PubMed

Tang, Huan-Huan; Li, Hai-Long; Li, Yue-Xuan; You, Yan; Guan, Yun-Yun; Zhang, Su-Lin; Liu, Li-Xin; Bao, Wei-Lian; Zhou, Yong; Shen, Xiao-Yan

2018-05-10

Jiang-Xian HuGan (JXHG) formulated by five natural products including Freshwater clam (Corbicula fluminea), Curcuma longa L., Ligustrum lucidum, Eclipta prostrata (L.) L. and Paeonia lactiflora Pall., has exhibited a great hepatoprotective effect. We investigated the effect of JXHG on concanavalin A (ConA)-induced acute live injury in mice, and to elucidate its underlying molecular mechanisms. Jiangkanling Capsule (900 mg/kg), low-dose JXHG (LJXHG, 700 mg/kg), high-dose JXHG (HJXHG, 1400 mg/kg) were administered to mice by oral gavage daily for 20 days prior to a single intravenous injection of ConA (20 mg/kg). Liver injury was evaluated by measuring the serum levels of enzymes and cytokines as well as liver histological analysis. We also measured the hepatic expression of cytokines at mRNA levels and the proteins related to NF-κB and Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling pathways. Our results showed that JXHG pretreatment significantly alleviated ConA-induced live injury as evidenced by decreased serum levels of glutamic-pyruvic transaminase (ALT) and glutamic oxalacetic transaminase (AST), and reduced hepatocyte apoptosis and mortality. Furthermore, JXHG was able to significantly reduce the serum levels of proinflammatory cytokines, down-regulate the mRNA expression of interleukin-6 (IL-6) and interferon-γ (IFN-γ), and up-regulate IL-10 as well as superoxide-dimutase-1 (SOD1), glutathione reductase (GSR) and Glutathione peroxidase 2 (GPX2) mRNA in the liver tissues after Con A injection. In addition, JXHG pretreatment dramatically suppressed the phosphorylation of NF-κB p65 (p65), increased Nrf2 expression, and decreased the expression ratio of cleaved caspase-3/caspase-3 in liver tissues. These results suggest that JXHG protects against ConA-induced acute live injury through inhibiting NF-κB mediated inflammatory pathway and promoting Nrf2 mediated anti-oxidative stress signaling pathway. Copyright © 2018 Elsevier B.V. All rights reserved.

Amplified RLR signaling activation through an interferon-stimulated gene-endoplasmic reticulum stress-mitochondrial calcium uniporter protein loop

PubMed Central

Cheng, Jinbo; Liao, Yajin; Zhou, Lujun; Peng, Shengyi; Chen, Hong; Yuan, Zengqiang

2016-01-01

Type I interferon (IFN-I) is critical for a host against viral and bacterial infections via induction of hundreds of interferon-stimulated genes (ISGs), but the mechanism underlying the regulation of IFN-I remains largely unknown. In this study, we first demonstrate that ISG expression is required for optimal IFN-β levels, an effect that is further enhanced by endoplasmic reticulum (ER) stress. Furthermore, we identify mitochondrial calcium uniporter protein (MCU) as a mitochondrial antiviral signaling protein (MAVS)-interacting protein that is important for ER stress induction and amplified MAVS signaling activation. In addition, by performing an ectopic expression assay to screen a library of 117 human ISGs for effects on IFN-β levels, we found that tumor necrosis factor receptor 1 (TNFR1) significantly increases IFN-β levels independent of ER stress. Altogether, our findings suggest that MCU and TNFR1 are involved in the regulation of RIG-I-like receptors (RLR) signaling. PMID:26892273

Evaluation of the binding effect of human serum albumin on the properties of granules.

PubMed

Kristó, Katalin; Bajdik, János; Eros, István; Pintye-Hódi, Klára

2008-11-01

The main objective of this study was the application of a solution of human serum albumin as a granulating fluid. The properties of the granules formed were evaluated and compared with those when a conventional binder was applied in the same concentration. The powder mixture contained a soluble (mannitol) and an insoluble component (different types of cellulose). The protein solution applied exerted an appropriate aggregating effect if the system contained microcrystalline celluloses. Powdered cellulose was not suitable for the granulation with human serum albumin solution. As compared with the same concentration of the conventionally applied cellulose ethers as binder, the prepared granules exhibited a larger particle size, a significantly better compressibility, a higher breaking hardness and a favourable deformation process. These findings mainly reflect the good adhesive properties of the protein. The best compressibility and mechanical behaviour were attained on the application of the microcrystalline cellulose Vivapur type 105. This favourable behaviour may be connected with the wettability of cellulose. These results suggest that the formulation of tablets may be easier from an active agent in the serum that binds to albumin (e.g. interferon) since the amount of additives (binder) can be reduced.

Results of interferon treatment in children with chronic hepatitis B.

PubMed

Grigorescu-Sido, Paula; Călin, Lazăr; Manasia, Rodica; Mireştean, Stefan; Creţ, Victoria; Skorka, Cristina; Grigorescu-Sido, Anca

2002-12-01

Many observations report a variable therapeutical response to interferon in children with chronic hepatitis B. In order to evaluate the efficiency of alpha-interferon treatment in the downregulation of viral replication and in the eradication of infection in these patients, we assessed HBeAg/HBeAb and HBsAg/HBsAb seroconversion (as well as with clinical outcome and the changes in the plasma level of aminotransferases) in 61 treated patients. The diagnosis was established by means of the usual clinical, biochemical and histopathological criteria. There was no possibility to viral DNA test and no control group was included. Patients were selected for interferon treatment who displayed at least a two fold rise in the plasma level of aminotransferases as compared to normal values, as well as necroinflammatory activity (score > or = 6) and positive HBeAg as a marker of viral replication. Treatment was carried out with alpha-2a interferon or alpha-2b interferon in a dose of 3 million U/m2/dose in 3 weekly doses for a period of 4-6 months. The monitoring interval was 6.6+/-3 years. HBeAg/HBeAb seroconversion was registered in 77.2% of the patients and mainly occurred during the first year of follow-up (50.9 %). HBsAg/HBsAb seroconversion was revealed in 1.75% of the cases. The therapeutical response was complete, incomplete, transient and absent in 1.75%, 64.9%, 10.5% and 22.8% of the patients, respectively. The results show that the eradication of HBV infection is insignificant, but the downregulation of viral replication and, subsequently the halt of further progression of hepatic lesions is obtained in a high percentage of cases, highlighting the efficiency of this treatment in children with chronic hepatitis B

Newly designed modifier prolongs the action of short-lived peptides and proteins by allowing their binding to serum albumin.

PubMed

Shechter, Yoram; Sasson, Keren; Lev-Goldman, Vered; Rubinraut, Sara; Rubinstein, Menachem; Fridkin, Mati

2012-08-15

We found that human serum albumin (HSA) contains a single binding domain for derivatives of long-chain fatty acid (LCFA)-like molecules in which the carboxylate is replaced by sulfonate. Accordingly, we have synthesized 16-sulfo-hexadecanoic acid-N-hydroxysuccinimide ester [HO(3)S-(CH(2))(15)-CONHS], an agent that reacts selectively with the amino side chains of peptides and proteins. A macromolecule containing a single 16-sulfohexadecanoate moiety associating with albumin with a K(a) value of 0.83 ± 0.08 × 10(6) M(-1), a sufficient affinity to extend the actions in vivo of such short-lived peptides and proteins. Subcutaneous administration of insulin-NHCO-(CH(2))(15)-SO(3)(-) into mice facilitated a glucose-lowering effect 4.3 times in duration and 6.6 times in area under the curve (AUC) as compared to an in vitro equipotent amount of Zn(2+)-free insulin. Similarly, subcutaneous and intravenous administration of exendin-4-NHCO-(CH(2))(15)-SO(3)(-) to mice yielded prolonged and stable reduction in glucose level, 5-9-fold longer than that of exendin-4. Also, a single subcutaneous administration of human interferon-α2-[NH-CO-(CH(2))(15)-SO(3)(-)](3) to mice yielded circulating antiviral activity over a period of 40 h. In conclusion, a simple, hydrophilic reagent has been engineered, synthesized, and studied. Its linkage to peptides and proteins in a monomodified fashion yielded hydrophilic, prolonged acting derivatives, due to their acquired ability to associate with serum albumin after administration.

Inhibition of autoimmune diabetes in NOD mice with serum from streptococcal preparation (OK-432)-injected mice.

PubMed Central

Seino, H; Satoh, J; Shintani, S; Takahashi, K; Zhu, X P; Masuda, T; Nobunaga, T; Saito, M; Terano, Y; Toyota, T

1991-01-01

We have recently reported that systemic and chronic administration of recombinant tumour necrosis factor alpha (TNF-alpha), as well as streptococcal preparation (OK-432), inhibits development of insulin-dependent diabetes mellitus (IDDM) in NOD mice and BB rats, models of IDDM. In this study we examined whether serum containing endogenous TNF induced by OK-432 injection could inhibit IDDM in NOD mice. Treatment twice a week from 4 weeks of age with OK-432-injected mouse serum, which contained endogenous TNF (75U), but not IL-1, IL-2 and interferon-gamma (IFN-gamma) activity, reduced the intensity of insulitis and significantly inhibited the cumulative incidence of diabetes by 28 weeks of age in NOD mice, as compared with the incidence in non-treated mice (P less than 0.01) and in mice treated with control serum (P less than 0.02). This inhibitory effect of the serum was diminished, although not significantly, by neutralization of serum TNF activity with anti-mouse TNF antibody. In the mice treated with the serum from OK-432-injected mice, Thy-1.2+ or CD8+ spleen cells decreased (P less than 0.01) and surface-Ig+ (S-Ig+) cells increased (P less than 0.05), whereas the proliferative response of spleen cells to concanavalin A (P less than 0.01) and lipopolysaccharide (P less than 0.05) increased. The results indicate that the inhibition by OK-432 treatment of IDDM in NOD mice was partially mediated by serum factors including endogenous TNF. PMID:1747949

Autosomal-dominant chronic mucocutaneous candidiasis with STAT1-mutation can be complicated with chronic active hepatitis and hypothyroidism.

PubMed

Hori, Tomohiro; Ohnishi, Hidenori; Teramoto, Takahide; Tsubouchi, Kohji; Naiki, Takafumi; Hirose, Yoshinobu; Ohara, Osamu; Seishima, Mariko; Kaneko, Hideo; Fukao, Toshiyuki; Kondo, Naomi

2012-12-01

To describe a case of autosomal-dominant (AD)-chronic mucocutaneous candidiasis (CMC) with a signal transducer and activator of transcription (STAT) 1 gene mutation, and some of the important complications of this disease such as chronic hepatitis. We present a 23-year-old woman with CMC, chronic active hepatitis, and hypothyroidism. Her father also had CMC. We performed several immunological analyses of blood and liver samples, and searched for gene mutations for CMC in the patient and her father. We identified the heterozygous substitution c.821 G > A (p.Arg274Gln) in the STAT1 gene of both the patient and her father. The level of β-glucan induced interferon (IFN)-γ in her blood cells was significantly low. Immunoblot analysis detected serum anti-interleukin (IL)-17 F autoantibody. She was found to have increased (low-titer) antibodies related to her hypothyroidism and hepatitis. Her serum IL-18 levels fluctuated with her AST and ALT levels. Liver biopsy revealed CD68-positive cell infiltration and IL-18 expression in the sinusoidal regions. These results suggest that the chronic active hepatitis in this patient may be exacerbated by the excessive IL-18 accumulation caused by recurrent mucocutaneous fungal infection, and decreased IFN-γ production. AD-CMC is known to be caused by a gain-of-function mutation of the STAT1 gene. Chronic active hepatitis is a rare complication of AD-CMC, with currently unknown pathogenesis. It seems that the clinical phenotype in this patient is modified by autoimmune mechanisms and cytokine dysregulation. AD-CMC can be complicated by various immune disorders including autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Evidence of a cellular immune response against sialyl-Tn in breast and ovarian cancer patients after high-dose chemotherapy, stem cell rescue, and immunization with Theratope STn-KLH cancer vaccine.

PubMed

Sandmaier, B M; Oparin, D V; Holmberg, L A; Reddish, M A; MacLean, G D; Longenecker, B M

1999-01-01

Seven ovarian and 33 breast high-risk stage II/III and stage IV cancer patients received high-dose chemotherapy followed by stem cell rescue. Thirty to 151 days after stem cell transplantation, the patients received their first immunotherapy treatment with Theratope STn-KLH cancer vaccine. Most patients developed increasing IgG anti-STn titers to a sustained peak after the fourth or fifth immunizations. Only one patient had elevated CA27.29 (MUC1 mucin) serum levels at trial entry. Five of the seven patients with preimmunotherapy elevated serum CA125 levels demonstrated decreasing CA125 levels during immunotherapy, consistent with an antitumor response. Evidence of STn antigen-specific T-cell proliferation was obtained from 17 of the 27 evaluable patients who received at least three immunotherapy treatments. Eleven of the 26 patients tested had evidence of an anti-STn TH1 antigen-specific T-cell response as determined by interferon-gamma, but not interleukin (IL)-4, production. After immunization, lytic activity of peripheral blood lymphocytes (PBLs) tested against a lymphokine activated killer (LAK)-sensitive cell line, a natural killer (NK)-sensitive cell line, and an STn-expressing cancer cell line (OVCAR) increased significantly. In vitro IL-2 treatment of the PBLs after vaccination greatly enhanced killing of the STn+ cancer cell line. Evidence of the development of OVCAR specific killing activity, over and above that seen due to LAK or NK killing, is presented. These studies provide the strongest evidence in humans of the development of an antitumor T-cell response after immunization with a cancer-associated carbohydrate antigen.

Effect of oral tolerance in a mouse model of allergic rhinitis.

PubMed

Shin, Ji-Hyeon; Kang, Jun Myung; Kim, Sung Won; Cho, Jin-Hee; Park, Yong Jin; Kim, Soo Whan

2010-03-01

Induction of oral tolerance (OT) is known to prevent allergic inflammation in models of asthma. This study investigated the preventive effect of OT and airway remodeling in a mouse model of allergic rhinitis (AR). An in vivo study using an animal model. Catholic Research Institutes of Medical Science. Forty six-week-old, female BALB/c mice were divided into four groups: control, AR, low-dose OT, and high-dose OT. To induce OT, mice were fed ovalbumin (OVA) before sensitization with OVA/aluminum hydroxide, 1 mg for six days in the low-dose OT group and a 25 mg single dose in the high-dose OT group. Mice in the AR group were fed phosphate-buffered saline. After sensitization followed by challenges with OVA during six weeks, nasal behaviors, interleukin (IL)-13 and interferon gamma (IFN-gamma) levels in nasal lavage (NAL) fluids, as well as OVA-specific IgE levels in serum, were measured. The degree of goblet cell hyperplasia and thickness of lamina propria were observed in nasal tissues by periodic acid-Schiff and Masson's trichrome stain. A P value < 0.05 was accepted as statistically significant. Both OT groups showed a significant decrease in inflammatory cells, IL-13 and IFN-gamma in NAL fluids, as well as OVA-specific IgE levels in serum compared with the AR group. In addition, the degree of goblet cell hyperplasia and thickness of lamina propria were attenuated in both OT groups compared with the AR group. Further, these alterations did not differ significantly between the two OT groups. These results suggest that OT may effectively reduce allergic inflammation as well as airway remodeling in a mouse model of AR. Copyright 2010 American Academy of Otolaryngology-Head and Neck Surgery Foundation. Published by Mosby, Inc. All rights reserved.

Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice.

PubMed

Bercik, Premysl; Verdu, Elena F; Foster, Jane A; Macri, Joseph; Potter, Murray; Huang, Xiaxing; Malinowski, Paul; Jackson, Wendy; Blennerhassett, Patricia; Neufeld, Karen A; Lu, Jun; Khan, Waliul I; Corthesy-Theulaz, Irene; Cherbut, Christine; Bergonzelli, Gabriela E; Collins, Stephen M

2010-12-01

Clinical and preclinical studies have associated gastrointestinal inflammation and infection with altered behavior. We investigated whether chronic gut inflammation alters behavior and brain biochemistry and examined underlying mechanisms. AKR mice were infected with the noninvasive parasite Trichuris muris and given etanercept, budesonide, or specific probiotics. Subdiaphragmatic vagotomy was performed in a subgroup of mice before infection. Gastrointestinal inflammation was assessed by histology and quantification of myeloperoxidase activity. Serum proteins were measured by proteomic analysis, circulating cytokines were measured by fluorescence activated cell sorting array, and serum tryptophan and kynurenine were measured by liquid chromatography. Behavior was assessed using light/dark preference and step-down tests. In situ hybridization was used to assess brain-derived neurotrophic factor (BDNF) expression in the brain. T muris caused mild to moderate colonic inflammation and anxiety-like behavior that was associated with decreased hippocampal BDNF messenger RNA (mRNA). Circulating tumor necrosis factor-α and interferon-γ, as well as the kynurenine and kynurenine/tryptophan ratio, were increased. Proteomic analysis showed altered levels of several proteins related to inflammation and neural function. Administration of etanercept, and to a lesser degree of budesonide, normalized behavior, reduced cytokine and kynurenine levels, but did not influence BDNF expression. The probiotic Bifidobacterium longum normalized behavior and BDNF mRNA but did not affect cytokine or kynurenine levels. Anxiety-like behavior was present in infected mice after vagotomy. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry, which can be normalized by inflammation-dependent and -independent mechanisms, neither of which requires the integrity of the vagus nerve. Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

The effect of Bacillus coagulans-fermented and nonfermented Ginkgo biloba on the immunity status of broiler chickens.

PubMed

Liu, Xiaoyan; Cao, Guanjun; Wang, Qin; Yao, Xuan; Fang, Binghu

2015-07-01

To evaluate and compare the effects of Bacillus coagulans-fermented Ginkgo biloba (FG) and nonfermented Ginkgo biloba (NFG) on the immunity status of broiler chickens, 180 1-d-old female Arbor Acres chicks were divided into 3 groups and fed either a basal diet, a basal diet supplemented with 0.3% NFG, or a basal diet supplemented with 0.3% FG. Blood samples were taken on the seventh (before vaccination), 14th, 21st, 28th and 35th day for the assessment of serum IL-18 and interferon γ (IFN-γ) levels by ELISA. In addition, Newcastle disease antibody titer analysis was made via hemagglutination and hemagglutination inhibition test methods. On d 35, 6 chickens from each group were sacrificed and the thymus, liver, spleen, small intestine (jejunum segment), cecum, and bursa of Fabricius from each chicken were removed for analysis. RNA was isolated for defensin expression detection by real-time PCR (q-PCR). The results showed that serum IL-18 and IFN-γ levels decreased after treatment with NFG and FG compared with untreated control chickens. The ND antibody titers did not differ significantly between the 3 groups on the seventh, 14th, 21st and 28th day; however, on the 35th day, the ND antibody titers of the NFG and FG chickens were both significantly higher than those of control group chickens. Defensin RNA expression levels were inhibited by NFG; however, they were induced by FG. In conclusion, fermentation of Ginkgo biloba with Bacillus coagulans can promote the beneficial effect of Gingko biloba on the immunity status of broiler chickens.

Comparison of in vivo toxicity, antioxidant and immunomodulatory activities of coconut, nipah and pineapple juice vinegars.

PubMed

Mohamad, Nurul Elyani; Keong Yeap, Swee; Beh, Boon Keen; Romli, Muhammad Firdaus; Yusof, Hamidah Mohd; Kristeen-Teo, Ye Wen; Sharifuddin, Shaiful Adzni; Long, Kamariah; Alitheen, Noorjahan Banu

2018-01-01

Vinegar is widely used as a food additive, in food preparation and as a food supplement. This study compared the phenolic acid profiles and in vivo toxicities, and antioxidant and immunomodulatory effects of coconut, nipah and pineapple juice vinegars, which were respectively prepared via a two-step fermentation using Saccharomyces cerevisiae 7013 INRA and Acetobacter aceti vat Europeans. Pineapple juice vinegar, which had the highest total phenolic acid content, also exhibited the greatest in vitro antioxidant capacity compared to coconut juice and nipah juice vinegars. Following acute and sub-chronic in vivo toxicity evaluation, no toxicity and mortality were evident and there were no significant differences in the serum biochemical profiles between mice administered the vinegars versus the control group. In the sub-chronic toxicity evaluation, the highest liver antioxidant levels were found in mice fed with pineapple juice vinegar, followed by coconut juice and nipah juice vinegars. However, compared to the pineapple juice and nipah juice vinegars, the mice fed with coconut juice vinegar, exhibited a higher population of CD4 + and CD8 + T-lymphocytes in the spleen, which was associated with greater levels of serum interleukin-2 and interferon-γ cytokines. Overall, the data suggested that not all vinegar samples cause acute and sub-chronic toxicity in vivo. Moreover, the in vivo immunity and organ antioxidant levels were enhanced, to varying extents, by the phenolic acids present in the vinegars. The results obtained in this study provide appropriate guidelines for further in vivo bioactivity studies and pre-clinical assessments of vinegar consumption. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Prevalence of interferon type I signature in CD14 monocytes of patients with Sjögren's syndrome and association with disease activity and BAFF gene expression

PubMed Central

Brkic, Zana; Maria, Naomi I; van Helden-Meeuwsen, Cornelia G; van de Merwe, Joop P; van Daele, Paul L; Dalm, Virgil A; Wildenberg, Manon E; Beumer, Wouter; Drexhage, Hemmo A; Versnel, Marjan A

2013-01-01

Objective To determine the prevalence of upregulation of interferon (IFN) type I inducible genes, the so called ‘IFN type I signature’, in CD14 monocytes in 69 patients with primary Sjögren's syndrome (pSS) and 44 healthy controls (HC) and correlate it with disease manifestations and expression of B cell activating factor (BAFF). Methods Expression of IFI44L, IFI44, IFIT3, LY6E and MX1 was measured using real time quantitative PCR in monocytes. Expression values were used to calculate IFN type I scores for each subject. pSS patients positive for the IFN type I signature (IFN score≥10) and patients negative for the signature (IFN score<10) were then compared for clinical disease manifestations and BAFF expression. A bioassay using a monocytic cell line was performed to study whether BAFF mRNA expression was inducible by IFN type I activity in serum of patients with pSS. Results An IFN type I signature was present in 55% of patients with pSS compared with 4.5% of HC. Patients with the IFN type I signature showed: (a) higher EULAR Sjögren's Syndrome Disease Activity Index scores; higher anti-Ro52, anti-Ro60 and anti-La autoantibodies; higher rheumatoid factor; higher serum IgG; lower C3, lower absolute lymphocyte and neutrophil counts; (b)higher BAFF gene expression in monocytes. In addition, serum of signature-positive patients induced BAFF gene expression in monocytes. Conclusions The monocyte IFN type I signature identifies a subgroup of patients with pSS with a higher clinical disease activity together with higher BAFF mRNA expression. Such patients might benefit from treatment blocking IFN type I production or activity. PMID:22736090

Cumulative Review of Thrombotic Microangiopathy, Thrombotic Thrombocytopenic Purpura, and Hemolytic Uremic Syndrome Reports with Subcutaneous Interferon β-1a.

PubMed

Ben-Amor, Ali-Frédéric; Trochanov, Anton; Fischer, Tanya Z

2015-05-01

Rare cases of thrombotic microangiopathy (TMA), manifested as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS), have been reported with interferon β products. We performed a cumulative review of TMA cases recorded in a Global Safety Database for patients with multiple sclerosis who received subcutaneous interferon β-1a treatment. Search criteria were: all reported cases, serious and non-serious, from all sources (including non-health care professionals and clinical trial reports), regardless of event ranking and causality assessment by reporter or company. Data lock was May 3, 2014, with additional analysis of cases reported between August 1, 2014-November 30, 2014. Ninety-one patient cases (76.9% female) with 105 events were retrieved. Time to onset varied from 2 months to 14 years, and in 31.9% of patients the event occurred within 2 years of treatment initiation. Seven patients had a fatal outcome (five were secondary to other causes and two reported insufficient information). Forty-four patients recovered, 32 patients had not recovered at the time of the report, and in eight cases outcome was either not reported or unknown. Treatment was discontinued in 84.6% (77/91) of patients. In 67% (61/91) of patients, the reporter suspected a causal association between treatment and TMA/TTP-HUS. Risk factors and/or confounding factors were present in 45.1% (41/91) of patients. Early prodromal syndrome or specific patterns were not detected, although 54.9% (50/91) of cases contained insufficient information. Overall reporting rate of TMA/TTP-HUS was estimated as 7.2 per 100,000 patient-years. Reporting rates for human serum album (HSA)-containing and HSA-free formulations were 5.72 and 7.68 per 100,000 patient-years, respectively. No new signal relating specifically to increased frequency of TMA/TTP-HUS with HSA-free subcutaneous interferon β-1a was detected and no additional risk mitigation measures are required regarding the different formulations. The benefit-risk balance of subcutaneous interferon β-1a remains positive, and routine pharmacovigilance monitoring is appropriate. Ares Trading SA, Aubonne, Switzerland, a subsidiary of Merck Serono SA.

INF-β1b therapy modulates L-arginine and nitric oxide metabolism in patients with relapse remittent multiple sclerosis.

PubMed

Stojanovic, Ivana; Vojinovic, Slobodan; Ljubisavljevic, Srdjan; Pavlovic, Radmila; Basic, Jelena; Pavlovic, Dusica; Ilic, Andjelka; Cvetkovic, Tatjana; Stukalov, Maja

2012-12-15

The scope of this study is the examination of NO(2)+NO(3), 3-nitrotyrosine (3-NT), S-nitrosothiols (RSNO), arginase activity and asymmetric (ADMA) and symmetric (SDMA) dimethyl-L-arginine concentrations in plasma of MS patients during interferon-β1b therapy. The study population included 15 (12 women, 3 men) untreated MS patients and 12 (10 women, 2 men) interferon-β1b treated MS patients with clinically definite relapsing MS (McDonalds criteria) for at least 1 year and a baseline EDSS score of 1.0 to 3.5 inclusive. Patients were treated with 250 μg IU interferon-β1b s.c. every second day during 30 months. The disease course was evaluated using correlations between baseline EDSS score and relapse rates in both groups. During interferon-β1b treatment, EDSS scores in treated patients were decreased compared to untreated ones - after 18 and 30 months (p<0.05). In interferon-β1b treated MS patients, NO(2)+NO(3), 3-NT and RSNO plasma concentrations were significantly lower (p<0.05), while arginase activity, ADMA and SDMA levels were significantly increased (p<0.05) during the therapy, compared to the baseline levels in treated patients. The investigated parameters may be the new biomarkers, providing information for the therapeutic approach and valuable in clinical monitoring. Copyright © 2012 Elsevier B.V. All rights reserved.

Antifibrotic mechanism of deferoxamine in concanavalin A induced-liver fibrosis: Impact on interferon therapy.

PubMed

Darwish, Samar F; El-Bakly, Wesam M; El-Naga, Reem N; Awad, Azza S; El-Demerdash, Ebtehal

2015-11-01

Iron-overload is a well-known factor of hepatotoxicity and liver fibrosis, which found to be a common finding among hepatitis C virus patients and related to interferon resistance. We aimed to elucidate the potential antifibrotic effect of deferoxamine; the main iron chelator, and its additional usefulness to interferon-based therapy in concanavalin A-induced immunological model of liver fibrosis. Rats were treated with deferoxamine and/or pegylated interferon-α for 6 weeks. Hepatotoxicity indices, oxidative stress, inflammatory and liver fibrosis markers were assessed. Concanavalin A induced a significant increase in hepatotoxicity indices and lipid peroxidation accompanied with a significant depletion of total antioxidant capacity, glutathione level and superoxide dismutase activity. Besides, it increased CD4(+) T-cells content and the downstream inflammatory cascades, including NF-κB, TNF-α, iNOS, COX-2, IL-6 and IFN-γ. Furthermore, α-SMA, TGF-β1 and hydroxyproline were increased markedly, which confirmed by histopathology. Treatment with either deferoxamine or pegylated interferon-α alone reduced liver fibrosis markers significantly and improved liver histology. However, some of the hepatotoxicity indices and oxidative stress markers did not improve upon pegylated interferon-α treatment alone, besides the remarkable increase in IL-6. Combination therapy of deferoxamine with pegylated interferon-α further improved all previous markers, ameliorated IL-6 elevation, as well as increased hepcidin expression. In conclusion, our study provides evidences for the potent antifibrotic effects of deferoxamine and the underlying mechanisms that involved attenuating oxidative stress and subsequent inflammatory cascade, as well as the production of profibrogenic factors. Addition of deferoxamine to interferon regimen for HCV patients may offer a promising adjuvant modality to enhance therapeutic response. Copyright © 2015 Elsevier Inc. All rights reserved.

IgE Inhibits Toll-like Receptor 7- and Toll-like Receptor 9-Mediated Expression of Interferon-α by Plasmacytoid Dendritic Cells in Patients With Systemic Lupus Erythematosus.

PubMed

Khoryati, Liliane; Augusto, Jean-François; Shipley, Emilie; Contin-Bordes, Cécile; Douchet, Isabelle; Mitrovic, Stéphane; Truchetet, Marie-Elise; Lazaro, Estibaliz; Duffau, Pierre; Couzi, Lionel; Jacquemin, Clément; Barnetche, Thomas; Vacher, Pierre; Schaeverbeke, Thierry; Blanco, Patrick; Richez, Christophe

2016-09-01

Plasmacytoid dendritic cells (PDCs) play a central role in pathogenesis of systemic lupus erythematosus (SLE) through their unique ability to produce large amounts of type I interferon (IFN) upon Toll-like receptor 7 (TLR-7) and TLR-9 triggering. PDCs express specific surface regulatory receptors involved in negative regulation of IFNα secretion. These receptors use the γ-chain of high-affinity Fc receptor (FcR) for IgE, FcɛRI. We undertook this study to test our hypothesis that IgE engagement of FcɛRI on PDCs may impact IFNα production in SLE patients. Serum levels of total IgE were measured in healthy volunteers, SLE patients, and patients with IgE-dependent allergic disorders. FcɛRI expression on PDCs from SLE patients was evaluated by flow cytometry. Purified PDCs were incubated with monoclonal IgE for 24 hours, then stimulated for 18 hours with TLR agonists or immune complexes (ICs). IFNα production by PDCs was detected by quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. Expression of TLR-7, TLR-9, and IFN regulatory factor 7 (IRF-7) in PDCs was quantified by quantitative real-time PCR. We observed significantly higher IgE levels in SLE patients with quiescent disease than in those with active disease. In SLE patients, IgE levels correlated inversely with disease activity. IgE levels were not associated with the presence of antinuclear IgE. Purified PDCs treated for 24 hours with monoclonal IgE up-regulated FcɛRI expression in an IgE dose-dependent manner. IgE-treated PDCs significantly decreased IFNα secretion and down-regulated CCR7 expression upon stimulation with TLR-7 and TLR-9 ligands and ICs from lupus patients. IgE treatment down-regulated expression of TLR-9 and IRF-7. Our results support the notion that IgE plays a protective role in SLE pathogenesis through the modulation of inflammatory response by PDCs. © 2016, American College of Rheumatology.

Soluble interleukin-18 receptor complex is a novel biomarker in rheumatoid arthritis

PubMed Central

2011-01-01

Introduction There has been no report in the literature of a soluble form of interleukin (IL)-18 receptor α (IL-18Rα). In this study, we evaluated the levels and characteristics of soluble IL-18Rα (sIL-18Rα) in the sera of patients with rheumatoid arthritis (RA) and compared these results to control populations. Methods The sIL-18Rα complex was isolated from pooled human blood serum using an anti-IL-18Rα monoclonal antibody affinity column. The purified sIL-18Rα was then examined using Western blot analysis and used in experiments to evaluate the effects on an IL-18-responsive natural killer (NK) human cell line, NK0. An enzyme-linked immunosorbent assay was developed, and sera from 145 patients with RA, 6 patients with adult-onset Still's disease, 31 patients with osteoarthritis (OA), 39 patients with systemic lupus erythematosus (SLE) and 67 controls were tested, along with levels of immunoglobulin M, rheumatoid factor, anticyclic citrullinated peptide antibody, IL-18, IL-13 and interferon (IFN)-γ. Area under the receiver operating characteristic curve (ROC-AUC) analysis was used to evaluate the diagnostic utility of the sIL-18Rα complex. Results The isolated sIL-18Rα complex can be associated with IL-18 and the soluble form of the IL-18Rβ chain. The sIL-18Rα complex bound to the surface to the NK0 cell line, antagonized the stimulatory effects of IL-18 and IL-2 on the NK0 cell line and inhibited IFN-γ production by the cells. The serum levels of sIL-18Rα complex in RA (186.0 ± 33.5 ng/mL, n = 145) and adult-onset Still's disease (98.2 ± 8.9 ng/mL, n = 6) were significantly (P < 0.001) higher than those in the healthy controls (52.3 ± 8.5 ng/mL, n = 67), OA (38.6 ± 5.4 ng/mL, n = 31), SLE (44.6 ± 3.2 ng/mL, n = 39). The serum level of sIL-18Rα complex was not significantly different between RA and adult-onset Still's disease patients. The serum levels of IL-18, IL-13 and IFN-γ in the RA patients were significantly (P < 0.01) higher than in OA and SLE patients as well as healthy controls. ROC-AUC analysis of the serum concentration of sIL-18Rα indicated that it was significantly diagnostic of RA. Moreover, a tumor necrosis factor inhibitor, etanercept, significantly (P < 0.0001) decreased levels of sIL-18Rα in the sera of 29 RA patients 6 months after treatment. Conclusions The sIL-18Rα complex could be a potentially useful biomarker for the diagnosis of RA. PMID:21435242

Probiotic Lactobacillus johnsonii BS15 Improves Blood Parameters Related to Immunity in Broilers Experimentally Infected with Subclinical Necrotic Enteritis

PubMed Central

Wang, Hesong; Ni, Xueqin; Qing, Xiaodan; Liu, Lei; Xin, Jinge; Luo, Min; Khalique, Abdul; Dan, Yan; Pan, Kangcheng; Jing, Bo; Zeng, Dong

2018-01-01

The probiotic strain Lactobacillus johnsonii BS15 could exert beneficial effects on growth performance, lipid metabolism, and intestinal microflora in healthy broilers and those afflicted with subclinical necrotic enteritis (SNE). In particular, BS15 prevents SNE by enhancing intestinal immunity. To further understand the immune regulatory mechanism of BS15, we evaluated its effects on the overall immunity of broilers by determining blood parameters in healthy and SNE broilers. In this study, two experiments were conducted. Experiment 1 involved a 42-day experimental period and used 450 1-day-old male chicks. The chicks were randomly divided into three groups and fed with a basal diet with or without 1 × 105 or 106 colony-forming units (cfu) BS15/g as feed. Experiment 2 involved a 28-day experimental period and used 180 1-day-old male chicks. The chicks were randomly allotted into three groups and given with or without 1 × 106 cfu BS15/g BS15 as feed. SNE infection was treated in all broilers, except in those in the normal diet group. Antioxidant abilities, immunoglobulins, and cytokines in the serum were assessed. T-lymphocyte subsets in peripheral blood were also determined. The first experiment demonstrated that BS15 enhanced the antioxidant abilities; the serum levels of immunoglobulins, interleukin-2, and interferon-gamma; and CD3+CD4+ T-lymphocyte percentage in peripheral blood on day 21. However, limited significant changes were observed on day 42. The second experiment revealed that BS15 supplementation positively influenced the antioxidant abilities and increased the serum levels of immunoglobulins and cytokines that were affected by SNE. BS15 also positively affected T-lymphocyte subsets in peripheral blood during SNE infection. These findings suggest that BS15 supplementation may prevent SNE in broilers by improving blood parameters related to immunity and enhancing intestinal immunity. Furthermore, BS15 supplementation can improve blood parameters in healthy broilers, especially at the starter phase. PMID:29441047

A novel role for adiponectin in regulating the immune responses in chronic hepatitis C virus infection.

PubMed

Palmer, Clovis; Hampartzoumian, Taline; Lloyd, Andrew; Zekry, Amany

2008-08-01

Adipose tissue releases pro-inflammatory and anti-inflammatory mediators, including adiponectin, which elicit a broad range of metabolic and immunological effects. The study aim was to determine in subjects infected with chronic hepatitis C virus (HCV) the effects of total adiponectin and its high-molecular-weight (HMW) and low-molecular-weight isoforms on HCV-specific immune responses. Serum levels of total adiponectin and its isoforms were determined by immunoassay. The ex vivo effect of adiponectin on the HCV-specific T-cell response was examined by interferon gamma (IFN-gamma) enzyme-linked immunosorbent spot and enzyme-linked immunosorbent assay cytokine assays. The role of the mitogen-activated protein kinase (MAPK) signaling pathway in mediating the adiponectin effect on T cells was also evaluated. We found that serum levels of total and HMW adiponectin were significantly decreased in subjects with chronic HCV and increased body mass index (BMI) compared with HCV-infected lean subjects. The presence of an anti-HCV specific immune response was strongly associated with lower BMI (P = 0.004) and higher serum total (P = 0.01) and HMW (P = 0.02) adiponectin. In ex vivo assays, total adiponectin and the HMW adiponectin isoform enhanced HCV-specific IFN-gamma production (P = 0.02 and 0.03, respectively). Adiponectin-R1 receptors were expressed on T cells and monocytes. In depletion experiments, the IFN-gamma response to adiponectin was entirely dependent on the simultaneous presence of both CD4 and CD8 T cells, and to a lesser extent, natural killer cells. Selective inhibition of p38MAPK activity by SB203580 abrogated the IFN-gamma response to adiponectin, whereas extracellular signal-regulated kinase 1/2 inhibition by PD98059 did not affect the response. In chronic HCV, a reciprocal association exists between BMI, adiponectin, and the anti-HCV immune responses, emphasizing the important role played by adiposity in regulating the immune response in HCV infection.

Probiotic Lactobacillus johnsonii BS15 Improves Blood Parameters Related to Immunity in Broilers Experimentally Infected with Subclinical Necrotic Enteritis.

PubMed

Wang, Hesong; Ni, Xueqin; Qing, Xiaodan; Liu, Lei; Xin, Jinge; Luo, Min; Khalique, Abdul; Dan, Yan; Pan, Kangcheng; Jing, Bo; Zeng, Dong

2018-01-01

The probiotic strain Lactobacillus johnsonii BS15 could exert beneficial effects on growth performance, lipid metabolism, and intestinal microflora in healthy broilers and those afflicted with subclinical necrotic enteritis (SNE). In particular, BS15 prevents SNE by enhancing intestinal immunity. To further understand the immune regulatory mechanism of BS15, we evaluated its effects on the overall immunity of broilers by determining blood parameters in healthy and SNE broilers. In this study, two experiments were conducted. Experiment 1 involved a 42-day experimental period and used 450 1-day-old male chicks. The chicks were randomly divided into three groups and fed with a basal diet with or without 1 × 10 5 or 10 6 colony-forming units (cfu) BS15/g as feed. Experiment 2 involved a 28-day experimental period and used 180 1-day-old male chicks. The chicks were randomly allotted into three groups and given with or without 1 × 10 6 cfu BS15/g BS15 as feed. SNE infection was treated in all broilers, except in those in the normal diet group. Antioxidant abilities, immunoglobulins, and cytokines in the serum were assessed. T-lymphocyte subsets in peripheral blood were also determined. The first experiment demonstrated that BS15 enhanced the antioxidant abilities; the serum levels of immunoglobulins, interleukin-2, and interferon-gamma; and CD3 + CD4 + T-lymphocyte percentage in peripheral blood on day 21. However, limited significant changes were observed on day 42. The second experiment revealed that BS15 supplementation positively influenced the antioxidant abilities and increased the serum levels of immunoglobulins and cytokines that were affected by SNE. BS15 also positively affected T-lymphocyte subsets in peripheral blood during SNE infection. These findings suggest that BS15 supplementation may prevent SNE in broilers by improving blood parameters related to immunity and enhancing intestinal immunity. Furthermore, BS15 supplementation can improve blood parameters in healthy broilers, especially at the starter phase.

Discriminatory potential of C-reactive protein, cytokines, and fecal markers in infectious gastroenteritis in adults.

PubMed

Weh, Julia; Antoni, Christoph; Weiß, Christel; Findeisen, Peter; Ebert, Matthias; Böcker, Ulrich

2013-09-01

This study evaluates potential markers in blood and stools for their ability to distinguish bacterial from viral gastroenteritis. A total of 108 patients were prospectively recruited, of which 27 showed bacterial, 30 viral, and 51 no detectable pathogen, respectively. Cytokines, C-reactive protein (CRP), and white blood cells as well as the 2 fecal markers lactoferrin and calprotectin were determined. Statistics comprised Kruskal-Wallis test and U test in addition to an assessment of receiver operating characteristic. Interferon γ (IFNγ) levels were significantly increased in the viral group compared to the bacterial and nonspecific group. For the bacterial group, both fecal markers lactoferrin and calprotectin as well as CRP were significantly higher in comparison to the other 2 groups. To differentiate between bacterial and viral gastroenteritis, CRP, serum IFNγ, and the fecal proteins lactoferrin and calprotectin may be useful. A corresponding algorithm should be evaluated prospectively. Copyright © 2013 Elsevier Inc. All rights reserved.

PASylation: a biological alternative to PEGylation for extending the plasma half-life of pharmaceutically active proteins

PubMed Central

Schlapschy, Martin; Binder, Uli; Börger, Claudia; Theobald, Ina; Wachinger, Klaus; Kisling, Sigrid; Haller, Dirk; Skerra, Arne

2013-01-01

A major limitation of biopharmaceutical proteins is their fast clearance from circulation via kidney filtration, which strongly hampers efficacy both in animal studies and in human therapy. We have developed conformationally disordered polypeptide chains with expanded hydrodynamic volume comprising the small residues Pro, Ala and Ser (PAS). PAS sequences are hydrophilic, uncharged biological polymers with biophysical properties very similar to poly-ethylene glycol (PEG), whose chemical conjugation to drugs is an established method for plasma half-life extension. In contrast, PAS polypeptides offer fusion to a therapeutic protein on the genetic level, permitting Escherichia coli production of fully active proteins and obviating in vitro coupling or modification steps. Furthermore, they are biodegradable, thus avoiding organ accumulation, while showing stability in serum and lacking toxicity or immunogenicity in mice. We demonstrate that PASylation bestows typical biologics, such as interferon, growth hormone or Fab fragments, with considerably prolonged circulation and boosts bioactivity in vivo. PMID:23754528

Nontuberculous mycobacterial infection with concurrent IgG4-related lymphadenopathy.

PubMed

Liu, Ting-Ting; Weng, Shao-Wen; Wang, Ming-Chung; Huang, Wan-Ting

2016-03-01

Disseminated nontuberculous mycobacteria (NTM) infection with concurrent IgG4-related lymphadenopathy has not been reported. We described a patient with neutralizing autoantibodies to interferon-gamma (IFN-γ) and elevated levels of serum IgG4 presenting with generalized lymphadenopathy and reactive dermatosis. Histologically, lymph nodes (LNs) showed effaced nodal architecture with polymorphic infiltrates, mimicking angioimmunoblastic T-cell lymphoma. Both the absolute number and the ratio of IgG4+ plasma cells to IgG+ plasma cells were increased. Mycobacterium abscessus was isolated from cultures of LNs, and demonstrated by polymerase chain reaction-restriction fragment length polymorphism. The skin biopsy showed neutrophilic dermatosis, consistent with Sweet syndrome. The patient met the criteria of both adult-onset immunodeficiency syndrome and IgG4-related lymphadenopathy. This case provides evidence of disseminated NTM infection with concurrent type III IgG4-related lymphadenopathy in the patient with anti-IFN-γ autoantibodies. © 2015 APMIS. Published by John Wiley & Sons Ltd.

Antibodies to the HIV-1 Tat protein correlated with nonprogression to AIDS: a rationale for the use of Tat toxoid as an HIV-1 vaccine.

PubMed

Zagury, J F; Sill, A; Blattner, W; Lachgar, A; Le Buanec, H; Richardson, M; Rappaport, J; Hendel, H; Bizzini, B; Gringeri, A; Carcagno, M; Criscuolo, M; Burny, A; Gallo, R C; Zagury, D

1998-01-01

To investigate which immune parameters, such as antibodies against HIV-1 specificities, or viral parameters, such as p24 antigenemia, are predictive of disease progression. We performed studies on serum collected from individuals exhibiting two extremes of disease evolution--67 fast progressors (FP) and 182 nonprogressors (NP)--at their enrollment. After a 1- to 2-year clinical follow-up of 104 nonprogressors after their enrollment, we could determine the best serologic predictors for disease progression. We investigated levels of antibodies to tetanus toxoid and to HIV antigens including Env, Gag, Nef, and Tat proteins, as well as p24 antigenemia, viremia, CD4 cell count, and interferon-alpha (IFN-alpha) titers in FPs and NPs, and we correlated these data with clinical and biologic signs of progression. p24 Antigenemia, a marker of viral replication, and anti-Tat antibodies were highly and inversely correlated in both groups (P < .001). Furthermore, anti-p24 antibodies and low serum IFN-alpha levels were correlated to the NP versus the FP cohort. Finally, among NPs, only antibodies to Tat and not to the other HIV specificities (Env, Nef, Gag) were significantly predictive of clinical stability during their follow-up. Antibodies toward HIV-1 Tat, which are inversely correlated to p24 antigenemia, appear as a critical marker for a lack of disease progression. This study strongly suggests that rising anti-Tat antibodies through active immunization may be beneficial in AIDS vaccine development to control viral replication.

Low-molecular-weight polysaccharides from Agaricus blazei Murrill modulate the Th1 response in cancer immunity.

PubMed

Jiang, Liyan; Yu, Zhipu; Lin, Yu; Cui, Liran; Yao, Shujuan; Lv, Liyan; Liu, Jicheng

2018-03-01

To assess the effect of low-molecular-weight polysaccharides from Agaricus blazei Murrill (ABP-AW1) as an immunoadjuvant therapy for type 1 T-helper (Th1) responses in tumorigenesis, C57BL/6 mice were inoculated subcutaneously with ovalbumin (E.G7-OVA). After 3, 10 and 17 days, the mice were immunized with PBS, OVA alone, or OVA and ABP-AW1, at low (50 µg), intermediate (100 µg) or high (200 µg) doses. Tumor growth was examined and compared among the groups, as were the following parameters: Splenocyte viability/proliferation, peripheral blood CD4 + /CD8 + T cell ratio, serum OVA-specific IgG1 and IgG2b, secretion of interleukin (IL)-2 and interferon (IFN)-γ, and IFN-γ production on a single cell level from cultured splenocytes. Tumor growth in mice treated with OVA and ABP-AW1 (100 or 200 µg) was significantly slower, compared with in the other groups at the same time-points. OVA with 100 or 200 µg ABP-AW1 was associated with a higher number of total splenocytes, a higher ratio of peripheral blood CD4 + /CD8 + T-lymphocytes, higher serum levels of OVA-specific Th1-type antibody IgG2b and greater secretion of the Th1 cytokines IL-1 and IFN-γ from splenocytes. ABP-AW1 is a promising immunoadjuvant therapy candidate, due to its ability to boost the Th1 immune response when co-administered with a cancer vaccine intended to inhibit cancer progression.

Low-molecular-weight polysaccharides from Agaricus blazei Murrill modulate the Th1 response in cancer immunity

PubMed Central

Jiang, Liyan; Yu, Zhipu; Lin, Yu; Cui, Liran; Yao, Shujuan; Lv, Liyan; Liu, Jicheng

2018-01-01

To assess the effect of low-molecular-weight polysaccharides from Agaricus blazei Murrill (ABP-AW1) as an immunoadjuvant therapy for type 1 T-helper (Th1) responses in tumorigenesis, C57BL/6 mice were inoculated subcutaneously with ovalbumin (E.G7-OVA). After 3, 10 and 17 days, the mice were immunized with PBS, OVA alone, or OVA and ABP-AW1, at low (50 µg), intermediate (100 µg) or high (200 µg) doses. Tumor growth was examined and compared among the groups, as were the following parameters: Splenocyte viability/proliferation, peripheral blood CD4+/CD8+ T cell ratio, serum OVA-specific IgG1 and IgG2b, secretion of interleukin (IL)-2 and interferon (IFN)-γ, and IFN-γ production on a single cell level from cultured splenocytes. Tumor growth in mice treated with OVA and ABP-AW1 (100 or 200 µg) was significantly slower, compared with in the other groups at the same time-points. OVA with 100 or 200 µg ABP-AW1 was associated with a higher number of total splenocytes, a higher ratio of peripheral blood CD4+/CD8+ T-lymphocytes, higher serum levels of OVA-specific Th1-type antibody IgG2b and greater secretion of the Th1 cytokines IL-1 and IFN-γ from splenocytes. ABP-AW1 is a promising immunoadjuvant therapy candidate, due to its ability to boost the Th1 immune response when co-administered with a cancer vaccine intended to inhibit cancer progression. PMID:29467867

The frequency of hypothyroidism and its relationship with HCV positivity in patients with thalassemia major in southern Iran.

PubMed

Haghpanah, Sezaneh; Jelodari, Shohreh; Karamifar, Hammdollah; Saki, Forough; Rahimi, Rahil; De Sanctis, Vincenzo; Dehbozorgian, Javad; Karimi, Mehran

2018-03-27

Hypothyroidism is one the most complication due to iron overload in patients with β-thalassemia major (TM). On the other hand these patients are prone to Hepatitis C virus (HCV) infection that can cause  thyroid dysfunction by itself or as the side effect of treatment with interferon (INF) or IFN plus ribavirin. The aim of this study is to evaluate the association of hypothyroidism with HCV positivity and serum ferritin levels in patients with TM. In this cross-sectional study, 201 randomly selected patients with TM who were registered at the Thalassemia Clinic of a tertiary hospital in Shiraz, southern Iran were investigated. Thyroid function tests and serologic screening assays for HCV seropositivity (HCV Ab and HCV-RNA) were conducted for all patients. Frequency of hypothyroidism was 22.9% including 19.9% subclinical hypothyroidism, 2% primary overt hypothyroidism and 1% central hypothyroidism. Eighty six patients (42.8%) were HCV Ab positive and 60 patients (29.9%) were HCV RNA positive. No significant relationship was found between hypothyroidism and HCV positivity or receiving IFN-α (P>0.05). Hypothyroidism showed a borderline significant association with high serum ferritin levels in TM patients (P=0.055). Our results showed no significant association between hypothyroidism and HCV infection in TM patients. It seems that the main mechanism of hypothyroidism in our patients is iron overload; however, for better evaluation a larger multicenter study is recommended.  Also due to the importance of consequences of HCV infection, more careful pre-transfusional screening of blood should be considered in TM patients.

Lowered serum dipeptidyl peptidase IV activity is associated with depressive symptoms and cytokine production in cancer patients receiving interleukin-2-based immunotherapy.

PubMed

Maes, M; Capuron, L; Ravaud, A; Gualde, N; Bosmans, E; Egyed, B; Dantzer, R; Neveu, P J

2001-02-01

There is some evidence that treatment with interleukin-2 (IL-2) and interferon-alpha (IFNalpha) frequently induces depressive symptoms and activation of the inflammatory response system (IRS). There is evidence that major depression is accompanied by lowered serum activity of dipeptidyl peptidase IV (DPP IV; EC 3.4.14.5), a membrane-bound serine protease which catalyses the cleavage of some cytokines and neuro-active peptides and which modulates T cell activation and the production of cytokines, such as IL-2. This study was carried out to examine the effects of immunochemotherapy with IL-2 and IFNalpha, alone and together, in cancer patients on serum DPP IV activity in relation to changes in depressive symptoms and the IRS. The Montgomery and Asberg Rating Scale (MADRS), serum DPP IV activity, and the serum IL-6, and IL-2 receptor (IL-2R) concentrations were measured in 26 patients with metastatic cancers before and three and five days after treatment with IL-2 and IFNalpha, alone or together. Treatment with IL-2 with or without IFNalpha significantly suppressed serum DPP IV activity. The MADRS scores were significantly elevated by treatment with IL-2 with or without IFNalpha, but not IFNalpha alone. The immunochemotherapy-induced decreases in serum DPP IV were significantly and inversely correlated with the increases in the MADRS. Treatment with IL-2 alone or combined with IFNalpha also elevated serum IL-6 and IL-2R. There were significant and inverse correlations between the immuchemotherapy-induced decreases in serum DPP IV and the elevations in serum IL-6 or IL-2R. In conclusion, treatment with IL-2/IFNalpha decreases serum DPP IV activity within 3-5 days and the immunochemotherapy-induced decreases in serum DPP IV activity are significantly and inversely related to treatment-induced increases in severity of depression and signs of activation of the IRS.

Hepatitis C virus (HCV) RNA level determined by second-generation branched-DNA probe assay as predictor of response to interferon treatment in patients with chronic HCV viremia.

PubMed

Furusyo, Norihiro; Hayashi, Jun; Kashiwagi, Kenichiro; Nakashima, Hisashi; Nabeshima, Shigeki; Sawayama, Yasunori; Kinukawa, Naoko; Kashiwagi, Seizaburo

2002-03-01

Using first- and second-generation branched-DNA probe assays (1st- and 2nd-bDNA), we investigated the predictors of favorable clinical response to interferon (IFN) treatment in patients with chronic HCV viremia. A total of 122 patients (85 genotype lb and 37 genotype 2a) with chronic HCV viremia received 24-week IFN-alpha treatment. Patients with sustained clearance of serum HCV RNA by polymerase chain reaction at six months after IFN treatment were defined as having a sustained response (SR). HCV RNA level was determined by 1st- and 2nd-bDNA assays prior to treatment. Mean HCV RNA level by 1st-bDNA was significantly higher in genotype lb patients [5.4 x 10(6) HCV genome equivalent (Meq)/ ml] than in genotype 2a patients (0.9 Meq/ml) (P < 0.05). There was no significant difference between patients with these genotypes in the level by 2nd-bDNA (1b: 5.2 Meq/ml and 2a: 3.1 Meq/ml). SR was achieved by 43 (35.2%) of 122 patients. Mean HCV RNA levels by both the 1st- and 2nd-bDNA of SR patients (1.0 and 1.9 Meq/ml) were significantly lower than those of non-SR patients (5.3 and 6.0 Meq/ml) (both P < 0.05). The SR rate in genotype 2a patients (59.5%) was significant higher than in genotype lb patients (24.7%) (P < 0.05). Stepwise logistic regression analysis showed that HCV RNA level < or = 1.0 Meq/ml by 2nd-bDNA (odds ratio = 7.6, compared to level > 1.0 Meq/ml, P < 0.05) was a significant predictive cutoff for SR. Using 2nd-bDNA, a significantly higher rate of SR was found in genotype lb patients with level < or = 1.0 Meq/ml (57.6%) than in those with level > 1.0 Meq/ml (3.8%) (P < 0.05). The SR rate of genotype 2a patients with level >1.0 Meq/ml (68.6%) was somewhat higher than for those with level < or = 1.0 Meq/ml (52.4%). These findings suggested that, using 2nd-bDNA, a low HCV RNA level of < or = 1.0 Meq/ml was the most favorable marker of successful IFN treatment and that patients with genotype 2a, even those with level >1.0 Meq/ml, had a high rate of SR to IFN treatment.

[Spleen, liver and kidney-strengthening formula combined with polyethylene glycol interferon in treatment of chronic hepatitis B].

PubMed

Chen, Wei

2016-02-01

To observe the clinical efficacy of spleen, liver and kidney-strengthening formula combined with polyethylene glycol interferon in the treatment of HBeAg positive chronic hepatitis B(HP-HBV).One hundred and twenty-six patients with HP-HBV, who were treated in the hospital from June 2012 to December 2014, were selected and injected with polyethylene glycol interferon α-2a(or α-2b). The treatment course for the patients lasted for 24 weeks. Base on the level of HBV-DNA, patients are divided into response group and poor response group. According to random number table, the poor response group were randomized into control group and test group. Patients in the control group were injected with polyethylene glycol interferon α-2a(or α-2b), and patients in the test group were treated with spleen, liver and kidney-strengthening formula combined with polyethylene glycol interferon. Clinical efficacies of the 2 groups were observed, and changes in the level of HBeAg, ALT and HBV-DNA were observed before treatment and at the 24th week after treatment, and virological and serological response, biochemical responses, integral clinical symptoms and signs, adverse reactions were observed after 48 weeks of treatment.After 24 weeks of treatment, the response group was significantly better than the poor response group in HBeAg, ALT and the level of HBV-DNA(P<0.05). After 48 weeks of treatment, there was statistical significance in HBV-DNA negative conversion rate, HBeAg negative conversion rate between the 2 groups(P<0.05), and the test group was better in the two indicators. And the test group was significantly lower than the control group in clinical symptoms and signs score at the 48th week after treatment(P<0.05), with a significantly lower adverse reaction rate than the control group(P<0.05).Combination of spleen, liver and kidney-strengthening formula and polyethylene glycol interferon α-2a was effective and safe in the treatment of chronic hepatitis B, and so worth promoting in clinic. Copyright© by the Chinese Pharmaceutical Association.

Lead exposure and increased food allergic sensitization in U.S. children and adults.

PubMed

Mener, David J; Garcia-Esquinas, Esther; Navas-Acien, Ana; Dietert, Rodney R; Shargorodsky, Josef; Lin, Sandra Y

2015-03-01

Whether blood lead levels are associated with sensitization to food allergens in adults and children is unclear. Prior studies have shown that exposure to lead is associated with atopic sensitization and modulation of several cytokines (eg, interleukin [IL]-12, IL-10, interferon [IFN]-γ, and IL-4 production) and with T-cell dysregulation and bias toward T helper 2 (Th2) activity. The objective of this work was to assess whether exposure to lead is independently associated with allergic symptoms and sensitizations in a large nationally representative sample of children and adults. We studied 2712 children and 4333 adults enrolled in the 2005-2006 cycle of the National Health and Nutritional Examination Surveys (NHANES). Participants were tested for serum-specific immunoglobulin E (IgE) levels to food allergens as well as blood lead levels. Food allergens tested included shrimp, egg, peanut, and milk. Logistic regression models adjusted for demographic factors, body mass index, history of asthma, smoking, housing characteristics, and current exposure to animals in the home, to assess the association of blood lead levels with sensitization to food allergens. Median (interquartile range [IQR]) for serum blood was 0.87 μg/L (0.61 to 1.31) in children and 1.48 μg/L (0.92 to 2.34) in adults. At baseline, 672 (24.7%) of children participants and 719 (16.6%) of adult participants tested positive for increased sensitization to food allergens. A 2-fold increase in blood lead levels in adult participants was associated with increased sensitization to food allergens (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.02 to 1.22). Blood lead was not associated with sensitization to food allergens among pediatric participants (OR, 0.95; 95% CI, 0.82 to 1.10). Exposure to lead was associated with increased odds of sensitization to food allergens in adult but not children participants. © 2014 ARS-AAOA, LLC.

Cytokine levels (IL-4, IL-6, IL-8 and TGFβ) as potential biomarkers of systemic inflammatory response in trauma patients.

PubMed

Volpin, Gershon; Cohen, Miri; Assaf, Michael; Meir, Tamar; Katz, Rina; Pollack, Shimon

2014-06-01

Much research is now being conducted in order to understand the role of cytokines in the development of the inflammatory response following trauma. The purpose of this study was to evaluate whether serum levels of certain cytokines, measured immediately after initial injury, can be used as potential biomarkers for predicting the development and the degree of severity of the systemic inflammatory response (SIRS) in patients with moderate and severe trauma. We conducted a prospective study with 71 individuals of whom 13 (18.3 %) were healthy controls and 58 (81.7 %) were traumatized orthopaedic patients who were categorized into two groups: 31 (43.6 %) with moderate injuries and 27 (38.1 %) patients with severe orthopaedic trauma. Thirty cc of heparinized blood were drawn from each individual within a few hours after the injury. Serum levels of pro-inflammatory, regulatory and anti-inflammatory cytokines were measured in each individual participant. High levels of pro-inflammatory cytokines IL-1β,-6,-8,-12, tumour necrosis factor alpha and interferon gamma were found in all injured patients compared to healthy controls. Only IL-6 and IL-8 were significantly higher in the injured patients. Levels of the regulatory cytokines, transformed growth factor beta (TGF-β) and IL-10 were higher in the injured patients, but significant only for TGF-β. Levels of IL-4 were significantly lower in the injured groups as compared to the controls. Secretion of large amounts of pro-inflammatory cytokines and decreased level of anti-inflammatory cytokines during the acute phase of trauma may lead to the development of systemic inflammatory response syndrome (SIRS) in unstable polytraumatized patients. SIRS may result in life threatening conditions as acute respiratory distress syndrome (ARDS) and multiple organ failure (MOF). High levels of IL-6, IL-8, TGFβ and low levels of IL-4 were found to be reliable markers for the existence of immune reactivity in trauma patients. More research is needed to study pattern of cytokine levels along the acute period of injury, after surgical interventions and during recovery.

Genetic manipulation of the ApoF/Stat2 locus supports an important role for type I interferon signaling in atherosclerosis.

PubMed

Lagor, William R; Fields, David W; Bauer, Robert C; Crawford, Alison; Abt, Michael C; Artis, David; Wherry, E John; Rader, Daniel J

2014-03-01

Apolipoprotein F (ApoF) is a sialoglycoprotein that is a component of the HDL and LDL fractions of human serum. We sought to test the hypothesis that ApoF plays an important role in atherosclerosis in mice by modulating lipoprotein function. Atherosclerosis was assessed in male low density lipoprotein receptor knockout (Ldlr KO) and ApoF/Ldlr double knockout (DKO) mice fed a Western diet for 16 weeks. ApoF/Ldlr DKO mice showed a 39% reduction in lesional area by en face analysis of aortas (p < 0.05), despite no significant differences in plasma lipid parameters. ApoF KO mice had reduced expression of Interferon alpha (IFNα) responsive genes in liver and spleen, as well as impaired macrophage activation. Interferon alpha induced gene 27 like 2a (Ifi27l2a), Oligoadenylate synthetases 2 and 3 (Oas2 and Oas3) were significantly reduced in the ApoF KO mice relative to wild type controls. These effects were attributable to hypomorphic expression of Stat2 in the ApoF KO mice, a critical gene in the Type I IFN pathway that is situated just 425 base pairs downstream of ApoF. These studies implicate STAT2 as a potentially important player in atherosclerosis, and support the growing evidence that the Type I IFN pathway may contribute to this complex disease. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Recombinant interferon-gamma secreted by Chinese hamster ovary-320 cells cultivated in suspension in protein-free media is protected against extracellular proteolysis by the expression of natural protease inhibitors and by the addition of plant protein hydrolysates to the culture medium.

PubMed

Mols, J; Peeters-Joris, C; Wattiez, R; Agathos, S N; Schneider, Y-J

2005-01-01

Biosafety requirements increasingly restrict the cultivation of mammalian cells producing therapeutic glycoproteins to conditions that are devoid of any compound of animal origin. On cultivation in serum-free media, the proteases inhibitors, usually found in serum, cannot protect secreted recombinant proteins against unwanted endogenous proteolysis. Chinese hamster ovary (CHO) cells, secreting recombinant human interferon-gamma (CHO-320 cell line) and cultivated in suspension in an original protein-free medium, expressed at least two members of the matrix metalloproteinases (MMP), either at the cell surface (proMMP-14 and MMP-14) or secreted (proMMP-9). In addition, tissue- and urinary-type plasminogen activators were also secreted in such culture conditions. At the cell surface, dipeptidyl peptidase IV and tripeptidyl peptidase II (TPPII) activities were also detected, and their activities decreased during time course of batch cultures. The proteolytic activities of these proteins were counterbalanced by (1) their expression as zymogens (proMMP-9, proMMP-14), (2) the expression of their natural inhibitors, tissue inhibitors of metalloproteinases-1 and -2 and plasminogen activator inhibitor-1 (PAI-1), or (3) the addition of plant protein hydrolysates to the culture medium, acting as a nonspecific source of TPPII inhibitors. This study points out that, even in protein-free media, recombinant proteins secreted by CHO cells are actively protected against physiological and unwanted extracellular proteolysis either by endogenous or by exogenous inhibitors.

Dietary Supplementation of Phoenix dactylifera Seeds Enhances Performance, Immune Response, and Antioxidant Status in Broilers.

PubMed

El-Far, Ali H; Ahmed, Hamada A; Shaheen, Hazem M

2016-01-01

The date palm ( Phoenix dactylifera ) seeds were utilized in some traditional medical remedies and have been investigated for their possible health benefits. This proposed study wanted to assess the effect of date palm seeds (DPS) dietary supplementation in comparison to mannan-oligosaccharides (Bio-Mos®) and β -glucan over antioxidant and immunity events that have effect on growth and carcass performances of broilers. An aggregate of 180, one-day-old, chicks were raised in the wire-floored cages and allotted into control, Bio-Mos (0.1%  Bio-Mos), β -glucan (0.1%   β -glucan), DPS2 (2% date crushed seeds), DPS4 (4% date crushed seeds), and DPS6 (6% date crushed seeds) groups. Broilers in DPS2 and DPS4 groups showed significant variations ( P < 0.05) in relative growth rate (RGR), feed conversion ratio (FCR), and efficiency of energy utilization in comparison to control group. Moreover, all DPS fed groups showed significant increases ( P < 0.05) in serum reduced glutathione (GSH) values. Meanwhile, both serum interferon-gamma (IFN- γ ) and interleukin-2 (IL-2) levels were significantly increased ( P < 0.05) in DPS2. Consequently, obtained data revealed a substantial enhancement of performance, immunity, and antioxidant status by DPS supplementation in broiler that might be related to the antioxidant and immune-stimulant constituents of P. dactylifera seeds.

Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever.

PubMed

Blohmke, Christoph J; Darton, Thomas C; Jones, Claire; Suarez, Nicolas M; Waddington, Claire S; Angus, Brian; Zhou, Liqing; Hill, Jennifer; Clare, Simon; Kane, Leanne; Mukhopadhyay, Subhankar; Schreiber, Fernanda; Duque-Correa, Maria A; Wright, James C; Roumeliotis, Theodoros I; Yu, Lu; Choudhary, Jyoti S; Mejias, Asuncion; Ramilo, Octavio; Shanyinde, Milensu; Sztein, Marcelo B; Kingsley, Robert A; Lockhart, Stephen; Levine, Myron M; Lynn, David J; Dougan, Gordon; Pollard, Andrew J

2016-05-30

Enteric fever, caused by Salmonella enterica serovar Typhi, is an important public health problem in resource-limited settings and, despite decades of research, human responses to the infection are poorly understood. In 41 healthy adults experimentally infected with wild-type S. Typhi, we detected significant cytokine responses within 12 h of bacterial ingestion. These early responses did not correlate with subsequent clinical disease outcomes and likely indicate initial host-pathogen interactions in the gut mucosa. In participants developing enteric fever after oral infection, marked transcriptional and cytokine responses during acute disease reflected dominant type I/II interferon signatures, which were significantly associated with bacteremia. Using a murine and macrophage infection model, we validated the pivotal role of this response in the expression of proteins of the host tryptophan metabolism during Salmonella infection. Corresponding alterations in tryptophan catabolites with immunomodulatory properties in serum of participants with typhoid fever confirmed the activity of this pathway, and implicate a central role of host tryptophan metabolism in the pathogenesis of typhoid fever. © 2016 Blohmke et al.

Interferon-driven alterations of the host’s amino acid metabolism in the pathogenesis of typhoid fever

PubMed Central

Jones, Claire; Waddington, Claire S.; Zhou, Liqing; Hill, Jennifer; Clare, Simon; Mukhopadhyay, Subhankar; Schreiber, Fernanda; Roumeliotis, Theodoros I.; Yu, Lu; Ramilo, Octavio; Sztein, Marcelo B.; Kingsley, Robert A.; Levine, Myron M.

2016-01-01

Enteric fever, caused by Salmonella enterica serovar Typhi, is an important public health problem in resource-limited settings and, despite decades of research, human responses to the infection are poorly understood. In 41 healthy adults experimentally infected with wild-type S. Typhi, we detected significant cytokine responses within 12 h of bacterial ingestion. These early responses did not correlate with subsequent clinical disease outcomes and likely indicate initial host–pathogen interactions in the gut mucosa. In participants developing enteric fever after oral infection, marked transcriptional and cytokine responses during acute disease reflected dominant type I/II interferon signatures, which were significantly associated with bacteremia. Using a murine and macrophage infection model, we validated the pivotal role of this response in the expression of proteins of the host tryptophan metabolism during Salmonella infection. Corresponding alterations in tryptophan catabolites with immunomodulatory properties in serum of participants with typhoid fever confirmed the activity of this pathway, and implicate a central role of host tryptophan metabolism in the pathogenesis of typhoid fever. PMID:27217537

Effects of combined treatment with interferon and mezerein on melanogenesis and growth in human melanoma cells.

PubMed

Fisher, P B; Prignoli, D R; Hermo, H; Weinstein, I B; Pestka, S

1985-01-01

We have analyzed the effects of various human interferons produced in bacteria and the antileukemic compound mezerein (MEZ) on growth and melanogenesis in human melanoma cells. In four human melanoma cell lines, recombinant human fibroblast interferon (IFN-beta) was more active than recombinant human leukocyte interferons (IFN-alpha A, IFN-alpha D, or IFN-alpha A/D (Bgl] in inhibiting cellular proliferation. When monolayer cultures were exposed to 1000 IU/ml IFN-beta for four days the degree of growth inhibition in the different melanoma cell lines varied between 94 and 26%. Similarly, four days growth in medium containing 10 ng/ml MEZ resulted in either no inhibition of growth or as much as 53% inhibition of growth, depending on the specific melanoma cell line tested. MEZ induced dendrite-like processes, cytoplasmic projections morphologically similar to those normally found in neurons and melanocytes, in all four melanoma cell lines, whereas none of the interferons tested had this effect. The combination of interferon and MEZ resulted in a dramatic inhibition in cellular proliferation in all four melanoma cell lines. When cell extracts were assayed for melanin content, a marker of melanoma cell differentiation, the combination of IFN-beta and MEZ resulted in higher levels of melanin than with either agent alone. Dendrite-like formation was also prominent in the cultures treated with this combination. These results indicate that the antiproliferative effect of interferon toward human melanoma dells can be enhanced by treatment with MEZ and that this effect is associated with an enhancement of terminal differentiation.

Effects of night shift working on some immunological, prostate specific antigen, cortisol level and malondialdehyde in male nurses at Hawler city

NASA Astrophysics Data System (ADS)

Muhammad, Dilshad Hussein; Qadir, Fikry Ali

2017-09-01

The present study was carried out to show the effects of nightshift working on some immunological, serum cortisol level, and malondialdehyde (MDA) on male nurses in Hawler city hospitals. After performing the exclusion and inclusion criteria, ninety-six male nurses were participated in this study. According to working shifts, the participants were divided into two groups. First group includes sixty seven night-shift male nurses working for 3-12 years with 8-10 nights/month. The second group consisted of twenty-nine day-shift male nurses working for 3-12 years. The age range of both groups was (≥20-40≤). The second group was used as a control group for statistical comparison. The results showed that night-shift working in male nurses was associated with significant increases in tumor necrosis factor-α (TNF-α) (77.15 ± 3.328 vs.101.1 ± 6.968, p=0.024), interleukin-2 (IL-2) (1147 ± 59.54vs1626 ± 34.71, p=0.001), and interferon-γ (IFN-γ) (272.3 ± 16.00 vs. 319.6 ± 12.48, p=0.029) when compared with day-shift group. Two-fold significant increase of high-sensitive C-reactive protein (hs-CRP) (3154 ± 403.3 vs. 6739 ± 334.0, p=0.001) was found in nightshift group as compared with day-shift group. Prostate specific antigen (PSA) estimation showed no significant increase in night-shift group in comparison with day-shift group (1.755 ± 0.202 vs. 1.987 ± 0.159, p=0.424). The results also showed that night-shift working was associated with significant elevations in serum cortisol levels when compared with dayshift nurses (7.844 ± 0.529 vs. 11.18 ± 0.406, p=0.001). Similar significant increasing was also observed for serum malondialdehyde (MDA) (1.124 ± 0.075 vs. 1.681 ± 0.079, p=0.001) in night-shift group when compared with day-shift group.

Interferon production and signaling pathways are antagonized during henipavirus infection of fruit bat cell lines.

PubMed

Virtue, Elena R; Marsh, Glenn A; Baker, Michelle L; Wang, Lin-Fa

2011-01-01

Bats are natural reservoirs for a spectrum of infectious zoonotic diseases including the recently emerged henipaviruses (Hendra and Nipah viruses). Henipaviruses have been observed both naturally and experimentally to cause serious and often fatal disease in many different mammal species, including humans. Interestingly, infection of the flying fox with henipaviruses occurs in the absence of clinical disease. The extreme variation in the disease pattern between humans and bats has led to an investigation into the effects of henipavirus infection on the innate immune response in bat cell lines. We report that henipavirus infection does not result in the induction of interferon expression, and the viruses also inhibit interferon signaling. We also confirm that the interferon production and signaling block in bat cells is not due to differing viral protein expression levels between human and bat hosts. This information, in addition to the known lack of clinical signs in bats following henipavirus infection, suggests that bats control henipavirus infection by an as yet unidentified mechanism, not via the interferon response. This is the first report of henipavirus infection in bat cells specifically investigating aspects of the innate immune system.

An open-label, multicenter study to evaluate the safe and effective use of the single-use autoinjector with an Avonex® prefilled syringe in multiple sclerosis subjects

PubMed Central

2011-01-01

Background The ability to self-inject in patients with multiple sclerosis (MS) has been associated with a reduced risk of missed injections and drug discontinuation, and a beneficial effect on patients' independence. However, injection anxiety, needle phobia and disease-related disability are major barriers to a patient's ability to self-administer treatment. Use of an autoinjector may improve patients' ability to self-inject. This study evaluated the safe and effective use of Avonex Pen™ (prefilled pen), a single use autoinjector, for intramuscular delivery of interferon beta-1a (IM IFNβ-1a, Avonex) in MS patients. Methods This was a Phase IIIb, open-label, single-country, multicenter trial in MS patients currently using IM IFNβ-1a prefilled syringes. Patients received weekly 30 mcg IM IFNβ-1a treatment over 4 weeks. On Day 1, patients self-administered IM IFNβ-1a using a prefilled syringe at the clinic. On Day 8, patients received training on the prefilled pen and self-administered IM IFNβ-1a using the device. On Day 15, patients self-administered IM IFNβ-1a at home using the prefilled pen. A final injection occurred at the clinic on Day 22 when patients self-administered IM IFNβ-1a using the prefilled pen while clinic staff observed and completed a detailed questionnaire documenting patients' ability to self-inject with the device. Serum neopterin levels were evaluated pre and post-injection on Days 1 and 8. Adverse events were monitored throughout. Results Seventy-one (96%) patients completed the study. The overall success rate in safely and effectively using the prefilled pen was 89%. No device malfunctions occurred. One unsuccessful administration occurred at Day 22 due to patient error; no patient injury resulted. Patients gave the prefilled pen high ratings (8.7-9.3) on a 10-point scale for ease of use (0 = extremely difficult, 10 = extremely easy). Ninety-four percent of patients preferred the prefilled pen over the prefilled syringe. Induction of serum neopterin levels, serving as a biomarker for type 1 interferon action, was similar to that of the prefilled syringe. The prefilled pen demonstrated a safety profile comparable to the prefilled syringe. Conclusions The prefilled pen is a safe and effective device for administration of IM IFNβ-1a and represents an alternative method for self-injection for MS patients using this therapy. Trial registration This study is registered at clinicaltrials.gov, identifier: NCT00828204 PMID:21999176

Serum adiposity-induced biomarkers in obese and lean children with recently diagnosed autoimmune type 1 diabetes.

PubMed

Redondo, M J; Rodriguez, L M; Haymond, M W; Hampe, C S; Smith, E O; Balasubramanyam, A; Devaraj, S

2014-12-01

Obesity increases the risk of cardiovascular disease and diabetic complications in type 1 diabetes. Adipokines, which regulate obesity-induced inflammation, may contribute to this association. We compared serum adipokines and inflammatory cytokines in obese and lean children with new-onset autoimmune type 1 diabetes. We prospectively studied 32 lean and 18 obese children (age range: 2-18 yr) with new-onset autoimmune type 1 diabetes and followed them for up to 2 yr. Serum adipokines [leptin, total and high molecular weight (HMW) adiponectin, omentin, resistin, chemerin, visfatin], cytokines [interferon (IFN)-gamma, interleukin (IL)-10, IL-12, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha] and C-reactive protein (CRP) were measured at a median of 7 wk after diagnosis (range: 3-16 wk). Lean children were 71.9% non-Hispanic White, 21.9% Hispanic, and 6.3% African-American, compared with 27.8, 55.6, and 16.7%, respectively, for obese children (p = 0.01). Compared with lean children, obese children had significantly higher serum leptin, visfatin, chemerin, TNF-alpha and CRP, and lower total adiponectin and omentin after adjustment for race/ethnicity and Tanner stage. African-American race was independently associated with higher leptin among youth ≥10 yr (p = 0.007). Leptin levels at onset positively correlated with hemoglobin A1c after 1-2 yr (p = 0.0001) independently of body mass index, race/ethnicity, and diabetes duration. Higher TNF-alpha was associated with obesity and female gender, after adjustment for race/ethnicity (p = 0.0003). Obese children with new-onset autoimmune type 1 diabetes have a proinflammatory profile of circulating adipokines and cytokines that may contribute to the development of cardiovascular disease and diabetic complications. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Spirulina lipopolysaccharides inhibit tumor growth in a Toll-like receptor 4-dependent manner by altering the cytokine milieu from interleukin-17/interleukin-23 to interferon-γ

PubMed Central

Okuyama, Hiromi; Tominaga, Akira; Fukuoka, Satoshi; Taguchi, Takahiro; Kusumoto, Yutaka; Ono, Shiro

2017-01-01

Th17 cells and the cytokine they produce, interleukin (IL)-17, play an important role in tumor progression in humans and in mice. IL-6 and IL-23 are critical cytokines for the differentiation and propagation of Th17 cells, respectively. Bacterial lipopolysaccharides (LPS) are known to stimulate immune cells to produce such inflammatory cytokines. Contrary to Escherichia coli (E. coli) LPS, LPS from Spirulina has low toxicity and barely induces in vivo production of IL-6 and IL-23 in mice. We examined the antitumor effects of Spirulina LPS compared to E. coli LPS in an MH134 hepatoma model. Administration of Spirulina LPS suppressed tumor growth in C3H/HeN mice, but not in Toll-like receptor 4 (TLR4)-mutant C3H/HeJ mice, by reducing serum levels of IL-17 and IL-23, while increasing interferon (IFN)-γ levels. The antitumor activity and IFN-γ production were mediated by T cells. Moreover, in vitro experiments showed that Spirulina LPS impaired the antigen-presenting function that supports the generation of IL-17-producing cells in a toll-like receptor (TLR)4-dependent manner. Of note, injection of anti-IL-17 antibody in tumor-bearing C3H/HeN mice in the absence of Spirulina LPS markedly suppressed tumor growth and augmented IFN-γ responses. Thus, our results support the notion that IFN-γ and IL-17/IL-23 mutually regulate Th17 and Th1 responses in tumor-bearing hosts, and Spirulina LPS modulates the balance of the IFN-γ-IL-17/IL-23 axis towards IFN-γ production, which leads to tumor inhibition. Furthermore, Spirulina LPS effectively inhibited the spontaneous development of mammary tumors. This study has important implications for the exploitation of TLR-based immunomodulators for cancer immunotherapy. PMID:28075473

Matrix metalloproteinase and tissue inhibitor of metalloproteinase in serum and synovial fluid of osteoarthritic dogs.

PubMed

Salinardi, B J; Roush, J K; Schermerhorn, T; Mitchell, K E

2006-01-01

To better understand the mechanisms responsible for the pathological processes of osteoarthritis (OA) and to potentially identify a profile of changes that could be predictive of early OA, matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) in the synovial fluid and serum of normal and osteoarthritic dogs were examined. The concentration of MMP-1 in the synovial fluid of osteoarthritic dogs (0.62 +/- 0.16), as measured by densitometry, was significantly higher than that found in control dogs (0.42 +/- 0.19) (P = 0.03). The concentration of MMP-1 in the serum of osteoarthritic dogs (0.74 +/- 0.16) was significantly less than that found in control dogs (0.87 +/- 0.08) (P = 0.05). The concentration of TIMP-2 in the synovial fluid of osteoarthritic dogs (46.2 +/- 21.9 ng/ml) was significantly less than that of control dogs (122.0 +/- 66.5 ng/ml) (P = 0.009). The concentration of TIMP-2 in the serum of osteoarthritic dogs (116.2 +/- 43.1 ng/ml) was not significantly different than that of control dogs (95.1 +/- 94.4 ng/ml) (P = 0.554). In addition, a phospho-tyrosine immunoprecipitation and mass spectrometry were used to isolate and identify interferon-alpha in canine synovial fluid.

Serum Level of Antibodies Against Hepatitis B Core Protein Is Associated With Clinical Relapse After Discontinuation of Nucleos(t)ide Analogue Therapy.

PubMed

Chi, Heng; Li, Zhandong; Hansen, Bettina E; Yu, Tao; Zhang, Xiaoyong; Sun, Jian; Hou, Jinlin; Janssen, Harry L A; Peng, Jie

2018-06-11

Levels of antibodies against the hepatitis B virus (HBV) core protein (anti-HBc) have been associated with response to nucleos(t)ide analogue and (peg)interferon therapy in patients with chronic HBV infection. We performed a prospective study to determine whether the total serum level of anti-HBc level (immunoglobulins M and G) is associated with clinical relapse after discontinuation of nucleos(t)ide analogue-based therapy. We collected data from patients with chronic HBV infection who discontinued nucleos(t)ide analogue therapy according to pre-specified stopping criteria, recruited from November 2012 through July 2016 at an academic hospital in Guangzhou, China. Patients were followed through February 2017. We performed comprehensive biochemical and virologic tests at every visit, and anti-HBc was quantified for 2 years after treatment cessation (at baseline and weeks 4, 8, 12, 24, 48, and 96). The primary endpoint was clinical relapse, defined as level of HBV DNA >2000 IU/mL and level of alanine aminotransferase more than 2-fold the upper limit of normal-these were also the criteria for retreatment. We followed 100 patients (71% positive for HB e antigen [HBeAg] at the start of nucleos(t)ide analogue therapy, 43% treated with entecavir or tenofovir) for a median of 2.5 years after stopping therapy. Clinical relapse occurred in 39 patients (in 46% of patients at year 4 after discontinuation). High level of anti-HBc at the end of treatment (hazard ratio [HR], 0.31 per log IU/mL; P=.002) and low level of HB surface antigen (HBsAg) at the end of treatment (HR, 1.71 per log IU/mL; P=.032) were associated with a reduced risk of clinical relapse after adjusting for age, start of nucleos(t)ide analogue therapy HBeAg-status, and consolidation therapy duration. At year 4, 21% of patients with anti-HBc levels at the end of treatment ≥1000 IU/mL developed a clinical relapse compared to 85% of patients with levels <100 IU/mL (P<.001). An HBsAg level at the end of treatment ≤100 IU/mL was associated with a reduced risk of relapse (HR 0.30; P=.045). However, 82% of patients had levels of HBsAg above 100 IU/mL; for these patients, level of anti-HBc at the end of treatment could be used to determine the risk of relapse (HR 0.39 per log IU/mL; P=.005). In a median 2.5-year follow-up study of patients with chronic HBV infection who stopped nucleos(t)ide analogue therapy, total serum level of anti-HBc at the end of treatment was associated with risk of clinical relapse. Serum level of anti-HBc might be used to select patients suitable for discontinuing nucleos(t)ide analogue therapy. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Effects of polysaccharide from mycelia of Ganoderma lucidum on intestinal barrier functions of rats.

PubMed

Jin, Mingliang; Zhu, Yimin; Shao, Dongyan; Zhao, Ke; Xu, Chunlan; Li, Qi; Yang, Hui; Huang, Qingsheng; Shi, Junling

2017-01-01

The intestinal mucosal barriers play essential roles not only in the digestion and absorption of nutrients, but also the innate defense against most intestinal pathogens. In the present study, polysaccharide from the mycelia of Ganoderma lucidum was given via oral administration to rats (100mg/kg body weight, 21days) to investigate its effects on intestinal barrier functions, including the mechanical barrier, immunological barrier and biological barrier function. It was found that the polysaccharide administration could significantly up-regulate the expression of occludin, nuclear factor-κB p65 (NF-κB p65) and secretory immunoglobulin A (SIgA) in ileum, markedly improve the levels of interferon-γ (IFN-γ), interleukin-2 (IL-2), and IL-4, and decrease the level of diamine oxidase (DAO) in serum. Meanwhile, rats from the polysaccharide group showed significant higher microbiota richness in cecum as reflected by the Chao 1 index compared with the control group. Moreover, the polysaccharide decreased the Firmicutes-to-Bacteroidetes ratio. Our results indicated that the polysaccharide from the mycelia of G. lucidum might be used as functional agent to regulate the intestinal barrier functions. Copyright © 2016 Elsevier B.V. All rights reserved.

The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by immunomodulatory therapies.

PubMed

McKay, Fiona C; Gatt, Prudence N; Fewings, Nicole; Parnell, Grant P; Schibeci, Stephen D; Basuki, Monica A I; Powell, Joseph E; Goldinger, Anita; Fabis-Pedrini, Marzena J; Kermode, Allan G; Burke, Therese; Vucic, Steve; Stewart, Graeme J; Booth, David R

2016-02-01

Multiple Sclerosis (MS) is an autoimmune disease treated by therapies targeting peripheral blood cells. We previously identified that expression of two MS-risk genes, the transcription factors EOMES and TBX21 (ET), was low in blood from MS and stable over time. Here we replicated the low ET expression in a new MS cohort (p<0.0007 for EOMES, p<0.028 for TBX21) and demonstrate longitudinal stability (p<10(-4)) and high heritability (h(2)=0.48 for EOMES) for this molecular phenotype. Genes whose expression correlated with ET, especially those controlling cell migration, further defined the phenotype. CD56+ cells and other subsets expressed lower levels of Eomes or T-bet protein and/or were under-represented in MS. EOMES and TBX21 risk SNP genotypes, and serum EBNA-1 titres were not correlated with ET expression, but HLA-DRB1*1501 genotype was. ET expression was normalised to healthy control levels with natalizumab, and was highly variable for glatiramer acetate, fingolimod, interferon-beta, dimethyl fumarate. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Phase 1/2 study of immunotherapy with dendritic cells pulsed with autologous tumor lysate in patients with refractory bone and soft tissue sarcoma.

PubMed

Miwa, Shinji; Nishida, Hideji; Tanzawa, Yoshikazu; Takeuchi, Akihiko; Hayashi, Katsuhiro; Yamamoto, Norio; Mizukoshi, Eishiro; Nakamoto, Yasunari; Kaneko, Shuichi; Tsuchiya, Hiroyuki

2017-05-01

There are limited options for the curative treatment of refractory bone and soft tissue sarcomas. The purpose of this phase 1/2 study was to assess the immunological and clinical effects of dendritic cells (DCs) pulsed with autologous tumor lysate (TL) in patients with advanced bone and soft tissue sarcomas. Thirty-seven patients with metastatic or recurrent sarcomas were enrolled in this study. Peripheral blood mononuclear cells obtained from the patients were suspended in media containing interleukin 4 (IL-4) and granulocyte-macrophage colony-stimulating factor. Subsequently, these cells were treated with TL, tumor necrosis factor α, and OK-432. The DCs were injected into the inguinal or axillary region. One treatment course comprised 6 weekly DC injections. The toxicity, clinical response (tumor volume, serum interferon-γ [IFN-γ], and serum IL-12), and oncological outcomes were observed. In total, 47 courses of DC therapy were performed in 37 patients. No severe adverse events or deaths associated with the DC injections were observed in the study patients. Increased serum IFN-γ and IL-12 levels were observed 1 month after the DC injection. Among the 37 patients, 35 patients were assessed for clinical responses: 28 patients showed tumor progression, 6 patients had stable disease, and 1 patient showed a partial response 8 weeks after the DC injection. The 3-year overall and progression-free survival rates of the patients were 42.3% and 2.9%, respectively. Although DC therapy appears safe and resulted in an immunological response in patients with refractory sarcoma, it resulted in an improvement of the clinical outcome in only a small number of patients. Cancer 2017;123:1576-1584. © 2017 American Cancer Society. © 2017 American Cancer Society.

The effect of garlic consumption on Th1/Th2 cytokines in phytohemagglutinin (PHA) activated rat spleen lymphocytes.

PubMed

Zamani, Alireza; Vahidinia, Aliasghar; Ghannad, Masoud Sabouri

2009-04-01

The balance and regulation of T helper 1 (Th1) and Th2-type cytokines are important in the effective immune response to different diseases. To clarify the effect of garlic (Allium sativum L.) consumption on the Th1/Th2 balance, the secretion of gamma interferon (IFN-gamma) and interleukin-4 (IL-4), as two prototypes of Th1/Th2 cytokines, were compared in serum and supernatant of in vitro phytohemagglutinin activated rat spleen lymphocytes. Thirty male rats were divided equally into two groups. The treatment group received garlic solution in water (600 mg/kg/4 mL) and controls received distilled water by gavage. After 1 month, serum and supernatant of PHA activated spleen lymphocytes were analysed for IFN-gamma and IL-4 by the enzyme-linked immunosorbent assay test and thymus and spleen weights were measured. The garlic treatment group showed significantly decreased production of IFN-gamma from 101.73 +/- 4.62 to 74.64 +/- 4.64 pg/mL and significantly increased IL-4 production from 26.75 +/- 3.35 to 83.92 +/- 6.56 pg/mL (p < 0.001) in the supernatant of PHA induced spleen lymphocytes. The serum level of these cytokines was undetectable. The mean weight of thymuses in the garlic fed animals was significantly reduced from 0.456 +/- 0.016 to 0.368 +/- 0.023 g compared with the control group (p < 0.005). There were no significant differences between the spleen weights in the two groups. In conclusion, oral garlic treatment may favor a Th2 or humoral immune response. (c) 2008 John Wiley & Sons, Ltd.

Interferon-β1a reduces plasma CD31+ endothelial microparticles (CD31+EMP) in multiple sclerosis

PubMed Central

Sheremata, William A; Jy, Wenche; Delgado, Sylvia; Minagar, Alireza; McLarty, Jerry; Ahn, Yeon

2006-01-01

Background A correlation between plasma CD31+ endothelial microparticles (CD31+EMP) levels and clinical, as well as brain MRI activity, in multiple sclerosis (MS) patients has been previously reported. However, the effect(s) of treatment with interferon-β1a (IFN-β1a) on plasma levels of CD31+EMP has not been assessed. In a prospective study, we measured plasma CD31+EMP levels in 30 patients with relapsing-remitting MS. Methods Using flow cytometry, in a blinded study, we measured plasma CD31+EMP in 30 consecutive patients with relapsing-remitting MS (RRMS) prior to and 4, 12, 24 and 52 weeks after initiation of intramuscular therapy with interferon-β1a (IFN-β1a), 30 micrograms weekly. At each visit, clinical examination was performed and expanded disability status scale (EDSS) scores were assessed. Results Plasma levels of CD31+EMP were significantly reduced from 24 through 52 weeks following initiation of treatment with IFN-β1a. Conclusion Our data suggest that serial measurement of plasma CD31+EMP levels may be used as a surrogate marker of response to therapy with INF-β1a. In addition, the decline in plasma levels of CD31+EMP further supports the concept that IFN-β1a exerts stabilizing effect on the cerebral endothelial cells in pathogenesis of MS. PMID:16952316

Interferon-beta1a reduces plasma CD31+ endothelial microparticles (CD31+EMP) in multiple sclerosis.

PubMed

Sheremata, William A; Jy, Wenche; Delgado, Sylvia; Minagar, Alireza; McLarty, Jerry; Ahn, Yeon

2006-09-04

A correlation between plasma CD31+ endothelial microparticles (CD31+EMP) levels and clinical, as well as brain MRI activity, in multiple sclerosis (MS) patients has been previously reported. However, the effect(s) of treatment with interferon-beta1a (IFN-beta1a) on plasma levels of CD31+EMP has not been assessed. In a prospective study, we measured plasma CD31+EMP levels in 30 patients with relapsing-remitting MS. Using flow cytometry, in a blinded study, we measured plasma CD31+EMP in 30 consecutive patients with relapsing-remitting MS (RRMS) prior to and 4, 12, 24 and 52 weeks after initiation of intramuscular therapy with interferon-beta1a (IFN-beta1a), 30 micrograms weekly. At each visit, clinical examination was performed and expanded disability status scale (EDSS) scores were assessed. Plasma levels of CD31+EMP were significantly reduced from 24 through 52 weeks following initiation of treatment with IFN-beta1a. Our data suggest that serial measurement of plasma CD31+EMP levels may be used as a surrogate marker of response to therapy with INF-beta1a. In addition, the decline in plasma levels of CD31+EMP further supports the concept that IFN-beta1a exerts stabilizing effect on the cerebral endothelial cells in pathogenesis of MS.

Interferon induction by and toxicity of polyriboinosinic acid [poly(rI)].polyribocytidylic acid [poly (rC)], mismatched analog poly (rI).poly[r(C12Uracil)n], and poly(rI).poly(rC) L-lysine complexed with carboxymethylcellulose.

PubMed Central

Stringfellow, D A; Weed, S D

1980-01-01

The ability of polyriboinosionic acid [poly(rI)].polyribocytidylic acid [poly(rC)], mismatched analog poly (rI).poly[r(C12Uracil)n], and poly(rI).poly(rC) complexed with poly L-lysine and carboxymethylcellulose [poly(ICLc)] to induce interferon and the comparative toxicity of each in cats were evaluated. Each induced high levels of circulating interferon, although poly(ICLC) injected intravenously at 1 to 4 mg/kg induced up to 10 times more interferon than the other compounds. Each compound was pyrogenic and caused a transient decrease in leukocyte numbers. Poly(rI).poly(rC) and the mismatched analog caused severe diarrhea and nausea at the highest drug concentrations (1 to 4 mg/kg), but poly (ICLC) did not. Each compound also caused depression and lethargy and impaired coordination. PMID:6157363

Investigation of antiviral state mediated by interferon-inducible transmembrane protein 1 induced by H9N2 virus and inactivated viral particle in human endothelial cells.

PubMed

Feng, Bo; Zhao, Lihong; Wang, Wei; Wang, Jianfang; Wang, Hongyan; Duan, Huiqin; Zhang, Jianjun; Qiao, Jian

2017-11-03

Endothelial cells are believed to play an important role in response to virus infection. Our previous microarray analysis showed that H9N2 virus infection and inactivated viral particle inoculation increased the expression of interferon-inducible transmembrane protein 1 (IFITM1) in human umbilical vein endothelial cells (HUVECs). In present study, we deeply investigated the expression patterns of IFITM1 and IFITM1-mediated antiviral response induced by H9N2 virus infection and inactivated viral particle inoculation in HUVECs. Epithelial cells that are considered target cells of the influenza virus were selected as a reference control. First, we quantified the expression levels of IFITM1 in HUVECs induced by H9N2 virus infection or viral particle inoculation using quantitative real-time PCR and western blot. Second, we observed whether hemagglutinin or neuraminidase affected IFITM1 expression in HUVECs. Finally, we investigated the effect of induced-IFITM1 on the antiviral state in HUVECs by siRNA and activation plasmid transfection. Both H9N2 virus infection and viral particle inoculation increased the expression of IFITM1 without elevating the levels of interferon-ɑ/β in HUVECs. HA or NA protein binding alone is not sufficient to increase the levels of IFITM1 and interferon-ɑ/β in HUVECs. IFITM1 induced by viral particle inoculation significantly decreased the virus titers in culture supernatants of HUVECs. Our results showed that inactivated viral particle inoculation increased the expression of IFITM1 at mRNA and protein levels. Moreover, the induction of IFITM1 expression mediated the antiviral state in HUVECs.

Lactobacillus frumenti Facilitates Intestinal Epithelial Barrier Function Maintenance in Early-Weaned Piglets

PubMed Central

Hu, Jun; Chen, Lingli; Zheng, Wenyong; Shi, Min; Liu, Liu; Xie, Chunlin; Wang, Xinkai; Niu, Yaorong; Hou, Qiliang; Xu, Xiaofan; Xu, Baoyang; Tang, Yimei; Zhou, Shuyi; Yan, Yiqin; Yang, Tao; Ma, Libao; Yan, Xianghua

2018-01-01

Increased intestinal epithelial barrier function damages caused by early weaning stress have adverse effects on swine health and feed utilization efficiency. Probiotics have emerged as the promising antibiotic alternatives used for intestinal barrier function damage prevention. Our previous data showed that Lactobacillus frumenti was identified as a predominant Lactobacillus in the intestinal microbiota of weaned piglets. However, whether the intestinal epithelial barrier function in piglets was regulated by L. frumenti is still unclear. Here, piglets received a PBS vehicle or PBS suspension (2 ml, 108 CFU/ml) containing the L. frumenti by oral gavage once a day during the period of 6–20 days of age prior to early weaning. Our data demonstrated that oral administration of L. frumenti significantly improved the intestinal mucosal integrity and decreased the serum endotoxin and D-lactic acid levels in early-weaned piglets (26 days of age). The intestinal tight junction proteins (including ZO-1, Occludin, and Claudin-1) were significantly up-regulated by L. frumenti administration. The serum immunoglobulin G (IgG) levels, intestinal secretory immunoglobulin A (sIgA) levels, and interferon-γ (IFN-γ) levels were significantly increased by L. frumenti administration. Furthermore, our data revealed that oral administration of L. frumenti significantly increased the relative abundances of health-promoting microbes (including L. frumenti, Lactobacillus gasseri LA39, Parabacteroides distasonis, and Kazachstania telluris) and decreased the relative abundances of opportunistic pathogens (including Desulfovibrio desulfuricans and Candida humilis). Functional alteration of the intestinal bacterial community by L. frumenti administration was characterized by the significantly increased fatty acids and protein metabolism and decreased diseases-associated metabolic pathways. These findings suggest that L. frumenti facilitates intestinal epithelial barrier function maintenance in early-weaned piglets and may be a promising antibiotic alternative used for intestinal epithelial barrier function damage prevention in mammals. PMID:29867808

Aneuploidy assessed by DNA index influences the effect of iron status on plasma and/or supernatant cytokine levels and progression of cells through the cell cycle in a mouse model.

PubMed

Kuvibidila, Solo; Porretta, Connie; Baliga, Surendra

2014-02-01

Aneuploidy, a condition associated with altered chromosome number, hence DNA index, is frequently seen in many diseases including cancers and affects immunity. Iron, an essential nutrient for humans, modulates the immune function and the proliferation of normal and cancer cells. To determine whether impaired immunity seen in iron-deficient subjects may be related to aneuploidy, we measured spleen cell DNA index, percent of cells in different phases of the cell cycle, plasma and/or supernatant IL-2, IL-10, IL-12, and interferon-gamma in control, pair-fed, iron-deficient, and iron-replete mice (N=20-22/group). The test and control diets differed only in iron content (0.09mmol/kg versus 0.9mmol/kg) and were fed for 68days. Mean levels of hemoglobin and liver iron stores of iron-deficient and iron-replete mice were 40-60% lower than those of control and pair-fed mice (P<0.05). Mean plasma levels of IL-10, interferon-gamma and percent of cells in S+G2/M phases were lower in mice with than in those without aneuploidy (P<0.05). Lowest plasma IL-12 and interferon-gamma concentrations were observed in iron-deficient mice with aneuploidy. Mean percents of cultures with aneuploidy and DNA indexes were higher in iron-deficient and iron-replete than in control and pair-fed mice likely due to delayed cell division (P<0.05). Aneuploidy decreased the concentration of IL-2 and interferon-gamma in baseline cultures while it increased that of interferon-gamma in anti-CD3 treated cultures. Aneuploidic indexes negatively correlated with cytokine levels, percents of cells in S+G2/M phases and indicators of iron status (P<0.05). Although chromosome cytogenetics was not performed, for the first time, we report that increased aneuploidy rate may modulate the immune function during iron-deficiency. Copyright © 2014. Published by Elsevier Ltd.

Monitoring interferon β treatment response with magnetic resonance spectroscopy in relapsing remitting multiple sclerosis.

PubMed

Yetkin, Mehmet Fatih; Mirza, Meral; Dönmez, Halil

2016-09-01

The aim of this study is to compare the white matter of multiple sclerosis (MS) patients with healthy controls and to monitor the response to the treatment with magnetic resonance spectroscopy (MRS).Fifteen healthy controls and 36 recently diagnosed MS patients never treated with interferon β were included in this study. In the patient group, MRS was performed before treatment, at 6th and 12th month after the initiation of treatment and once in control group. Patient group was divided into 3 interferon groups randomly. Physical examination findings were recorded as Expanded Disability Status Scale scores before treatment, at 6th and 12th month of interferon treatment.At the end of 1 year follow up, 26 of 36 patients completed the study. In patients' white matter lesions, N-acetylaspartate/creatine (NAA/Cr) ratios were lower than control group's white matters. NAA/Cr ratios were higher in control group's white matter than patient's normal appearing white matter but this difference was not statistically significant. There was no difference in choline/creatine (Cho/Cr) ratios between 2 groups. In follow-up period, NAA/Cr and Cho/Cr ratios obtained from patients' white matter lesions and normal appearing white matter did not change statistically.This study showed that in MS patients' white matters, especially in white matter lesions, neuron viability is reduced compared with healthy controls' normal white matter; and in the patients treated with interferon β NAA/Cr ratios remained stable. These stable levels of metabolite ratios in the patients who received interferon β therapy can be explained with either the shortness of the follow-up period post-treatment or may reflect a positive effect of the beta interferon therapy on the progress of MS.

Altered immune responses in broiler chicken husbandry workers and their association with endotoxin exposure

PubMed Central

GAUTAM, Ravi; HEO, Yong; LIM, GyeongDong; SONG, EunSeob; ROQUE, Katharine; LEE, JaeHee; KIM, YeonGyeong; CHO, AhRang; SHIN, SoJung; KIM, ChangYul; BANG, GiHwan; BAHNG, JiYun; KIM, HyoungAh

2017-01-01

Exposure to bioaerosols in indoor animal farms associates with respiratory illnesses, but little is known about the immune modulation to chicken farmers. This study aimed to compare the general immunity of chicken farmers with those of control subjects with non-agricultural jobs. Blood taken from the farmers and controls was subjected to plasma IgE and IgG subclass measurements. Isolated peripheral blood mononuclear cells (PBMC) were stimulated and cytokine production was measured. Indoor total and respirable dust levels and their endotoxin (LPS) and aflatoxin (AF) levels in the farms were measured. In total, 29 chicken farmers on 19 farms and 14 age- and sex-matched office workers participated. Hematological differences were not observed. The farmers tended to have higher serum IgE and IgG subclass levels with significance for IgG1. The cytokines released by PBMC from farmers indicated skewing toward Type-2 helper T-cell responses: interferon (IFN)-γ:interleukin (IL)-4 and IFNγ:IL-13 ratios were significantly lower than for control PBMC. The farms had 707.1 EU/m3 LPS in total dust, and 15.8 EU/m3 LPS in respirable dust. Farmers exhibited immune skewing towards allergic immune responses that correlated with the LPS levels on their farms. Chicken farmers may be at risk of respiratory allergies due to occupational endotoxin exposure. PMID:28835578

Bamboo salt attenuates CCl4-induced hepatic damage in Sprague-Dawley rats

PubMed Central

Zhao, Xin; Song, Jia-Le; Kil, Jeung-Ha

2013-01-01

Bamboo salt, a Korean folk medicine, is prepared with solar salt (sea salt) and baked several times at high temperatures in a bamboo case. In this study, we compared the preventive effects of bamboo salt and purified and solar salts on hepatic damage induced by carbon tetrachloride in Sprague-Dawley rats. Compared with purified and solar salts, bamboo salts prevented hepatic damage in rats, as evidenced by significantly reduced serum levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase (P < 0.05). Bamboo salt (baked 9×) triggered the greatest reduction in these enzyme levels. In addition, it also reduced the levels of the proinflammatory cytokines interleukin (IL)-6, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α. Histopathological sections of liver tissue demonstrated the protective effect of bamboo salt, whereas sections from animals treated with the other salt groups showed a greater degree of necrosis. We also performed reverse transcription-polymerase chain reaction and western blot analyses of the inflammation-related genes iNOS, COX-2, TNF-α, and IL-1β in rat liver tissues. Bamboo salt induced a significant decrease (~80%) in mRNA and protein expression levels of COX-2, iNOS, TNF-α, and IL-1β, compared with the other salts. Thus, we found that baked bamboo salt preparations could prevent CCl4-induced hepatic damage in vivo. PMID:23964314

[Improvement of sensitivity in the second generation HCV core antigen assay by a novel concentration method using polyethylene glycol (PEG)].

PubMed

Higashimoto, Makiko; Takahashi, Masahiko; Jokyu, Ritsuko; Syundou, Hiromi; Saito, Hidetsugu

2007-11-01

A HCV core antigen (Ag) detection assay system, Lumipulse Ortho HCV Ag has been developed and is commercially available in Japan with a lower detection level limit of 50 fmol/l, which is equivalent to 20 KIU/ml in PCR quantitative assay. HCV core Ag assay has an advantage of broader dynamic range compared with PCR assay, however the sensitivity is lower than PCR. We developed a novel HCV core Ag concentration method using polyethylene glycol (PEG), which can improve the sensitivity five times better than the original assay. The reproducibility was examined by consecutive five-time measurement of HCV patients serum, in which the results of HCV core Ag original and concentrated method were 56.8 +/- 8.1 fmol/l (mean +/- SD), CV 14.2% and 322.9 +/- 45.5 fmol/l CV 14.0%, respectively. The assay results of HCV negative samples in original HCV core Ag were all 0.1 fmol/l and the results were same even in the concentration method. The results of concentration method were 5.7 times higher than original assay, which was almost equal to theoretical rate as expected. The assay results of serially diluted samples were also as same as expected data in both original and concentration assay. We confirmed that the sensitivity of HCV core Ag concentration method had almost as same sensitivity as PCR high range assay in the competitive assay study using the serially monitored samples of five HCV patients during interferon therapy. A novel concentration method using PEG in HCV core Ag assay system seems to be useful for assessing and monitoring interferon treatment for HCV.

Dietary supplementation with rice bran fermented with Lentinus edodes increases interferon-γ activity without causing adverse effects: a randomized, double-blind, placebo-controlled, parallel-group study.

PubMed

Choi, Ji-Young; Paik, Doo-Jin; Kwon, Dae Young; Park, Yongsoon

2014-04-22

The purpose of this study was to investigate the hypothesis that dietary supplementation with rice bran fermented with Lentinus edodes (rice bran exo-biopolymer, RBEP), a substance known to contain arabinoxylan, enhances natural killer (NK) cell activity and modulates cytokine production in healthy adults. This study was designed in a randomized, double-blind, placebo-controlled, and parallel-group format. Eighty healthy participants with white blood cell counts of 4,000-8,000 cells/μL were randomly assigned to take six capsules per day of either 3 g RBEP or 3 g placebo for 8 weeks. Three participants in the placebo group were excluded after initiation of the protocol; no severe adverse effects from RBEP supplementation were reported. NK cell activity of peripheral blood mononuclear cells was measured using nonradioactive cytotoxicity assay kits and serum cytokine concentrations included interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-4, IL-10, and IL-12 were measured by Bio-Plex cytokine assay kit. This study was registered with the Clinical Research Information Service (KCT0000536). Supplementation of RBEP significantly increased IFN-γ production compared with the placebo group (P = 0.012). However, RBEP supplementation did not affect either NK cell activity or cytokine levels, including IL-2, IL-4, IL-10, IL-12, and TNF-α, compared with the placebo group. The data obtained in this study indicate that RBEP supplementation increases IFN-γ secretion without causing significant adverse effects, and thus may be beneficial to healthy individuals. This new rice bran-derived product may therefore be potentially useful to include in the formulation of solid and liquid foods designed for treatment and prevention of pathological states associated with defective immune responses.

Clinical evaluation of the branched DNA assay for hepatitis B virus DNA detection in patients with chronic hepatitis B lacking hepatitis B e antigen and treated with interferon-alpha.

PubMed

Habersetzer, F; Zoulim, F; Jusot, J F; Zhang, X; Trabaud, M A; Chevallier, P; Chevallier, M; Ahmed, S N; Sepetjan, M; Comanor, L; Minor, J; Trépo, C

1998-11-01

The aim of this study was to evaluate the Chiron branched DNA (bDNA) assay for detection of serum hepatitis B virus (HBV) DNA in patients with chronic hepatitis B lacking hepatitis B e antigen (HBeAg) and undergoing interferon (IFN) therapy. Results obtained with the bDNA assay were compared with those obtained using the Abbott liquid hybridization (LH) assay and the polymerase chain reaction (PCR). Serial samples (274) from 34 patients were analysed. Analysis of variance results indicated that bDNA values were more significantly correlated than LH values with both PCR positive/negative results (probability of artifact (Prob > F) = 0.7 and 0.09 for LH and bDNA assays, respectively) and presence/absence of precore mutations (Prob > F = 0.21 and 0.001 for LH and bDNA assays, respectively). Both bDNA and LH results correlated highly with alanine aminotransferase (ALT) values (both had Prob > F values of 0.0) while PCR was not correlated with ALT (Prob > F = 0.05). In 26 evaluable patients, a model based on a generalized Knodell score was used to predict response to IFN therapy, as defined by normalization of ALT values during therapy. This model discriminated well between non-responders and responders. The bDNA results correlated well with the generalized Knodell score, while the LH results did not (Prob > F = 0.04 and 0.19 for the bDNA and LH assays, respectively). In conclusion, the bDNA assay appears to be useful for quantification of HBV DNA levels in HBeAg-negative chronic hepatitis as it correlates with biochemical and histological indications of disease severity as well as with response to IFN therapy.

Enhanced actions of insulin-like growth factor-I and interferon-alpha co-administration in experimental cirrhosis.

PubMed

Tutau, Federico; Rodríguez-Ortigosa, Carlos; Puche, Juan Enrique; Juanarena, Nerea; Monreal, Iñigo; García Fernández, María; Clavijo, Encarna; Castilla, Alberto; Castilla-Cortázar, Inma

2009-01-01

Cirrhosis is a diffuse process of hepatic fibrosis and regenerative nodule formation. The liver is the major source of circulating insulin-like growth factor-I (IGF-I) whose plasma levels are diminished in cirrhosis. IGF-I supplementation has been shown to induce beneficial effects in cirrhosis, including antifibrogenic and hepatoprotective effects. On other hand, interferon-alpha (IFN-alpha) therapy seems to suppress the progression of hepatic fibrosis. The aim of this study was to investigate the effect of the co-administration of IGF-I+IFN-alpha to Wistar rats with CCl(4)-induced cirrhosis, exploring liver function tests, hepatic lipid peroxidation and histopathology. The mechanisms underlying the effects of these agents were studied by reverse transcription-polymerase chain reaction, determining the expression of some factors [hepatocyte growth factor (HGF), transforming growth factor-beta (TGF-beta), alpha-smooth muscle actin, collagen, tissular inhibitor of metalloproteinases-1 and pregnane X receptor (PXR)] involved in fibrogenesis, fibrolysis and/or hepatoprotection. Both IGF-I and IFN-alpha exerted significant effects on fibrogenesis. IGF-I significantly increased serum albumin and HGF whereas IFN-alpha-therapy did not. The inhibition of TGF-beta expression was only observed by the effect of IFN-alpha-therapy. In addition, only the co-administration of IGF-I and IFN-alpha was able to increase the PXR. The combined therapy with both factors improved liver function tests, hepatic lipid peroxidation and reduced fibrosis, inducing a relevant histological improvement, reducing fibrosis and recovering hepatic architecture. The co-administration IGF-I+IFN enhanced all the beneficial effects observed with each factor separately, showing an additive action on histopathology and PXR expression, which is involved in the inhibition of fibrogenesis.

Relative efficacy of casein or soya protein combined with palm or safflower-seed oil on hyperuricaemia in rats.

PubMed

Lo, Hui-Chen; Wang, Yao-Horng; Chiou, Hue-Ying; Lai, Shan-Hu; Yang, Yu

2010-07-01

Diets that ameliorate the adverse effects of uric acid (UA) on renal damage deserve attention. The effects of casein or soya protein combined with palm or safflower-seed oil on various serum parameters and renal histology were investigated on hyperuricaemic rats. Male Wistar rats administered with oxonic acid and UA to induce hyperuricaemia were fed with casein or soya protein plus palm- or safflower-seed oil-supplemented diets. Normal rats and hyperuricaemic rats with or without allopurinol treatment (150 mg/l in drinking water) were fed with casein plus maize oil-supplemented diets. After 8 weeks, allopurinol treatment and soya protein plus safflower-seed oil-supplemented diet significantly decreased serum UA in hyperuricaemic rats (one-way ANOVA; P < 0.05). In addition, soya protein and casein attenuated hyperuricaemia-induced decreases in serum albumin and insulin, respectively (two-way ANOVA; P < 0.05). Safflower-seed oil significantly decreased serum TAG and UA, whereas palm oil significantly increased serum cholesterol, TAG, blood urea N and creatinine. However, soya protein significantly decreased renal NO and nitrotyrosine and palm oil significantly decreased renal nitrotyrosine, TNF-alpha and interferon-gamma and increased renal transforming growth factor-beta. Casein with safflower-seed oil significantly attenuated renal tubulointerstitial nephritis, crystals and fibrosis. Comparing casein v. soya protein combined with palm or safflower-seed oil, the results support that casein with safflower-seed oil may be effective in attenuating hyperuricaemia-associated renal damage, while soya protein with safflower-seed oil may be beneficial in lowering serum UA and TAG.

Potential ex vivo immunomodulatory effects of San-Huang-Xie-Xin-Tang and its component herbs on mice and humans.

PubMed

Li, Chia-Yang; Hou, Yu-Chi; Lee Chao, Pei-Dawn; Shia, Chi-Sheng; Hsu, Ian C; Fang, Shih-Hua

2010-02-03

San-Huang-Xie-Xin-Tang (SHXXT), an important Chinese medicine formula, contains Rhei Rhizoma (RR), Scutellariae Radix (SR) and Coptidis Rhizoma (CR). RR and SR are abundant in anthraquinone and flavonoid polyphenols. Pharmacokinetic study of SHXXT indicated that glucuronides were the predominant forms of polyphenols in rats. As an extension of pharmacokinetic study, the serum metabolites of SHXXT, RR, SR and CR were prepared from rats and quantitated, then the immunomodulation effects were examined by culturing these serum metabolites with murine and human immune cells. The results indicated that the inhibitions on nitric oxide (NO) and cytokine production from mitogen-activated peritoneal macrophages by the serum metabolites of SHXXT, RR, SR and CR were through reducing the protein expression of inducible NO synthase (iNOS) and the IC(50) were 0.8%, 1.5%, 3.0% and 0.8% of their blood concentrations, respectively. In addition, the serum metabolites of SHXXT, RR, SR and CR significantly decreased the ratios of interferon-gamma (IFN-gamma) to interleukin (IL)-4 in mitogen-stimulated mice spleen cells and human peripheral blood mononuclear cells (PBMCs). Moreover, the serum metabolites of SHXXT and SR significantly arrested the mitogen-stimulated mice spleen cells at G2/M stage. In conclusion, the serum metabolites of SHXXT and the component herbs exerted promising modulation activities on the immune functions and the cell cycle distribution of mice and human immune cells. We suggest that SHXXT is a promising remedy for immunomodulation through Th1/Th2 regulation. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

The influence of interferon β-1b on gut microbiota composition in patients with multiple sclerosis.

PubMed

Castillo-Álvarez, F; Pérez-Matute, P; Oteo, J A; Marzo-Sola, M E

2018-06-09

The association between gut microbiota and animal models of multiple sclerosis has been well established; however, studies in humans are scarce. We performed a descriptive, cross-sectional study comparing the relative composition of gut microbiota in 30 patients with multiple sclerosis (15 treated with interferon β-1b, 15 not receiving this treatment) and 14 healthy controls using next generation sequencing. Patients with multiple sclerosis and controls showed differences in the proportion of Euryarchaeota, Firmicutes, Proteobacteria, Actinobacteria, and Lentisphaerae phyla and in 17 bacterial species. More specifically, we found significant differences in the proportion of Firmicutes, Actinobacteria, and Lentisphaerae and 6 bacteria species between controls and untreated patients; however, these differences disappeared when compared with treated patients. Untreated patients showed a significant reduction in the proportion of Prevotella copri compared to controls, while the bacteria was significantly more abundant in patients treated with interferon β-1b than in untreated patients, with levels resembling those observed in the healthy control group. We observed differences in gut microbiota composition between patients with multiple sclerosis and controls, and between patients treated and not treated with interferon β-1b. In most cases, no differences were observed between treated patients and healthy controls, particularly for P. copri levels. This suggests that the clinical improvements observed in patients with multiple sclerosis receiving interferon β-1b may result from the effect of the drug on gut microbiota. Longitudinal and functional studies are necessary to establish a causal relationship. Copyright © 2018 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

An Application of Fractional Factorial Designs to Study Drug Combinations

PubMed Central

Jaynes, Jessica; Ding, Xianting; Xu, Hongquan; Wong, Weng Kee; Ho, Chih-Ming

2013-01-01

Herpes simplex virus type 1 (HSV-1) is known to cause diseases of various severities. There is increasing interest to find drug combinations to treat HSV-1 by reducing drug resistance and cytotoxicity. Drug combinations offer potentially higher efficacy and lower individual drug dosage. In this paper, we report a new application of fractional factorial designs to investigate a biological system with HSV-1 and six antiviral drugs, namely, Interferon-alpha, Interferon-beta, Interferon-gamma, Ribavirin, Acyclovir, and TNF-alpha. We show how the sequential use of two- and three-level fractional factorial designs can screen for important drugs and drug interactions, as well as determine potential optimal drug dosages through the use of contour plots. Our initial experiment using a two-level fractional factorial design suggests that there is model inadequacy and drug dosages should be reduced. A follow-up experiment using a blocked three-level fractional factorial design indicates that TNF-alpha has little effect and HSV-1 infection can be suppressed effectively by using a right combination of the other five antiviral drugs. These observations have practical implications in the understanding of antiviral drug mechanism that can result in better design of antiviral drug therapy. PMID:22859316

Measles virus induces persistent infection by autoregulation of viral replication.

PubMed

Doi, Tomomitsu; Kwon, Hyun-Jeong; Honda, Tomoyuki; Sato, Hiroki; Yoneda, Misako; Kai, Chieko

2016-11-24

Natural infection with measles virus (MV) establishes lifelong immunity. Persistent infection with MV is likely involved in this phenomenon, as non-replicating protein antigens never induce such long-term immunity. Although MV establishes stable persistent infection in vitro and possibly in vivo, the mechanism by which this occurs is largely unknown. Here, we demonstrate that MV changes the infection mode from lytic to non-lytic and evades the innate immune response to establish persistent infection without viral genome mutation. We found that, in the persistent phase, the viral RNA level declined with the termination of interferon production and cell death. Our analysis of viral protein dynamics shows that during the establishment of persistent infection, the nucleoprotein level was sustained while the phosphoprotein and large protein levels declined. The ectopic expression of nucleoprotein suppressed viral replication, indicating that viral replication is self-regulated by nucleoprotein accumulation during persistent infection. The persistently infected cells were able to produce interferon in response to poly I:C stimulation, suggesting that MV does not interfere with host interferon responses in persistent infection. Our results may provide mechanistic insight into the persistent infection of this cytopathic RNA virus that induces lifelong immunity.

Anti-Interferon Alpha Antibodies in Patients with High-Risk BCR/ABL-Negative Myeloproliferative Neoplasms Treated with Recombinant Human Interferon-α

PubMed Central

Li, Limei

2018-01-01

Background The objective of this study was to characterize the incidence and impact of immunogenicity to interferon-α (IFN-α-2a, IFN-α-2b, and Peg-IFN-α-2a) over a period of 12 months in patients with BCR/ABL-negative myeloproliferative neoplasms (MPNs). Material/Methods A total of 131 patients from an observational prospective cohort were selected. Antidrug antibodies, in serial serum samples obtained monthly after initiation of therapy, were measured by ELISA and WISH/VSV CPE assays. The association between antidrug antibodies and treatment response and adverse effects was evaluated. Results Among patients who completed 12 months of follow-up, binding antibodies (BAbs) were detected in 53% of those receiving IFN-α (69 of 131) and neutralizing antibodies (NAbs) were detected in 19% (25 of 131). NAbs-positivity was correlated with poorer clinical response, and Bab-positivity was associated with more adverse events. Almost all BAbs and NAbs appeared within 8 months after treatment began (≥95%). Complete remission (CR) rate was 62% for patients who were BAbs-positive and 69% for patients who were BAbs-negative; however, the CR rate of patients with NAbs(+) (24%) was obviously lower than in patients with NAbs(−) (75%). Patients with BAbs(+) had more immune adverse effects (including fever, myalgia, skin reaction, and stomatitis) than BAbs(−) patients, and NAbs to IFN-α had no obvious influence on the adverse effects rate. Conclusions The development of BAbs and NAbs can adversely affect IFN-α treatment in patients with MPN. PMID:29693647

Anti-Interferon Alpha Antibodies in Patients with High-Risk BCR/ABL-Negative Myeloproliferative Neoplasms Treated with Recombinant Human Interferon-α.

PubMed

Aruna; Li, Limei

2018-04-17

BACKGROUND The objective of this study was to characterize the incidence and impact of immunogenicity to interferon-a (IFN-α-2a, IFN-α-2b, and Peg-IFN-α-2a) over a period of 12 months in patients with BCR/ABL-negative myeloproliferative neoplasms (MPNs). MATERIAL AND METHODS A total of 131 patients from an observational prospective cohort were selected. Antidrug antibodies, in serial serum samples obtained monthly after initiation of therapy, were measured by ELISA and WISH/VSV CPE assays. The association between antidrug antibodies and treatment response and adverse effects was evaluated. RESULTS Among patients who completed 12 months of follow-up, binding antibodies (BAbs) were detected in 53% of those receiving IFN-α (69 of 131) and neutralizing antibodies (NAbs) were detected in 19% (25 of 131). NAbs-positivity was correlated with poorer clinical response, and Bab-positivity was associated with more adverse events. Almost all BAbs and NAbs appeared within 8 months after treatment began (≥95%). Complete remission (CR) rate was 62% for patients who were BAbs-positive and 69% for patients who were BAbs-negative; however, the CR rate of patients with NAbs(+) (24%) was obviously lower than in patients with NAbs(-) (75%). Patients with BAbs(+) had more immune adverse effects (including fever, myalgia, skin reaction, and stomatitis) than BAbs(-) patients, and NAbs to IFN-α had no obvious influence on the adverse effects rate. CONCLUSIONS The development of BAbs and NAbs can adversely affect IFN-a treatment in patients with MPN.

A trial with 3'-azido-2',3'-dideoxythymidine and human interferon-α in cats naturally infected with feline leukaemia virus.

PubMed

Stuetzer, Bianca; Brunner, Konstanze; Lutz, Hans; Hartmann, Katrin

2013-08-01

Feline leukaemia virus (FeLV) infection is still one of the leading causes of infection-related deaths in domestic cats. Treatment with various drugs has been attempted, but none has resulted in cure or complete virus elimination. Human interferon-α2a (huIFN-α2a) and 3'-azido-2',3'-dideoxythymidine (AZT) have been proven to decrease antigenaemia in cats infected experimentally with FeLV. The purpose of this study was to assess the efficacy of huIFN-α2a, AZT and a combination of both drugs in cats infected naturally with FeLV in a placebo-controlled double-blinded trial. Fourty-four FeLV-infected cats in which free FeLV p27 antigen was detected in serum by enzyme-linked immunosorbent assay were included in the study. Cats were assigned to one of four treatment groups that received either high dose huIFN-α2a (10(5) IU/kg q24h; 12 cats), AZT (5 mg/kg q12h; 10 cats, both of these treatments (12 cats) or placebo (10 cats). All cats were treated for 6 weeks. Clinical variables, including stomatitis, and laboratory parameters, such as CD4(+) and CD8(+) counts and serum FeLV p 27 antigen concentration, were recorded throughout the treatment period. No significant difference among the groups was observed during the treatment period for any of the parameters. Aside from anaemia in one cat treated with AZT, no adverse effects were observed. It was not possible to demonstrate efficacy of huIFN-α2a or AZT alone or together in cats infected naturally with FeLV when given according to this regimen for 6 weeks; however, no notable side effects were detected.

Effect of soluble factors derived from oral cancer cells on the production of interferon-γ from peripheral blood mononuclear cells following stimulation with OK-432.

PubMed

Ohe, Go; Sasai, Akiko; Uchida, Daisuke; Tamatani, Tetsuya; Nagai, Hirokazu; Miyamoto, Youji

2013-08-01

The streptococcal antitumor agent OK-432 is commonly used as an immunopotentiator for immunotherapy in various types of malignant tumors including oral cancer. It has been demonstrated that OK-432 elicits an antitumor effect by stimulating immunocompetent cells, thereby inducing multiple cytokines including interferon (IFN)-γ, interleukin (IL)-2 and IL-12. Serum concentrations of IFN-γ in patients with oral cancer were examined 24 h after administration of OK-432. Serum concentrations of IFN-γ in patients with advanced cancer were significantly lower than those in patients with early cancer. These results suggested that some soluble factors produced by cancer cells may inhibit IFN-γ production with OK-432. Thus, in the present study, an in vitro simulation model was established for the immune status of patients with oral cancer by adding conditioned medium (CM) derived from oral cancer cell lines into a culture of peripheral blood mononuclear cells (PBMCs) derived from a healthy volunteer. We investigated whether soluble factors derived from oral cancer cells affected IFN-γ production from PBMCs following stimulation with OK-432. PBMCs stimulated with OK-432 produced a large amount of IFN-γ; however, both IFN-γ production and cytotoxic activity from PBMCs induced by OK-432 were inhibited by the addition of CM in a dose-dependent manner. In order to examine these inhibitory effects against IFN-γ production, the contribution of inhibitory cytokines such as IL-4, IL-6, IL-10, transforming growth factor-β and vascular endothelial growth factor was investigated. However, neutralization of these inhibitory cytokines did not recover IFN-γ production inhibited by CM. These results indicated that unknown molecules may inhibit IFN-γ production from PBMCs following stimulation with OK-432.

Detection of bacterial pyrogens on the basis of their effects on gamma interferon-mediated formation of neopterin or nitrite in cultured monocyte cell lines.

PubMed Central

Werner-Felmayer, G; Baier-Bitterlich, G; Fuchs, D; Hausen, A; Murr, C; Reibnegger, G; Werner, E R; Wachter, H

1995-01-01

In a number of mammalian cell types, pteridine biosynthesis from guanosine 5'-triphosphate and formation of nitric oxide from L-arginine are induced by gamma interferon (IFN-gamma) and bacterial lipopolysaccharide (LPS). We assessed the possibility of using such metabolic alterations for the in vitro detection of pyrogens. Products from gram-negative and gram-positive bacteria and related synthetic compounds were tested for their potential to induce either of these pathways. Stimulation of pteridine biosynthesis was monitored as the formation of neopterin in the human myelomonocytic cell line THP-1. The formation of nitric oxide was determined as nitrite in murine J774A.1 macrophage cultures. The substances tested included toxic and detoxified parts of LPS and lipid A from Escherichia coli, Salmonella typhimurium, Salmonella minnesota, and Klebsiella pneumoniae as well as lipoteichoic acid and toxic shock syndrome toxin 1 from Staphylococcus aureus. Furthermore, two cell wall compounds from Mycobacterium tuberculosis, trehalose 6,6'-dimycolate and N-acetylmuramyl-L-alanyl-D-isoglutamine, which are active components of Freund's adjuvant, were used. When applied as a single stimulus, only the whole LPS molecule potently stimulated neopterin or nitrite formation. Lipid A and products from gram-positive bacteria were weakly active. For neopterin formation, lipid A required the presence of fetal calf serum. Besides detoxified LPS and independently from the presence of serum, all bacterial compounds tested strongly increased the effects mediated by IFN-gamma. Our results show that bacterial pyrogens can be detected by monitoring the formation of neopterin or nitrite. This may provide a basis for the development of an in vitro assay for the detection of pyrogenic contamination with the aim of replacing the currently used animal test. PMID:7664177

Gene expression and production of tumor necrosis factor alpha, interleukin 1, interleukin 6, and gamma interferon in C3H/HeN and C57BL/6N mice in acute Mycoplasma pulmonis disease.

PubMed Central

Faulkner, C B; Simecka, J W; Davidson, M K; Davis, J K; Schoeb, T R; Lindsey, J R; Everson, M P

1995-01-01

Studies were conducted to determine whether the production of various cytokines is associated with Mycoplasma pulmonis disease expression. Susceptible C3H/HeN and resistant C57BL/6N mice were inoculated intranasally with 10(7) CFU of virulent M. pulmonis UAB CT or avirulent M. pulmonis UAB T. Expression of genes for tumor necrosis factor alpha (TNF-alpha), interleukin 1 alpha (IL-1 alpha), IL-1 beta, IL-6, and gamma interferon (IFN-gamma) in whole lung tissue and TNF-alpha gene expression in bronchoalveolar lavage (BAL) cells was determined by reverse transcription-PCR using specific cytokine primers at various times postinoculation. In addition, concentrations of TNF-alpha, IL-1, IL-6, and IFN-gamma were determined in BAL fluid and serum samples at various times postinoculation. Our results showed that there was a sequential appearance of cytokines in the lungs of infected mice: TNF-alpha, produced primarily by BAL cells, appeared first, followed by IL-1 and IL-6, which were followed by IFN-gamma. Susceptible C3H/HeN mice had higher and more persistent concentrations of TNF-alpha and IL-6 in BAL fluid than did resistant C57BL/6N mice, indicating that TNF-alpha and possibly IL-6 are important factors in pathogenesis of acute M. pulmonis disease in mice. Serum concentrations of IL-6 were elevated in C3H/HeN mice, but not C57BL/6N mice, following infection with M. pulmonis, suggesting that IL-6 has both local and systemic effects in M. pulmonis disease. PMID:7558323

Correlations between endotoxin, interferon-gamma, biopterin and serum phospholipase A2-activities during lethal gram negative sepsis in rats.

PubMed

Hunsicker, A; Kullich, W; Weissenhofer, W; Lorenz, D; Petermann, J; Rokos, H; Schwesinger, G

1997-05-01

To establish a standardised reproducible animal model of intraperitoneal sepsis, and to investigate early immunoserological responses to find a mediator-based system for evaluation and grading of diffuse peritonitis in patients Prospective experimental study 4 Teaching hospitals, Germany and Austria 42 LEW. 1W rats, 12 of which acted as controls Gram negative sepsis was induced by intraperitoneal injection of 6 ml of a mixture of Escherichia coli (K1:H+) 10(10) organisms/ml, autogenous haemoglobin 2.9 ml (haemoglobin concentration 3%), 0.9% sodium chloride 3 ml, and suspension 0.1 ml. Control rats were given physiological saline 6 ml alone. Concentrations of endotoxin, interferon gamma (IFN-gamma), and biopterin, and serum phospholipase A2 (PLA2) activity. There were significant differences between the septic and control rats in concentrations of endotoxin (EU/ml) (median (interquartile range) 21.85 (2.02-159.5) compared with 0, p < 0.0001; IFN-gamma (pg/ml) 1263.0 (271.0-7575.0) compared with 101.0 (89.0-141.0), p < 0.0001; biopterin (nmol/L) 111.0 (66.4-156.3) compared with 53.7 (38.3-67.6), p < 0.001; and PLA2 (U/L) 163.0 (125.8-209.0) compared with 112.5 (88.5-126.5) p < 0.01. Measurements of concentrations of endotoxin, IFN-gamma, pteridines, and PLA2 activity may well be adequate markers for early recognition of sepsis, and perhaps for grading it during the first 6 hours after induction. The allow a clear distinction to be made between septic and non-septic disorders in 87% of cases.

Overproduction, purification and characterization of human interferon alpha2a-human serum albumin fusion protein produced in methilotropic yeast Pichia pastoris

NASA Astrophysics Data System (ADS)

Ningrum, R. A.; Santoso, A.; Herawati, N.

2017-05-01

Human interferon alpha2a (hIFNα2a) is a therapeutic protein that used in cancer and hepatitis B/C therapy. The main problem of using hIFNα-2a is its short elimination half life due to its low molecular weight. Development of higher molecular weight protein by albumin fusion technology is a rational strategy to solve the problem. In our previous research we constructed an open reading frame (ORF) encoding hIFNα2a-human serum albumin (HSA) fusion protein that expressed in Pichia pastoris (P. pastoris) protease deficient strain SMD1168. This research was performed to overproduce, purify and characterize the fusion protein. To overproduce the protein, cultivation was performed in buffered complex medium containing glyserol (BMGY) for 24 h and protein overproduction was applied in buffered complex medium containing methanol (BMMY) for 48 hours at 30°C. The fusion protein was purified by blue sepharose affinity chromatography. Molecular weight characterization by SDS PAGE corresponds with its theoretical size, 85 kDa. Western blot analysis demonstrated that the fusion protein was recognized by anti hIFNα2 and anti HSA monoclonal antibody as well. Amino acid sequence of the fusion protein was determined by LC MS/MS2 mass spectrometry with trypsin as proteolitic enzyme. There were three fragments that identified as hIFNα2a and seven fragments that identified as HSA. Total identified amino acids were 150 residues with 20% coverage from total residues. To conclude, hIFNα2a-HSA fusion protein was overproduced, purified and characterized. Characterization based on molecular weight, antibody recognition and amino acid sequence confirmed that the fusion protein has correct identity as theoretically thought.

An interferon signature identified by RNA-sequencing of mammary tissues varies across the estrous cycle and is predictive of metastasis-free survival

DOE PAGES

Snijders, Antoine M.; Langley, Sasha; Mao, Jian-Hua; ...

2014-06-30

The concept that a breast cancer patient's menstrual stage at the time of tumor surgery influences risk of metastases remains controversial. The scarcity of comprehensive molecular studies of menstrual stage-dependent fluctuations in the breast provides little insight. To gain a deeper understanding of the biological changes in mammary tissue and blood during the menstrual cycle and to determine the influence of environmental exposures, such as low-dose ionizing radiation (LDIR), we used the mouse to characterize estrous-cycle variations in mammary gene transcripts by RNA-sequencing, peripheral white blood cell (WBC) counts and plasma cytokine levels. We identified an estrous-variable and hormone-dependent genemore » cluster enriched for Type-1 interferon genes. Cox regression identified a 117-gene signature of interferon-associated genes, which correlated with lower frequencies of metastasis in breast cancer patients. LDIR (10cGy) exposure had no detectable effect on mammary transcripts. However, peripheral WBC counts varied across the estrous cycle and LDIR exposure reduced lymphocyte counts and cytokine levels in tumor-susceptible mice. Our finding of variations in mammary Type-1 interferon and immune functions across the estrous cycle provides a mechanism by which timing of breast tumor surgery during the menstrual cycle may have clinical relevance to a patient's risk for distant metastases.« less

An interferon signature identified by RNA-sequencing of mammary tissues varies across the estrous cycle and is predictive of metastasis-free survival

DOE Office of Scientific and Technical Information (OSTI.GOV)

Snijders, Antoine M.; Langley, Sasha; Mao, Jian-Hua

The concept that a breast cancer patient's menstrual stage at the time of tumor surgery influences risk of metastases remains controversial. The scarcity of comprehensive molecular studies of menstrual stage-dependent fluctuations in the breast provides little insight. To gain a deeper understanding of the biological changes in mammary tissue and blood during the menstrual cycle and to determine the influence of environmental exposures, such as low-dose ionizing radiation (LDIR), we used the mouse to characterize estrous-cycle variations in mammary gene transcripts by RNA-sequencing, peripheral white blood cell (WBC) counts and plasma cytokine levels. We identified an estrous-variable and hormone-dependent genemore » cluster enriched for Type-1 interferon genes. Cox regression identified a 117-gene signature of interferon-associated genes, which correlated with lower frequencies of metastasis in breast cancer patients. LDIR (10cGy) exposure had no detectable effect on mammary transcripts. However, peripheral WBC counts varied across the estrous cycle and LDIR exposure reduced lymphocyte counts and cytokine levels in tumor-susceptible mice. Our finding of variations in mammary Type-1 interferon and immune functions across the estrous cycle provides a mechanism by which timing of breast tumor surgery during the menstrual cycle may have clinical relevance to a patient's risk for distant metastases.« less

[Knockdown of indoleamine 2, 3-dioxygenase 2 (IDO2)gene inhibits tumor growth and enhances immune function in mice bearing melanoma].

PubMed

Liu, Yanling; Liu, Huan; Xiang, Yingqing; Chen, Xiaoyan; Xu, Ping; Min, Weiping

2017-12-01

Objective To study the role of indoleamine 2, 3-dioxygenase 2 (IDO2) in anti-tumor therapy and its effect on the immune response when using IDO2 as therapeutic target. Methods B16-BL6 cells were used to construct mouse xenografted melanoma model. IDO2-shRNA that contained IDO2-siRNA or control shRNA (scrambled-shRNA) was injected hydrodynamically via the tail vein to treat melanoma. The tumor size was measured by vernier caliper. Flow cytometry was performed to analyze the percentage of regulatory T cells (Tregs), T cell apoptosis rate in draining lymph nodes and the expressions of co-stimulatory molecules on splenic dendritic cells (DCs) from different treatment groups. The lactate dehydrogenase (LDH) assay was used to determine the CD8 + cytotoxic T lymphocyte (CTL) activity. The serum levels of tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ) were detected by ELISA. Results In the IDO2-shRNA treated group, the tumor formation time was delayed, tumor grew slowly, and excised tumor mass was significantly reduced. IDO2-shRNA treatment also decreased the percentage of Tregs and T cell apoptosis in draining lymph nodes and increased the expressions of co-stimulatory molecules CD80 and CD86 on splenic DCs. The capacity of CD8 + T cells to kill B16-BL6 cells was enhanced and the serum levels of TNF-α and IFN-γ were upregulated. Conclusion Silencing IDO2 can effectively inhibit the growth of melanoma and improve the anti-tumor immune response in vivo.

Antitumor effects of interleukin-18 gene-modified hepatocyte cell line on implanted liver carcinoma.

PubMed

Leng, Jianhang; Zhang, Lihuang; Yao, Hangping; Cao, Xuetao

2003-10-01

To investigate the antitumor effects of intrasplenically transplanted interleukin-18 (IL-18) gene-modified hepatocytes on murine implanted liver carcinoma. Embryonic murine hepatocyte cell line (BNL-CL2) was transfected with a recombinant adenovirus encoding IL-18 and used as delivery cells for IL-18 gene transfer. Two cell lines, BNL-LacZ and BNL-CL2, were used as controls. One week after intrasplenic injection of C26 cells (colon carcinoma line), tumor-bearing syngeneic mice underwent the intrasplenic transplantation of IL-18 gene-modified hepatocyte cell line and were divided into treatment group (BNL IL-18) and control groups (BNL-LacZ and BNL-CL2). Two weeks later, the serum levels of IL-18, interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) in the implanted liver carcinoma-bearing mice were assayed, the cytotoxicity of murine splenic cytotoxic T-lymphocytes (CTLs) was measured, and the morphology of the hepatic tumors was studied to evaluate the antitumor effects of the approach. In the treatment group, the serum levels of IL-18, IFN-gamma, TNF-alpha and NO increased significantly. The splenic CTL activity increased markedly (P < 0.01), accompanied by a substantial decrease in tumor volume and the percentage of tumor area and prolonged survival of liver carcinomo-being mice. In vivo IL-18 expression by ex vivo manipulated cells with IL-18 recombinant adenovirus is able to exert potent antitumor effects by inducing a predominantly T-cell-helper type 1 (Th1) immune response. Intrasplenic transplantation of adenovirus-mediated IL-18 gene-modified hepatocytes could be used as a targeting treatment for implanted liver carcinoma.

Hydrogen water ameliorates the severity of atopic dermatitis-like lesions and decreases interleukin-1β, interleukin-33, and mast cell infiltration in NC/Nga mice.

PubMed

Kajisa, Takuya; Yamaguchi, Takuji; Hu, Ailing; Suetake, Nobuhiro; Kobayashi, Hiroyuki

2017-09-01

To examine the effect of hydrogen water (HW) on the severity of atopic dermatitis (AD) and elucidate the underlying pathophysiological mechanisms. For this experimental study between March 2015 and December 2015, NC/Nga mice characterized by mild AD severity were given either HW (n=11) or purified water (PW) (n=9) ad libitum; specific-pathogen-free mice (n=9) were used as AD-free control. Atopic dermatitis severity score and transepidermal water loss (TEWL) were examined at baseline (0 week), and after 4 weeks of HW/PW treatment. Levels of serum thymus and activation-regulated chemokine (TARC) and cytokines in the AD lesion were measured by ELISA; and mRNA expression of TARC  and aquaporin (AQP-3) genes in the skin was examined by real-time polymerase chain reaction. Results: Mice treated with HW for 4 weeks demonstrated a significant decrease in the AD severity score compared with PW-treated mice (p less than 0.01). Hydrogen water administration also significantly reduced TEWL and serum TARC levels (p less than 0.01), infiltration of mast cells (p less than 0.05), and secretion of the proinflammatory cytokines interleukin (IL)-1β and IL-33 (p less than 0.05) in skin lesions compared with PW. However, no difference was observed between PW and HW groups in interferon-γ secretion and expression of AQP-3 and TARC genes. Conclusion: Hydrogen water suppressed inflammation in AD mice, leading to amelioration of disease severity, which suggests the therapeutic potential of HW in AD treatment.

Atorvastatin therapy reduces interferon-regulated chemokine CXCL9 plasma levels in patients with systemic lupus erythematosus.

PubMed

Ferreira, G A; Teixeira, A L; Sato, E I

2010-07-01

A recent study showed transcriptional levels of interferon-inducible chemokines in peripheral blood cells were associated with disease activity and organ damage in systemic lupus erythematosus, and may be useful in monitoring disease activity and prognosis. Our objective was to evaluate the capacity of atorvastatin to reduce plasma levels of interferon-regulated chemokines (CCL2, CCL3 and CXCL9) and to study the correlation between these chemokines and disease activity in patients with systemic lupus erythematosus. Eighty-eight female patients with systemic lupus erythematosus were divided into two groups: 64 receiving 20 mg/day of atorvastatin (intervention group) and 24 without atorvastatin (control group). All patients were followed for 8 weeks. At baseline and after 8 weeks laboratory tests were performed for all patients. Plasma levels of chemokines were measured by ELISA using commercial kits (DuoSet, R&D Systems, Minneapolis, USA). In a univariate analysis we found correlation between CCL2, CCL3 and CXCL9 plasma levels and SLEDAI score. In the intervention group we observed a significant decrease in CXCL9 plasma levels comparing baseline and levels at the end of the study (p = 0.04); however, no differences were observed regarding CCL2 or CCL3 plasma levels in this study. No significant difference was observed in the plasma levels of these chemokines in the control group. We conclude that treatment with atorvastatin was associated with a significant decrease in the plasma levels of CXCL9 in patients with systemic lupus erythematosus. As the plasma levels of CXCL9 correlated with the SLEDAI score, we ask whether reducing levels of this chemokine could help to control systemic lupus erythematosus activity.

[Fish interferon response and its molecular regulation: a review].

PubMed

Zhang, Yibing; Gui, Jianfang

2011-05-01

Interferon response is the first line of host defense against virus infection. Recent years have witnessed tremendous progress in understanding of fish innate response to virus infection, especially in fish interferon antiviral response. A line of fish genes involved in interferon antiviral response have been identified and functional studies further reveal that fish possess an IFN antiviral system similar to mammals. However, fish virus-induced interferon genes contain introns similar to mammalian type III interferon genes although they encode proteins similar to type I interferons, which makes it hard to understand the evolution of vertebrate interferon genes directly resulting in a debate on nomenclature of fish interferon genes. Actually, fish display some unique mechanisms underlying interferon antiviral response. This review documents the recent progress on fish interferon response and its molecular mechanism.

Safety and Immunogenicity of an Anti-Zika Virus DNA Vaccine - Preliminary Report.

PubMed

Tebas, Pablo; Roberts, Christine C; Muthumani, Kar; Reuschel, Emma L; Kudchodkar, Sagar B; Zaidi, Faraz I; White, Scott; Khan, Amir S; Racine, Trina; Choi, Hyeree; Boyer, Jean; Park, Young K; Trottier, Sylvie; Remigio, Celine; Krieger, Diane; Spruill, Susan E; Bagarazzi, Mark; Kobinger, Gary P; Weiner, David B; Maslow, Joel N

2017-10-04

Background Although Zika virus (ZIKV) infection is typically self-limiting, other associated complications such as congenital birth defects and the Guillain-Barré syndrome are well described. There are no approved vaccines against ZIKV infection. Methods In this phase 1, open-label clinical trial, we evaluated the safety and immunogenicity of a synthetic, consensus DNA vaccine (GLS-5700) encoding the ZIKV premembrane and envelope proteins in two groups of 20 participants each. The participants received either 1 mg or 2 mg of vaccine intradermally, with each injection followed by electroporation (the use of a pulsed electric field to introduce the DNA sequence into cells) at baseline, 4 weeks, and 12 weeks. Results The median age of the participants was 38 years, and 60% were women; 78% were white, and 22% black; in addition, 30% were Hispanic. At the interim analysis at 14 weeks (i.e., after the third dose of vaccine), no serious adverse events were reported. Local reactions at the vaccination site (e.g., injection-site pain, redness, swelling, and itching) occurred in approximately 50% of the participants. After the third dose of vaccine, binding antibodies (as measured on enzyme-linked immunosorbent assay) were detected in all the participants, with geometric mean titers of 1642 and 2871 in recipients of 1 mg and 2 mg of vaccine, respectively. Neutralizing antibodies developed in 62% of the samples on Vero-cell assay. On neuronal-cell assay, there was 90% inhibition of ZIKV infection in 70% of the serum samples and 50% inhibition in 95% of the samples. The intraperitoneal injection of postvaccination serum protected 103 of 112 IFNAR knockout mice (bred with deletion of genes encoding interferon-α and interferon-β receptors) (92%) that were challenged with a lethal dose of ZIKV-PR209 strain; none of the mice receiving baseline serum survived the challenge. Survival was independent of the neutralization titer. Conclusions In this phase 1, open-label clinical trial, a DNA vaccine elicited anti-ZIKV immune responses. Further studies are needed to better evaluate the safety and efficacy of the vaccine. (Funded by GeneOne Life Science and others; ZIKA-001 ClinicalTrials.gov number, NCT02809443 .).

Fermented Maesil (Prunus mume) with probiotics inhibits development of atopic dermatitis-like skin lesions in NC/Nga mice.

PubMed

Jung, Bock-Gie; Cho, Sun-Ju; Koh, Hong-Bum; Han, Dong-Un; Lee, Bong-Joo

2010-04-01

Maesil (Prunus mume Siebold & Zucc.), a potential source of free radical scavengers and inhibitor of pro-inflammatory mediators, is used in traditional Korean medical preparations as a remedy for skin disorders as have probiotics. The action of a probiotic fermented Maesil preparation on the development of atopic dermatitis (AD)-like skin lesions was determined in a NC/Nga mouse model as an initial step towards the development of a therapeutic feed supplement for use in dogs. Continuous ingestion of the experimental feed markedly inhibited the development of the AD-like skin lesions, as evidenced by a marked decrease in skin signs and reduced inflammation within the skin lesions. Efficacy was confirmed by significant decreases in eosinophil ratio and serum IgE concentration, and a reduction in the number of Staphylococcus aureus recovered from the ear. Relative mRNA expression levels of IL-4, interferon-gamma and tumour necrosis factor-alpha in the spleens of the experimental animals were also decreased and there was an increased serum concentration of IL-10 with a concurrent decreased IL-4 concentration in comparison to a control group. Taken together, the results indicate that some component(s) of fermented Maesil have the ability to suppress the development of AD-like skin lesions, possibly by stimulation of IL-10. Beneficial effects of fermented Maesil may thus be expected in dogs with AD, although this and the nature of the active pathway remain to be explored.

Cross-Regulation of Two Type I Interferon Signaling Pathways in Plasmacytoid Dendritic Cells Controls Anti-malaria Immunity and Host Mortality.

PubMed

Yu, Xiao; Cai, Baowei; Wang, Mingjun; Tan, Peng; Ding, Xilai; Wu, Jian; Li, Jian; Li, Qingtian; Liu, Pinghua; Xing, Changsheng; Wang, Helen Y; Su, Xin-Zhuan; Wang, Rong-Fu

2016-11-15

Type I interferon (IFN) is critical for controlling pathogen infection; however, its regulatory mechanisms in plasmacytoid cells (pDCs) still remain unclear. Here, we have shown that nucleic acid sensors cGAS-, STING-, MDA5-, MAVS-, or transcription factor IRF3-deficient mice produced high amounts of type I IFN-α and IFN-β (IFN-α/β) in the serum and were resistant to lethal plasmodium yoelii YM infection. Robust IFN-α/β production was abolished when gene encoding nucleic acid sensor TLR7, signaling adaptor MyD88, or transcription factor IRF7 was ablated or pDCs were depleted. Further, we identified SOCS1 as a key negative regulator to inhibit MyD88-dependent type I IFN signaling in pDCs. Finally, we have demonstrated that pDCs, cDCs, and macrophages were required for generating IFN-α/β-induced subsequent protective immunity. Thus, our findings have identified a critical regulatory mechanism of type I IFN signaling in pDCs and stage-specific function of immune cells in generating potent immunity against lethal YM infection. Copyright © 2016 Elsevier Inc. All rights reserved.

Interferon Lambda 4 Genotype Is Associated With Jaundice and Elevated Aminotransferase Levels During Acute Hepatitis C Virus Infection: Findings From the InC3 Collaborative.

PubMed

Page, Kimberly; Mirzazadeh, Ali; Rice, Thomas M; Grebely, Jason; Kim, Arthur Y; Cox, Andrea L; Morris, Meghan D; Hellard, Margaret; Bruneau, Julie; Shoukry, Naglaa H; Dore, Gregory J; Maher, Lisa; Lloyd, Andrew R; Lauer, Georg; Prins, Maria; McGovern, Barbara H

2016-01-01

Symptomatic acute HCV infection and interferon lambda 4 (IFNL4) genotypes are important predictors of spontaneous viral clearance. Using data from a multicohort database (Injecting Cohorts [InC3] Collaborative), we establish an independent association between host IFNL4 genotype and symptoms of acute hepatitis C virus infection. This association potentially explains the higher spontaneous clearance observed in some patients with symptomatic disease.

Interferon Lambda 4 Genotype Is Associated With Jaundice and Elevated Aminotransferase Levels During Acute Hepatitis C Virus Infection: Findings From the InC3 Collaborative

PubMed Central

Page, Kimberly; Mirzazadeh, Ali; Rice, Thomas M.; Grebely, Jason; Kim, Arthur Y.; Cox, Andrea L.; Morris, Meghan D.; Hellard, Margaret; Bruneau, Julie; Shoukry, Naglaa H.; Dore, Gregory J.; Maher, Lisa; Lloyd, Andrew R.; Lauer, Georg; Prins, Maria; McGovern, Barbara H.

2016-01-01

Symptomatic acute HCV infection and interferon lambda 4 (IFNL4) genotypes are important predictors of spontaneous viral clearance. Using data from a multicohort database (Injecting Cohorts [InC3] Collaborative), we establish an independent association between host IFNL4 genotype and symptoms of acute hepatitis C virus infection. This association potentially explains the higher spontaneous clearance observed in some patients with symptomatic disease. PMID:26973850

Association of monoclonal expansion of Epstein-Barr virus-negative CD158a+ NK cells secreting large amounts of gamma interferon with hemophagocytic lymphohistiocytosis.

PubMed

López-Alvarez, María R; Martínez-Sánchez, María V; Salgado-Cecilia, María G; Campillo, José A; Heine-Suñer, Damian; Villar-Permuy, Florentina; Fuster, José L; Bas, Agueda; Gil-Herrera, Juana; Muro, Manuel; García-Alonso, Ana M; Alvarez-López, María R; Minguela, Alfredo

2009-01-01

We report the first case of hemophagocytic lymphohistiocytosis (HLH) induced by the monoclonal expansion of Epstein-Barr virus (EBV)-negative NK cells. Consanguinity of the patient's parents made it necessary to discard familial HLH in the patient and her sister with identical HLA markers and demonstrate that no cause other than the expansion of NK cells, which secrete high levels of gamma interferon, was inducing HLH in this patient.

The antiviral activities of ISG15.

PubMed

Morales, David J; Lenschow, Deborah J

2013-12-13

Post-translational protein modification is an important strategy for the regulation of the cell proteome independent of the need for new gene expression. Ubiquitin and ubiquitin-like modifiers mediate the regulation of protein levels, signaling pathways, vesicular trafficking, and many other cellular processes through their covalent conjugation to proteins. Interferon stimulated gene 15 (ISG15) is a ubiquitin-like modifier induced by type I interferon. In addition to conjugating to potentially hundreds of target proteins, ISG15 can be found in an unconjugated form both inside of the cell and released from interferon stimulated cells into the extracellular environment. Due to its robust expression after type I interferon stimulation and the broad panel of proteins that it targets, ISG15 has drawn much attention as a potential regulator of the immune response and has been shown to mediate protection in a number of different viral infection models. Here we will review the current state of the field of ISG15, the viruses against which ISG15 mediates protection, and the mechanisms by which ISG15 exerts antiviral activity. © 2013.

Expression profiles of adult T-cell leukemia–lymphoma and associations with clinical responses to zidovudine and interferon α

PubMed Central

ALIZADEH, ASH A.; BOHEN, SEAN P.; LOSSOS, CHEN; MARTINEZ-CLIMENT, JOSE A.; RAMOS, JUAN CARLOS; CUBEDO-GIL, ELENA; HARRINGTON, WILLIAM J.; LOSSOS, IZIDORE S.

2014-01-01

Adult T-cell leukemia–lymphoma (ATLL) is an HTLV-1-associated lymphoproliferative malignancy that is frequently fatal. We compared gene expression profiles (GEPs) of leukemic specimens from nine patients with ATLL at the time of diagnosis and immediately after combination therapy with zidovudine (AZT) and interferon α (IFNα). GEPs were also related to genetic aberrations determined by comparative genomic hybridization. We identified several genes anomalously over-expressed in the ATLL leukemic cells at the mRNA level, including LYN, CSPG2, and LMO2, and confirmed LMO2 expression in ATLL cells at the protein level. In vivo AZT–IFNα therapy evoked a marked induction of interferon-induced genes accompanied by repression of cell-cycle regulated genes, including those encoding ribosomal proteins. Remarkably, patients not responding to AZT–IFNα differed most from responding patients in lower expression of these same IFN-responsive genes, as well as components of the antigen processing and presentation apparatus. Demonstration of specific gene expression signatures associated with response to AZT–IFNα therapy may provide novel insights into the mechanisms of action in ATLL. PMID:20370541

Expression of interferon-induced antiviral genes is delayed in a STAT1 knockout mouse model of Crimean-Congo hemorrhagic fever.

PubMed

Bowick, Gavin C; Airo, Adriana M; Bente, Dennis A

2012-06-19

Crimean Congo hemorrhagic fever (CCHF) is a tick-borne hemorrhagic zoonosis associated with high mortality. Pathogenesis studies and the development of vaccines and antivirals against CCHF have been severely hampered by the lack of suitable animal model. We recently developed and characterized a mature mouse model for CCHF using mice carrying STAT1 knockout (KO). Given the importance of interferons in controlling viral infections, we investigated the expression of interferon pathway-associated genes in KO and wild-type (WT) mice challenged with CCHF virus. We expected that the absence of the STAT1 protein would result in minimal expression of IFN-related genes. Surprisingly, the KO mice showed high levels of IFN-stimulated gene expression, beginning on day 2 post-infection, while in WT mice challenged with virus the same genes were expressed at similar levels on day 1. We conclude that CCHF virus induces similar type I IFN responses in STAT1 KO and WT mice, but the delayed response in the KO mice permits rapid viral dissemination and fatal illness.

Autonomous parvoviruses neither stimulate nor are inhibited by the type I interferon response in human normal or cancer cells.

PubMed

Paglino, Justin C; Andres, Wells; van den Pol, Anthony N

2014-05-01

Members of the genus Parvovirus are small, nonenveloped single-stranded DNA viruses that are nonpathogenic in humans but have potential utility as cancer therapeutics. Because the innate immune response to parvoviruses has received relatively little attention, we compared the response to parvoviruses to that of several other types of viruses in human cells. In normal human glia, fibroblasts, or melanocytes, vesicular stomatitis virus evoked robust beta interferon (IFN-β) responses. Cytomegalovirus, pseudorabies virus, and Sindbis virus all evoked a 2-log-unit or greater upregulation of IFN-β in glia; in contrast, LuIII and MVMp parvoviruses did not evoke a detectable IFN-β or interferon-stimulated gene (ISG; MX1, oligoadenylate synthetase [OAS], IFIT-1) response in the same cell types. The lack of response raised the question of whether parvoviral infection can be attenuated by IFN; interestingly, we found that IFN did not decrease parvovirus (MVMp, LuIII, and H-1) infectivity in normal human glia, fibroblasts, or melanocytes. The same was true in human cancers, including glioma, sarcoma, and melanoma. Similarly, IFN failed to attenuate transduction by the dependovirus vector adeno-associated virus type 2. Progeny production of parvoviruses was also unimpaired by IFN in both glioma and melanoma, whereas vesicular stomatitis virus replication was blocked. Sarcoma cells with upregulated IFN signaling that show high levels of resistance to other viruses showed strong infection by LuIII. Unlike many other oncolytic viruses, we found no evidence that impairment of innate immunity in cancer cells plays a role in the oncoselectivity of parvoviruses in human cells. Parvoviral resistance to the effects of IFN in cancer cells may constitute an advantage in the virotherapy of some tumors. Understanding the interactions between oncolytic viruses and the innate immune system will facilitate employing these viruses as therapeutic agents in cancer patients. The cancer-selective nature of some oncolytic viruses is based on the impaired innate immunity of many cancer cells. The parvoviruses H-1, LuIII, and MVM target cancer cells; however, their relationship with the innate immune system is relatively uncharacterized. Surprisingly, we found that these parvoviruses do not evoke an interferon response in normal human fibroblasts, glia, or melanocytes. Furthermore, unlike most other types of virus, we found that parvovirus infectivity is unaffected by interferon treatment of human normal or tumor cells. Finally, parvoviral replication was unimpaired by interferon in four human tumor types, including those with residual interferon functionality. We conclude that deficits in the interferon antiviral response of cancer cells do not contribute to parvoviral oncoselectivity in human cells. The interferon-resistant phenotype of parvoviruses may give them an advantage over interferon-sensitive oncolytic viruses in tumors showing residual interferon functionality.

Autonomous Parvoviruses neither Stimulate nor Are Inhibited by the Type I Interferon Response in Human Normal or Cancer Cells

PubMed Central

Paglino, Justin C.; Andres, Wells

2014-01-01

ABSTRACT Members of the genus Parvovirus are small, nonenveloped single-stranded DNA viruses that are nonpathogenic in humans but have potential utility as cancer therapeutics. Because the innate immune response to parvoviruses has received relatively little attention, we compared the response to parvoviruses to that of several other types of viruses in human cells. In normal human glia, fibroblasts, or melanocytes, vesicular stomatitis virus evoked robust beta interferon (IFN-β) responses. Cytomegalovirus, pseudorabies virus, and Sindbis virus all evoked a 2-log-unit or greater upregulation of IFN-β in glia; in contrast, LuIII and MVMp parvoviruses did not evoke a detectable IFN-β or interferon-stimulated gene (ISG; MX1, oligoadenylate synthetase [OAS], IFIT-1) response in the same cell types. The lack of response raised the question of whether parvoviral infection can be attenuated by IFN; interestingly, we found that IFN did not decrease parvovirus (MVMp, LuIII, and H-1) infectivity in normal human glia, fibroblasts, or melanocytes. The same was true in human cancers, including glioma, sarcoma, and melanoma. Similarly, IFN failed to attenuate transduction by the dependovirus vector adeno-associated virus type 2. Progeny production of parvoviruses was also unimpaired by IFN in both glioma and melanoma, whereas vesicular stomatitis virus replication was blocked. Sarcoma cells with upregulated IFN signaling that show high levels of resistance to other viruses showed strong infection by LuIII. Unlike many other oncolytic viruses, we found no evidence that impairment of innate immunity in cancer cells plays a role in the oncoselectivity of parvoviruses in human cells. Parvoviral resistance to the effects of IFN in cancer cells may constitute an advantage in the virotherapy of some tumors. IMPORTANCE Understanding the interactions between oncolytic viruses and the innate immune system will facilitate employing these viruses as therapeutic agents in cancer patients. The cancer-selective nature of some oncolytic viruses is based on the impaired innate immunity of many cancer cells. The parvoviruses H-1, LuIII, and MVM target cancer cells; however, their relationship with the innate immune system is relatively uncharacterized. Surprisingly, we found that these parvoviruses do not evoke an interferon response in normal human fibroblasts, glia, or melanocytes. Furthermore, unlike most other types of virus, we found that parvovirus infectivity is unaffected by interferon treatment of human normal or tumor cells. Finally, parvoviral replication was unimpaired by interferon in four human tumor types, including those with residual interferon functionality. We conclude that deficits in the interferon antiviral response of cancer cells do not contribute to parvoviral oncoselectivity in human cells. The interferon-resistant phenotype of parvoviruses may give them an advantage over interferon-sensitive oncolytic viruses in tumors showing residual interferon functionality. PMID:24554651

DNA nanotechnology-based composite-type gold nanoparticle-immunostimulatory DNA hydrogel for tumor photothermal immunotherapy.

PubMed

Yata, Tomoya; Takahashi, Yuki; Tan, Mengmeng; Nakatsuji, Hirotaka; Ohtsuki, Shozo; Murakami, Tatsuya; Imahori, Hiroshi; Umeki, Yuka; Shiomi, Tomoki; Takakura, Yoshinobu; Nishikawa, Makiya

2017-11-01

Success of tumor photothermal immunotherapy requires a system that induces heat stress in cancer cells and enhances strong anti-tumor immune responses. Here, we designed a composite-type immunostimulatory DNA hydrogel consisting of a hexapod-like structured DNA (hexapodna) with CpG sequences and gold nanoparticles. Mixing of the properly designed hexapodna and oligodeoxynucleotide-modified gold nanoparticles resulted in the formation of composite-type gold nanoparticle-DNA hydrogels. Laser irradiation of the hydrogel resulted in the release of hexapodna, which efficiently stimulated immune cells to release proinflammatory cytokines. Then, EG7-OVA tumor-bearing mice received an intratumoral injection of a gold nanoparticle-DNA hydrogel, followed by laser irradiation at 780 nm. This treatment increased the local temperature and the mRNA expression of heat shock protein 70 in the tumor tissue, increased tumor-associated antigen-specific IgG levels in the serum, and induced tumor-associated antigen-specific interferon-γ production from splenocytes. Moreover, the treatment significantly retarded the tumor growth and extended the survival of the tumor-bearing mice. Copyright © 2017 Elsevier Ltd. All rights reserved.

Consumption of Dairy Yogurt Containing Lactobacillus paracasei ssp. paracasei, Bifidobacterium animalis ssp. lactis and Heat-Treated Lactobacillus plantarum Improves Immune Function Including Natural Killer Cell Activity.

PubMed

Lee, Ayoung; Lee, Young Ju; Yoo, Hye Jin; Kim, Minkyung; Chang, Yeeun; Lee, Dong Seog; Lee, Jong Ho

2017-05-31

The aim of this study was to investigate the impact of consuming dairy yogurt containing Lactobacillus paracasei ssp. paracasei ( L. paracasei ), Bifidobacterium animalis ssp. lactis ( B. lactis ) and heat-treated Lactobacillus plantarum ( L. plantarum ) on immune function. A randomized, open-label, placebo-controlled study was conducted on 200 nondiabetic subjects. Over a twelve-week period, the test group consumed dairy yogurt containing probiotics each day, whereas the placebo group consumed milk. Natural killer (NK) cell activity, interleukin (IL)-12 and immunoglobulin (Ig) G1 levels were significantly increased in the test group at twelve weeks compared to baseline. Additionally, the test group had significantly greater increases in serum NK cell activity and interferon (IFN)-γ and IgG1 than placebo group. Daily consumption of dairy yogurt containing L. paracasei , B. lactis and heat-treated L. plantarum could be an effective option to improve immune function by enhancing NK cell function and IFN-γ concentration (ClinicalTrials.gov: NCT03051425).

Consumption of Dairy Yogurt Containing Lactobacillus paracasei ssp. paracasei, Bifidobacterium animalis ssp. lactis and Heat-Treated Lactobacillus plantarum Improves Immune Function Including Natural Killer Cell Activity

PubMed Central

Lee, Ayoung; Lee, Young Ju; Yoo, Hye Jin; Kim, Minkyung; Chang, Yeeun; Lee, Dong Seog; Lee, Jong Ho

2017-01-01

The aim of this study was to investigate the impact of consuming dairy yogurt containing Lactobacillus paracasei ssp. paracasei (L. paracasei), Bifidobacterium animalis ssp. lactis (B. lactis) and heat-treated Lactobacillus plantarum (L. plantarum) on immune function. A randomized, open-label, placebo-controlled study was conducted on 200 nondiabetic subjects. Over a twelve-week period, the test group consumed dairy yogurt containing probiotics each day, whereas the placebo group consumed milk. Natural killer (NK) cell activity, interleukin (IL)-12 and immunoglobulin (Ig) G1 levels were significantly increased in the test group at twelve weeks compared to baseline. Additionally, the test group had significantly greater increases in serum NK cell activity and interferon (IFN)-γ and IgG1 than placebo group. Daily consumption of dairy yogurt containing L. paracasei, B. lactis and heat-treated L. plantarum could be an effective option to improve immune function by enhancing NK cell function and IFN-γ concentration (ClinicalTrials.gov: NCT03051425). PMID:28561762

Efficacy and safety of adoptive immunotherapy using anti-CD19 chimeric antigen receptor transduced T-cells: a systematic review of phase I clinical trials.

PubMed

Xu, Xiao-Jun; Zhao, Hai-Zhao; Tang, Yong-Min

2013-02-01

There remain some key questions regarding the adoptive infusion of chimeric antigen receptor (CAR) transduced T-cells in the clinical setting. This article systematically reviews the phase I clinical trials using CARs targeting CD19 in B-lineage malignancies. Twenty-nine patients were enrolled and the 6-month progression free survival for this cohort was 50.0 ± 9.9%. Univariate analysis showed that patients benefited from lymphodepletion before CAR+T-cell infusion and the administration of interleukin-2 (IL-2). Longer-term persistence (≥ 4 weeks) and stronger expansion of CAR+ T-cells in the blood and higher peak serum interferon-γ (IFN-γ) level (≥ 200 pg/mL) were also related to superior outcome. Regarding treatment-related adverse events, the most prominent toxicities were fever, rigors, chills, acute renal failure, hypotension and capillary leak syndrome. In conclusion, anti-CD19 CAR+ T-cells have shown some benefits in patients with B-lineage malignancies and are well tolerated in most patients. Preconditioning and cytokine supplement are required to improve the clinical outcome.

[Interferon. An overview of the state of basic research with special regard to interferon-gamma].

PubMed

Günther, G; Otto, B

1993-02-01

Interferons / An overview on the state of basic research with special regard to interferon-gamma Interferons are multifunctional glycoproteins with a broad range of antiviral, antiproliferative and immunoregulatory effects on the target cell. This review deals with the basics as well as with more recent developments in interferon research. A historic overview of 35 years of interferon research since the discovery of interferons by Isaacs and Lindenmann in 1957 introduces the most important milestones in this field and appreciates the work of the participating researchers. A brief description of the classification of interferons based on different tissue sources, different antigenic properties and different induction behaviour is made. The main part of this review focuses on human interferon-gamma. We discuss recent work on the structure-function relationship of interferon-gamma. The interferon-gamma receptor and its role in signal transduction is another part of this paper. The structure and length of the C-terminal region of interferon-gamma seems to be important for receptor binding and expression of biological activities. A conservative estimate is that the family of IFN-activated genes numbers 15-20 in most cells.

Treatment of Waldenstrom's macroglobulinemia with very low doses of alpha interferon.

PubMed

Legouffe, E; Rossi, J F; Laporte, J P; Isnard, F; Oziol, E; Fabbro, M; Janbon, C; Jourdan, J; Najman, A

1995-10-01

Waldenström's macroglobulinemia (WM) is a differentiated B-cell malignancy which is usually less responsive to standard chemotherapy because of low-proliferating cells. Interferon alpha has been shown to possess a therapeutic action in numerous B-cell malignancies including the early stage of chronic lymphocytic leukemia, multiple myeloma, follicular lymphoma and hairy cell leukemia. Fourteen patients with progressive WM were included in a pilot study using very low dose of interferon alpha-2a (1 Million Units 3 times a week). The mean duration of treatment was 10.3 months (range 2-44). Six of 14 (42%) patients presented an increase in the hemoglobin level (> or = 0.9 g/dL) and 4/14 (28%) had a substantial decrease of the monoclonal component (> or = 20% of reduction). Only two patients presented both types of response, while the others with an increase in the hemoglobin level had a slight decrease in the monoclonal component (MC) (1 patient), a stable MC (1 patient) or a slight increase of MC (1 patient). One additional patient had a 15% decrease of the MC with a stable hemoglobin level. Response was observed within 3 months with a median duration of 6 months. Treatment was stopped for 3 patients because of flu-like symptoms (2 patients), or thrombocytopenia (1 patient). Follow up was possible in 12 patients lasting up to a maximum of 30 months after discontinuing treatment. Seven patients died, including 4 with progressive disease, two of infection and one of cardiac failure. In the view of these results, very low dose of interferon alpha may constitute a new approach for treatment of some cases of WM.

Meta-Analysis Identifies NF-κB as a Therapeutic Target in Renal Cancer

PubMed Central

Peri, Suraj; Devarajan, Karthik; Yang, Dong-Hua; Knudson, Alfred G.; Balachandran, Siddharth

2013-01-01

Objective To determine the expression patterns of NF-κB regulators and target genes in clear cell renal cell carcinoma (ccRCC), their correlation with von Hippel Lindau (VHL) mutational status, and their association with survival outcomes. Methods Meta-analyses were carried out on published ccRCC gene expression datasets by RankProd, a non-parametric statistical method. DEGs with a False Discovery Rate of < 0.05 by this method were considered significant, and intersected with a curated list of NF-κB regulators and targets to determine the nature and extent of NF-κB deregulation in ccRCC. Results A highly-disproportionate fraction (~40%; p < 0.001) of NF-κB regulators and target genes were found to be up-regulated in ccRCC, indicative of elevated NF-κB activity in this cancer. A subset of these genes, comprising a key NF-κB regulator (IKBKB) and established mediators of the NF-κB cell-survival and pro-inflammatory responses (MMP9, PSMB9, and SOD2), correlated with higher relative risk, poorer prognosis, and reduced overall patient survival. Surprisingly, levels of several interferon regulatory factors (IRFs) and interferon target genes were also elevated in ccRCC, indicating that an ‘interferon signature’ may represent a novel feature of this disease. Loss of VHL gene expression correlated strongly with the appearance of NF-κB- and interferon gene signatures in both familial and sporadic cases of ccRCC. As NF-κB controls expression of key interferon signaling nodes, our results suggest a causal link between VHL loss, elevated NF-κB activity, and the appearance of an interferon signature during ccRCC tumorigenesis. Conclusions These findings identify NF-κB and interferon signatures as clinical features of ccRCC, provide strong rationale for the incorporation of NF-κB inhibitors and/or and the exploitation of interferon signaling in the treatment of ccRCC, and supply new NF-κB targets for potential therapeutic intervention in this currently-incurable malignancy. PMID:24116146

Interleukin-10 Contributes to Therapeutic Effect of Mesenchymal Stem Cells for Acute Liver Failure via Signal Transducer and Activator of Transcription 3 Signaling Pathway

PubMed Central

Ma, Hu-Cheng; Wang, Xin; Wu, Min-Na; Zhao, Xin; Yuan, Xian-Wen; Shi, Xiao-Lei

2016-01-01

Background: Mesenchymal stem cells (MSCs) transplantation has been proven to have therapeutic potential for acute liver failure (ALF). However, the mechanism remains controversial. Recently, modulation of inflammation by MSCs has been regarded as a crucial mechanism. The aim of the present study was to explore the soluble cytokines secreted by MSCs and their therapeutic effects in ALF. Methods: MSCs isolated from Sprague-Dawley rats were identified by fluorescence-activated cell sorting analysis. Conditioned medium derived from MSCs (MSCs-CM) was collected and analyzed by a cytokine microarray. MSCs and MSCs-CM were transplanted into rats with D-galactosamine-induced ALF. Liver function, survival rate, histology, and inflammatory factors were determined. Exogenous recombinant rat interleukin (IL)-10, anti-rat IL-10 antibody, and AG490 (signal transducer and activator of transcription 3 [STAT3] signaling pathway inhibitor) were administered to explore the therapeutic mechanism of MSCs-CM. Statistical analysis was performed with SPSS version 19.0, and all data were analyzed by the independent-sample t-test. Results: There are statistical differences of the survival curve between ALF+MSCs group and ALF+Dulbecco's modified Eagle's medium (DMEM) group, as well as ALF+MSCs-CM group and ALF+DMEM group (all P < 0.05). Serum alanine aminotransferase (ALT) level in the ALF+MSCs and ALF+MSCs-CM groups was lower than that in the ALF+DMEM group (865.53±52.80 vs. 1709.75±372.12 U/L and 964.72±414.59 vs. 1709.75±372.12 U/L, respectively, all P < 0.05); meanwhile, serum aspartate aminotransferase (AST) level in the ALF+MSCs and ALF+MSCs-CM groups was lower than that in the ALF+DMEM group (2440.83±511.94 vs. 4234.35±807.30 U/L and 2739.83±587.33 vs. 4234.35±807.30 U/L, respectively, all P < 0.05). Furthermore, MSCs or MSCs-CM treatment significantly reduced serum interferon-γ (IFN-γ), IL-1β, IL-6 levels and increased serum IL-10 level compared with DMEM (all P < 0.05). Proteome profile analysis of MSCs-CM indicated the presence of anti-inflammatory factors and IL-10 was the most distinct. Blocking of IL-10 confirmed the therapeutic significance of this cytokine. Phosphorylated STAT3 was upregulated after IL-10 infusion and inhibition of STAT3 by AG490 reversed the therapeutic effect of IL-10. Conclusions: The factors released by MSCs, especially IL-10, have the potential for therapeutic recovery of ALF, and the STAT3 signaling pathway may mediate the anti-inflammatory effect of IL-10. PMID:27064043

Role of B7 costimulatory molecules in immune responses and T-helper cell differentiation in response to recombinant HagB from Porphyromonas gingivalis.

PubMed

Zhang, Ping; Martin, Michael; Yang, Qiu-Bo; Michalek, Suzanne M; Katz, Jannet

2004-02-01

In addition to antigen-specific signals mediated through the T-cell receptor, T cells also require antigen nonspecific costimulation for activation. The B7 family of molecules on antigen-presenting cells, which include B7-1 (CD80) and B7-2 (CD86), play important roles in providing costimulatory signals required for development of antigen-specific immune responses. Hemagglutinin B (HagB) is a nonfimbrial adhesin of the periodontopathic microorganism Porphyromonas gingivalis and is thought to be involved in the attachment of the bacterium to host tissues. However, the immune mechanisms involved in responses to HagB and their roles in pathogenesis have yet to be elucidated. Therefore, the purpose of this study was to determine the role of B7 costimulatory molecules on T-helper-cell differentiation for the induction of immune responses to HagB. Mice deficient in either or both of the costimulatory molecules B7-1 and B7-2 were used to explore their role in immune responses to HagB after subcutaneous immunization. B7-1(-/-) mice had levels of immunoglobulin G (IgG) anti-HagB antibody activity in serum similar to those of wild-type mice, whereas lower serum IgG anti-HagB antibody responses were seen in B7-2(-/-) mice. Moreover, significantly lower numbers of IgG antibody-secreting cells and lower levels of CD4(+)-T-cell proliferation were observed in B7-2(-/-) mice compared to wild-type mice. No serum IgG response to HagB was detected in B7-1/B7-2(-/-) mice. Analysis of the subclass of the serum IgG responses and the cytokines induced in response to HagB revealed that B7-2(-/-) mice had significantly lower IgG1 and higher IgG2a anti-HagB antibody responses compared to wild-type mice. The B7-2(-/-) mice also had significantly reduced levels of interleukin-4 (IL-4) and IL-5 and enhanced level of gamma interferon. Furthermore, assessment of B7-1 and B7-2 expression on B cells and macrophages derived from wild-type BALB/c mice after in vitro stimulation with HagB revealed a predominant upregulation in the expression of the B7-2 costimulatory molecule on B cells and macrophages. Essentially no change was seen in the expression of B7-1. Taken together, these results suggest a critical role for B7, especially B7-2, for the preferential induction of a Th2-like response to HagB.

Interferons and Their Receptors in Birds: A Comparison of Gene Structure, Phylogenetic Analysis, and Cross Modulation

PubMed Central

Zhou, Hao; Chen, Shun; Wang, Mingshu; Cheng, Anchun

2014-01-01

Interferon may be thought of as a key, with the interferon receptor as the signal lock: Crosstalk between them maintains their balance during viral infection. In this review, the protein structure of avian interferon and the interferon receptor are discussed, indicating remarkable similarity between different species. However, the structures of the interferon receptors are more sophisticated than those of the interferons, suggesting that the interferon receptor is a more complicated signal lock system and has considerable diversity in subtypes or structures. Preliminary evolutionary analysis showed that the subunits of the interferon receptor formed a distinct clade, and the orthologs may be derived from the same ancestor. Furthermore, the development of interferons and interferon receptors in birds may be related to an animal’s age and the maintenance of a balanced state. In addition, the equilibrium between interferon and its receptor during pathological and physiological states revealed that the virus and the host influence this equilibrium. Birds could represent an important model for studies on interferon’s antiviral activities and may provide the basis for new antiviral strategies. PMID:25405736

Community nurse-led initiation of antiviral therapy for chronic hepatitis C in people who inject drugs does not increase uptake of or adherence to treatment.

PubMed

Lewis, Heather; Kunkel, Jan; Axten, David; Dalton, Jane; Gardner, Hayley; Tippett, Andrew; Wynne, Stephanie; Wilkinson, Mandie; Foster, Graham R

2016-11-01

Chronic hepatitis C is common in people who inject drugs (PWID) and this population serves as a reservoir for infection. Treatment levels are low among this group, ranging from 1 to 19%. We explored whether a nurse-initiated community treatment model increased uptake of and adherence to interferon-based therapies. This was a cluster randomized trial of nurse-initiated versus physician-initiated antiviral therapy with pegylated interferon and ribavirin for hepatitis C virus in community clinics (trial registration: ISRCTN07774040). The proportion of participants initiating treatment during follow-up was 10% with nurse-initiated (6/62) and 9% with physician-initiated (6/76) therapy. Adherence was similar in both groups, with only one patient in each arm not adhering to therapy. There were no serious adverse events, but interferon-related side effects were common. Drug and alcohol use did not change during therapy. Despite easy access to antiviral therapy, uptake of treatment was poor, with no significant difference between the groups. Nurse-led initiation of interferon-based antiviral therapy in PWID did not lead to increased uptake of, response to or adherence with treatment. Further service improvement is unlikely to increase the proportion of PWID undergoing antiviral therapy for hepatitis C virus and early adoption of interferon-free regimens may increase the proportion initiating and completing treatment.

Changes in Fasting Plasma Glucose Levels with Ribavirin and Pegylated Interferon Treatment in Normal and Impaired Glucose Tolerant Patients with Chronic Hepatitis C

PubMed Central

Sarasombath, Ongkarn; Suwantarat, Nuntra; Tice, Alan D

2012-01-01

Background Patients with Hepatitis C Virus (HCV) infection have increased rates of glucose intolerance, and studies have shown the improvement of fasting plasma glucose (FPG) levels after clearance of HCV infection with standard ribavirin plus pegylated interferon treatment. The purpose of this study was to examine glycemic changes with standard HCV treatment in patients with impaired fasting glucose (IFG) and normal fasting glucose (NFG). Methods A retrospective study of FPG changes in HCV patients with IFG and NFG treated with standard HCV therapy was conducted. Baseline characteristics and viral responses were assessed; FPG levels before treatment, at the end of treatment, and more than one-month post treatment were compared. Results The mean FPG levels increased by 8.68 mg/dl at the end of treatment in the NFG group but decreased by 9.0 mg/dl in the IFG group, a statistically significant difference (P=0.019). The change in FPG levels remained significantly different after adjusting for weight change (P=0.009) and weight changes and initial weight (P=0.039). FPG change from baseline at more than one month after treatment were similar in both groups (P=0.145). The change in FPG levels was not associated with sustained viral response. Conclusions In HCV-infected patients, standard ribavirin plus pegylated interferon treatment reduced FPG levels in patients with IFG and increased FPG levels in NFG individuals; independent of initial weight, weight change, or viral response. Standard HCV treatment modulates fasting plasma glucose levels which supports the need for a prospective study to determine the clinical significance of this finding. PMID:22737650

Serum IFN-γ-induced protein 10 (IP-10) as a biomarker for severity of acute respiratory infection in healthy adults.

PubMed

Hayney, Mary S; Henriquez, Kelsey M; Barnet, Jodi H; Ewers, Tola; Champion, Heather M; Flannery, Sean; Barrett, Bruce

2017-05-01

The inflammatory chemokine, interferon-gamma inducible protein of 10kDa (IP-10), is a biomarker associated with several conditions. This study investigated serum concentrations of IP-10 in healthy individuals who developed acute respiratory infection (ARI). The hypothesis is that serum IP-10 concentrations correlate with ARI severity and detection of viral pathogens. Data come from a randomized controlled trial measuring the effects of mindfulness meditation or exercise on ARI (Clinical Trials ID: NCT01654289). Healthy adults ages 30-69 were followed for a single season for ARI incidence and severity. This trial is ongoing, and the investigators are still blinded. When a participant reported ARI symptoms, nasal swab and lavage for PCR-based viral identification and blood samples were collected within the first 72h of ARI symptoms. Serum IP-10 concentrations were measured by ELISA (R&D Systems, Inc., Quantikine ELISA, Minneapolis, MN). ARI severity was measured using the validated Wisconsin Upper Respiratory Symptom Survey (WURSS-24) until the ARI episode resolved. Serum IP-10 concentrations from 225 ARI episodes correlated with ARI global severity (rho 0.28 [95% CI: 0.15-0.39]; p<0.001). IP-10 concentrations were higher with an ARI in which a viral pathogen was detected compared to no viral pathogen detected (median 366pg/ml [IQR: 227-486] vs 163pg/ml [IQR: 127-295], p<0.0001). Influenza infections had higher IP-10 concentrations than coronavirus, enterovirus or rhinovirus, and paramyxovirus. Serum IP-10 concentration correlates with ARI global severity. Also, IP-10 concentration measured early in the course of the ARI correlates with the daily severity, duration, and illness symptoms. Copyright © 2017 Elsevier B.V. All rights reserved.

The Human Respiratory Syncytial Virus Nonstructural Protein 1 Regulates Type I and Type II Interferon Pathways*

PubMed Central

Hastie, Marcus L.; Headlam, Madeleine J.; Patel, Nirav B.; Bukreyev, Alexander A.; Buchholz, Ursula J.; Dave, Keyur A.; Norris, Emma L.; Wright, Cassandra L.; Spann, Kirsten M.; Collins, Peter L.; Gorman, Jeffrey J.

2012-01-01

Respiratory syncytial viruses encode a nonstructural protein (NS1) that interferes with type I and III interferon and other antiviral responses. Proteomic studies were conducted on human A549 type II alveolar epithelial cells and type I interferon-deficient Vero cells (African green monkey kidney cells) infected with wild-type and NS1-deficient clones of human respiratory syncytial virus to identify other potential pathway and molecular targets of NS1 interference. These analyses included two-dimensional differential gel electrophoresis and quantitative Western blotting. Surprisingly, NS1 was found to suppress the induction of manganese superoxide dismutase (SOD2) expression in A549 cells and to a much lesser degree Vero cells in response to infection. Because SOD2 is not directly inducible by type I interferons, it served as a marker to probe the impact of NS1 on signaling of other cytokines known to induce SOD2 expression and/or indirect effects of type I interferon signaling. Deductive analysis of results obtained from cell infection and cytokine stimulation studies indicated that interferon-γ signaling was a potential target of NS1, possibly as a result of modulation of STAT1 levels. However, this was not sufficient to explain the magnitude of the impact of NS1 on SOD2 induction in A549 cells. Vero cell infection experiments indicated that NS1 targeted a component of the type I interferon response that does not directly induce SOD2 expression but is required to induce another initiator of SOD2 expression. STAT2 was ruled out as a target of NS1 interference using quantitative Western blot analysis of infected A549 cells, but data were obtained to indicate that STAT1 was one of a number of potential targets of NS1. A label-free mass spectrometry-based quantitative approach is proposed as a means of more definitive identification of NS1 targets. PMID:22322095

Alpha Interferon Restricts Human T-Lymphotropic Virus Type 1 and 2 De Novo Infection through PKR Activation

PubMed Central

Cachat, Anne; Chevalier, Sébastien Alain; Alais, Sandrine; Ko, Nga Ling; Ratner, Lee; Journo, Chloé; Dutartre, Hélène

2013-01-01

Type I interferon (IFN-I) inhibits the replication of different viruses. However, the effect of IFN-I on the human T-lymphotropic virus type 1 (HTLV-1) viral cycle is controversial. Here, we investigated the consequences of IFN-α addition for different steps of HTLV-1 and HTLV-2 infection. We first show that alpha interferon (IFN-α) efficiently impairs HTLV-1 and HTLV-2 de novo infection in a T cell line and in primary lymphocytes. Using pseudotyped viruses expressing HTLV-1 envelope, we then show that cell-free infection is insensitive to IFN-α, demonstrating that the cytokine does not affect the early stages of the viral cycle. In contrast, intracellular levels of Gag, Env, or Tax protein are affected by IFN-α treatment in T cells, primary lymphocytes, or 293T cells transfected with HTLV-1 or HTLV-2 molecular clones, demonstrating that IFN-α acts during the late stages of infection. We show that IFN-α does not affect Tax-mediated transcription and acts at a posttranscriptional level. Using either small interfering RNA (siRNA) directed against PKR or a PKR inhibitor, we demonstrate that PKR, whose expression is induced by interferon, plays a major role in IFN-α-induced HTLV-1/2 inhibition. These results indicate that IFN-α has a strong repressive effect on the HTLV-1 and HTLV-2 viral cycle during de novo infection of cells that are natural targets of the viruses. PMID:24089560

Agaricus blazei Murrill and inflammatory mediators in elderly women: a randomized clinical trial.

PubMed

Lima, C U J O; Souza, V C; Morita, M C; Chiarello, M D; Karnikowski, M G de Oliveira

2012-03-01

There is scientific evidence to suggest that the medicinal mushroom Agaricus blazei Murrill (AbM) has immunomodulatory effects on cytokine synthesis, both in vitro and in vivo. This study was the first randomized, double-blind, placebo-controlled trial designed to investigate these purported actions in elderly women. The objective of this study was to ascertain the effects of AbM intake on serum levels of interleukin-6 (IL-6), interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α) in community-living seniors. The sample consisted of 57 elderly females who were carriers or homozygous for the majority allele of functional polymorphisms for the chosen cytokines. Subjects were randomly allocated to receive placebo (n = 29) or AbM dry extract (n = 28), 900 mg/day for 60 days. Body mass index, abdominal girth, body composition, blood pressure and cytokine (IL-6, IFN-γ, and TNF-α) levels were measured, and food intake was assessed as a possible confounder. Analysis of these parameters showed the sample was characterized by overweight and excess adiposity. After the study period, no changes from baseline were detectable for any parameter in either group. In this study, AbM extract had no modulating effect on IL-6, IFN-γ or TNF-α levels in elderly females. © 2011 The Authors. Scandinavian Journal of Immunology © 2011 Blackwell Publishing Ltd.

CRACC-CRACC Interaction between Kupffer and NK Cells Contributes to Poly I:C/D-GalN Induced Hepatitis

PubMed Central

Li, Yangxi; Cao, Guoshuai; Zheng, Xiaodong; Wang, Jun; Wei, Haiming; Tian, Zhigang; Sun, Rui

2013-01-01

CD2-like receptor activating cytotoxic cells (CRACC) is known as a critical activating receptor of natural killer (NK) cells. We have previously reported that NK cells contribute to Poly I:C/D-galactosamine (D-GalN)-induced fulminant hepatitis. Since natural killer group 2, member D (NKG2D) is considered critical but not the only activating receptor for NK cells, we investigated the role of CRACC in this model. We found that CRACC was abundant on hepatic NK cells but with low expression levels on Kupffer cells under normal conditions. Expression of CRACC on NK cells and Kupffer cells was remarkably upregulated after poly I:C injection. Hepatic CRACC mRNA levels were also upregulated in Poly I:C/D-GalN-treated mice, and correlated positively with the serum alanine aminotransferase (ALT) levels. CRACC expression on Kupffer cells was specifically silenced by nano-particle encapsulated siRNA in vivo, which significantly reduced Poly I:C/D-GalN-induced liver injury. In co-culture experiments, it was further verified that silencing CRACC expression or blockade of CRACC activation by mAb reduced the production of interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Collectively, our findings suggest that CRACC-CRACC interaction between NK cells and resident Kupffer cells contributes to Poly I:C/D-GalN-induced fulminant hepatitis. PMID:24098802

Enhanced IFN-α production is associated with increased TLR7 retention in the lysosomes of palasmacytoid dendritic cells in systemic lupus erythematosus.

PubMed

Murayama, Goh; Furusawa, Nanako; Chiba, Asako; Yamaji, Ken; Tamura, Naoto; Miyake, Sachiko

2017-10-19

Interferon-α (IFN-α) is increased and plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) are the main producer of IFN-α, but their IFN-α producing capacity has been shown to be unchanged or reduced when stimulated with a Toll-like receptor 9 (TLR9) agonist in patients with SLE compared to in healthy individuals. In this study, we investigated the IFN-α-producing capacity of lupus pDCs under different stimulation. pDCs from patients with SLE and healthy controls (HC) were stimulated with TLR9 or TLR7 agonist, and their IFN-α producing capacity was examined by intracellular cytokine staining and flow cytometry. The correlation of IFN-α-producing capacity with serum IFN-α levels and disease activity was assessed. The effect of in vitro IFN-α exposure on IFN-α production by pDCs was examined. Localization of TLR7 in cellular compartments in pDCs was investigated. The IFN-α producing capacity of pDCs was reduced after TLR9 stimulation, but increased when stimulated with a TLR7 agonist in SLE compared to in HC. IFN-α production by pDCs upon TLR9 stimulation was reduced and the percentage of IFN-α + pDC was inversely correlated with disease activity and serum IFN-α levels. However, the TLR7 agonist-induced IFN-α producing capacity of lupus pDCs was enhanced and correlated with disease activity and serum IFN-α. Exposure to IFN-α enhanced IFN-α production of TLR7-stimulated pDCs, but reduced that of pDCs activated with a TLR9 agonist. TLR7 localization was increased in late endosome/lysosome compartments in pDCs from SLE patients. These findings indicate that enhanced TLR7 responses of lupus pDCs, owing to TLR7 retention in late endosome/lysosome and exposure to IFN-α, are associated with the pathogenesis of SLE.

Evaluation of viremia, proviral load and cytokine profile in naturally feline immunodeficiency virus infected cats treated with two different protocols of recombinant feline interferon omega.

PubMed

Leal, Rodolfo O; Gil, Solange; Duarte, Ana; McGahie, David; Sepúlveda, Nuno; Niza, Maria M R E; Tavares, Luís

2015-04-01

This study assesses viremia, provirus and blood cytokine profile in naturally FIV-infected cats treated with two distinct protocols of interferon omega (rFeIFN-ω). Samples from FIV-cats previously submitted to two single-arm studies were used: 7/18 received the licensed/subcutaneous protocol (SC) while 11/18 were treated orally (PO). Viremia, provirus and blood mRNA expression of interleukin (IL)-1, IL-4, IL-6, IL-10, IL-12p40, Interferon-γ and Tumor Necrosis Factor-α were monitored by Real-Time qPCR. Concurrent plasma levels of IL-6, IL-12p40 and IL-4 were assessed by ELISA. IL-6 plasma levels decreased in the SC group (p = 0.031). IL-6 mRNA expression (p = 0.037) decreased in the PO group, albeit not sufficiently to change concurrent plasma levels. Neither viremia nor other measured cytokines changed with therapy. Proviral load increased in the SC group (p = 0.031), which can be justified by a clinically irrelevant increase of lymphocyte count. Independently of the protocol, rFeIFN-ω seems to act on innate immunity by reducing pro-inflammatory stimulus. Copyright © 2015 Elsevier Ltd. All rights reserved.