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Sample records for interferon beta-1a avonex

  1. Quality of Life Assessment in Patients with Multiple Sclerosis Receiving Interferon Beta-1a: A Comparative Longitudinal Study of Avonex and Its Biosimilar CinnoVex.

    PubMed

    Abolfazli, R; Hosseini, A; Gholami, Kh; Javadi, M R; Torkamandi, H; Emami, S

    2012-01-01

    Background. Multiple sclerosis (MS) is an autoimmune inflammatory disease of central nervous system (CNS). MS affects quality of Life (QOL) due to physical disability and other associated problems. Disease-modifying agents like interferon beta (IFNB) have been widely utilized in this patient population; however, their frequency, route of administration, side effects, high cost, and also the question of whether they are truly beneficial for longer-term outcomes and QOL need to be further investigated. Objectives. To assess QOL in patients with multiple sclerosis receiving interferon beta-1a (Avonex or CinnoVex) and in order to compare QOL in groups receiving Avonex and CinnoVex, respectively, also, to evaluate whether the more cost-effective biosimilar form of IFNB (CinnoVex) has the same effect on QOL and can be substituted for Avonex. Methods. We conducted a 30-month, nonrandomized longitudinal study and recruited a total of 92 patients diagnosed with relapsing-remitting MS. The patients were distributed in Avonex and CinnoVex groups with 46 patients in each group. Quality of life was assessed by means of MSQOL-54 questionnaire, four times a year, at baseline and at months 4, 8, and 12 of the study. Results. Mean age ± SD was 30.5 ± 8.9 and 32.3 ± 9.0 years in Avonex and CinnoVex groups, respectively, and P value of gender was different (P value : 0.036). The physical health composite scores were 61.8 and 59.8 (P values 0.677 and 0.884) for Avonex and CinnoVex groups, in that order. The results of the study revealed no significant difference between the two groups with regard to physical health, health perception, energy, and role limitations due to physical problems, pain, sexual and social function, and physical health distress scores. Further, interferon therapy did not significantly impact patients' QOL after a year of treatment with either Avonex or CinnoVex. Conclusions. According to the present study, treatment with IFNB (Avonex or Cinno

  2. Interferon Beta-1a Intramuscular Injection

    MedlinePlus

    Interferon beta-1a intramuscular injection is used to reduce the number of episodes of symptoms and slow ... and problems with vision, speech, and bladder control). Interferon beta-1a is in a class of medications ...

  3. Interferon Beta-1a Subcutaneous Injection

    MedlinePlus

    Interferon beta-1a subcutaneous injection is used to reduce episodes of symptoms and slow the development of ... and problems with vision, speech, and bladder control). Interferon beta-1a is in a class of medications ...

  4. Interferon-beta-1a: A Review of its Pharmacological Properties and Therapeutic Potential in Multiple Sclerosis.

    PubMed

    Holliday, S M; Benfield, P

    1997-10-01

    The presumed but as yet unspecified autoimmune-mediated basis for the pathogenesis of multiple sclerosis has led to attempts to modify the immune system of patients with this disease based on general and selective approaches. The rationale for using interferon-beta for the treatment of multiple sclerosis is based on its antiviral and complex immunoregulatory activities. Interferon-beta-1a (Avonex(R)) is a recombinant molecule which is indistinguishable from natural interferon-beta derived from human fibroblasts. Its precise mechanism of action is unknown, although effects on immune system processes which have been implicated in the pathogenesis of multiple sclerosis have been documented. T cell activation and migration into the CNS is a primary process in the pathogenesis of multiple sclerosis. In vitro and in vivo, interferon-beta-1a, compared with placebo or no treatment, significantly reduced expression of T cell surface activation markers, and significantly increased CNS levels of interleukin-10 - a potent inhibitor of cell-mediated immune responses. Pharmacokinetic studies indicate that intramuscular injection is the optimal route of administration for this formulation of interferon-beta-1a. In patients with relapsing-remitting multiple sclerosis who participated in a randomised double-blind trial, interferon-beta-1a 30mug (6 MIU) administered by intramuscular injection once weekly for 2 years (n = 158), compared with placebo (n = 143), significantly extended the time to onset of sustained neurological disability. Interferon-beta-1a also reduced the rate of disease relapse by approximately one-third compared with placebo, a finding which was supported by cranial magnetic resonance imaging (MRI) data showing significant reductions in lesion number and volume. Interferon-beta-1a was well tolerated, with influenza-like symptoms making up the majority of adverse reactions. The clinical significance of the beneficial effect of interferon-beta-1a on disease

  5. Economic evaluation of Avonex (interferon beta-Ia) in patients following a single demyelinating event.

    PubMed

    Iskedjian, Michael; Walker, John H; Gray, Trevor; Vicente, Colin; Einarson, Thomas R; Gehshan, Adel

    2005-10-01

    Interferon beta-Ia (Avonex) 30 microg, intramuscular (i.m.), once weekly is efficacious in delaying clinically definite multiple sclerosis (CDMS) following a single demyelinating event (SDE). This study determined the cost effectiveness of Avonex compared to current treatment in delaying the onset of CDMS. A cost-effectiveness analysis (CEA) and cost-utility analysis (CUA) were performed from Ministry of Health (MoH) and societal perspectives. For CEA, the outcome of interest was time spent in the pre-CDMS state, termed monosymptomatic life years (MLY) gained. For CUA, the outcome was quality-adjusted monosymptomatic life years (QAMLY) gained. A Markov model was developed with transitional probabilities and utilities derived from the literature. Costs were reported in 2002 Canadian dollars. Costs and outcomes were discounted at 5%. The time horizon was 12 years for the CEA, and 15 years for the CUA. All uncertainties were tested via univariate and multivariate sensitivity analyses. In the CEA, the incremental cost of Avonex per ILYgained was $53110 and $44789 from MoH and societal perspectives, respectively. In the CUA, the incremental cost of Avonex per QAMLY gained was $227586 and $189286 from MoH and societal perspectives, respectively. Both models were sensitive to the probability of progressing to CDMS and the analytical time horizon. The CUA was sensitive to the utilities value. Avonex may be considered as a reasonably cost-effective approach to treatment of patients experiencing an SDE In addition, the overall incremental cost-effectiveness profile of Avonex improves if treatment is initiated in pre-CDMS rather than waiting until CDMS.

  6. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis.

    PubMed

    Hauser, Stephen L; Bar-Or, Amit; Comi, Giancarlo; Giovannoni, Gavin; Hartung, Hans-Peter; Hemmer, Bernhard; Lublin, Fred; Montalban, Xavier; Rammohan, Kottil W; Selmaj, Krzysztof; Traboulsee, Anthony; Wolinsky, Jerry S; Arnold, Douglas L; Klingelschmitt, Gaelle; Masterman, Donna; Fontoura, Paulo; Belachew, Shibeshih; Chin, Peter; Mairon, Nicole; Garren, Hideki; Kappos, Ludwig

    2017-01-19

    B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks. The primary end point was the annualized relapse rate. The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred

  7. [The neurodegenerative process in multiple sclerosis and the possible neuroprotective effect of treatment with Β-interferon 1a (avonex)].

    PubMed

    Davydovskaia, M V; Boĭko, A N; Podoprigora, A E; Pronin, I N; Kornienko, V N; Gusev, E I

    2012-01-01

    The aim of the study was to investigate the change of NAA/Cr ratio in the brain parenchyma in patients with MS with the help of protonic multivoxel magnetic resonance spectroscopy (PMMRS) and to detect the correlation between this factor and clinical status of the patients. The study was also performed in order to investigate whether this method can be potentially used for monitoring of the severity of the disease and severity of the neurodegenerative process. On the basis of this knowledge potential neuroprotective effect of the interferon beta 1a (IFN Β1а) i.m. (avonex) was investigated. Twenty six patients with relapsing-remitting multiple sclerosis (RRMS) were included in the study. The procedures included examination of the history of the disease, neurological examination, EDSS, neuropsychological tests, dynamic MRI with PMMRS. The decrease of the NAA/Cr ratio in patients with RRMS compared to healthy controls was detected. The dynamic control in a year revealed the decrease NAA/Cr in patients with MS. Negative association was revealed between NAA/Cr in the brain and the level of neurological and cognitive deficit. The analysis of the 1 year therapy with IFN Β1а i.m. revealed neuroprotective effect which can be related to the possible positive effect of the drug on the neurodegenaration process.

  8. Pregnancy outcomes in multiple sclerosis following subcutaneous interferon beta-1a therapy.

    PubMed

    Sandberg-Wollheim, Magnhild; Alteri, Enrica; Moraga, Margaretha Stam; Kornmann, Gabrielle

    2011-04-01

    Women with multiple sclerosis (MS) are advised to discontinue interferon-beta therapy before trying to conceive. Unplanned pregnancies occur and risks related to exposure remain unclear. To determine pregnancy outcomes following interferon-beta therapy, we examined pregnancies from a global drug safety database containing individual case safety reports received in the post-marketing setting and safety data from clinical trials of subcutaneous interferon beta-1a in MS. One thousand and twenty-two cases of exposure to subcutaneous interferon beta-1a during pregnancy were retrieved; 679 had a documented outcome. In cases for which exposure duration was available (n  = 231), mean time of foetal exposure to subcutaneous interferon beta-1a before treatment discontinuation was 28 days; most pregnancies (199/231; 86.1%) were exposed for ≤ 45 days. To avoid bias, only outcomes for prospective data (n  = 425) in pregnancies exposed to interferon beta-1a in utero were analysed further. Of these, 324 (76.2%) resulted in normal live births and four (0.9%) in live births with congenital anomalies (3 [0.7%] were 'major'). Four (0.9%) pregnancies resulted in stillbirths (1 [0.2%] with foetal defects). There were 5 (1.2%) ectopic pregnancies, 49 (11.5%) spontaneous abortions and 39 (9.2%) elective terminations. Most pregnancies exposed to subcutaneous interferon beta-1a in utero were associated with normal live births. The rates of spontaneous abortion and major congenital anomalies in live births were in line with those observed in the general population. These data should be taken into account when considering options for women with MS who become pregnant or who are planning pregnancy while on treatment with subcutaneous interferon beta-1a.

  9. [Retinopathy secondary to treatment with Interferon beta-1a in a patient with multiple sclerosis].

    PubMed

    Mallada-Frechín, J; Abellán-Miralles, I; Alfaro-Beltra, M L; Medrano, V; Muñoz-Gil, M B; Fernández-Izquierdo, S; Piqueras-Rodríguez, L

    Although visual symptoms of multiple sclerosis (MS) are very frequent, they are rarely related with treatment with interferon. This is the first case reported in the literature of retinopathy associated with subcutaneous interferon beta-1a, and the second related to interferons in MS. A 30-year-old female diagnosed with relapsing-remitting MS who, at 3 months after starting treatment with subcutaneous interferon beta-1a (44 microg/3 times a week), displayed visual disorders. Retinal lesions in the form of cotton wool spots were found as symptoms of microinfarctions in the retina. The lesions got better after stopping treatment and the patient was found to be asymptomatic. The existence of retinopathy secondary to interferon has been known in the treatment of hepatitis C and neoplasias with interferon alfa since 1990. Despite being a frequently occurring complication, it is usually a mild condition and disappears on withdrawing treatment, or even if it is continued. It is attributed to deposits of immunocomplexes and complement activation in the blood vessels of the retina. Only one other case associated to treatment of MS with interferon beta has been reported in the literature, more specifically related to subcutaneous interferon beta-1b. The clinical characteristics of both cases are identical to those associated to interferon alfa. Despite the fact that the frequency of appearance seems to be lower than in the case of interferon alfa, the physician must bear in mind the possibility encountering this complication.

  10. [Neurodegenerative process in multiple sclerosis and a possible neuroprotective effect of β-interferon 1a (avonex)].

    PubMed

    Davydovskaia, M V; Boĭko, A N; Podoprigora, A E; Pronin, I N; Kornienko, V N; Gusev, E I

    2012-01-01

    To evaluate clinical perspectives of proton multi-voxel magnetic-resonance spectroscopy (PMMRS) for monitoring the severity of multiple sclerosis (MS) and neurodegenerative process, we studied the changes of the NAA/Cr ratio in the brain tissue of patients with MS and calculated the correlations between this parameter and the clinical state of patients. Based on these results, we studied the potential neuroprotective effect of β-interferon 1a (avonex) for intramuscular injection in patients with remitting MS. Twenty-six patients with remitting MS were enrolled in the study. The study of anamnesis, neurological examination using EDSS, neuropsychological testing and dynamic MRI using PMMRS were performed. The NAA/Cr ratio was decreased in patients compared to controls. An analysis of the NAA/Cr ratio after one year revealed the significant decrease of this parameter. The negative correlation between the NAA/Cr ratio in the brain tissue and the level of neurological and cognitive deficits was noted. The analysis of existing treatment of MS with β-interferon 1a for intramuscular injection revealed the neuroprotective stabilizing effect during one year of treatment that is probably associated with the effect of this drug on the neurodegenerative process in MS.

  11. 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.

  12. Impact of daclizumab versus interferon beta-1a on patient-reported outcomes in relapsing-remitting multiple sclerosis.

    PubMed

    Liu, Ying; Vollmer, Timothy; Havrdova, Eva; Riester, Katherine; Lee, Andrew; Phillips, Glenn; Wang, Ping; Sabatella, Guido

    2017-01-01

    Patient-reported outcomes (PROs) provide information on treatment effects from the patient's perspective that complement outcomes on clinical measures. In DECIDE, daclizumab demonstrated superior efficacy in reducing relapses, 24-week confirmed disability progression, and brain lesions (assessed by magnetic resonance imaging [MRI]) versus intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis. To examine the impact of daclizumab versus interferon beta-1a on PROs in DECIDE. DECIDE was a randomized, double-blind, active-controlled, phase 3 study comparing daclizumab 150mg subcutaneous every 4 weeks with interferon beta-1a 30mcg intramuscular once weekly. The 29-item Multiple Sclerosis Impact Scale (MSIS-29) and EuroQoL 5-Dimensions (EQ-5D) were assessed at baseline and every 24 weeks. Mean changes from baseline were analyzed using analysis of covariance models. Individual items for the MSIS-29 physical (PHYS) and psychological (PSYCH) subscales were analyzed post hoc. Daclizumab treatment resulted in greater mean improvements relative to baseline in MSIS-29 PHYS and PSYCH scores starting at week 24 that persisted over 96 weeks. Mean improvements from baseline in MSIS-29 PHYS and PSYCH scores were significantly greater for daclizumab versus intramuscular interferon beta-1a at week 96. Daclizumab-treated patients showed steady improvements in EQ-5D health utility index and EQ-5D visual analog scale scores over the study period, with significantly greater improvements versus intramuscular interferon beta-1a at week 96 (p=0.0048 and p=0.0006, respectively). Improvements in patient-reported physical and psychological functioning and general health status with daclizumab compared with intramuscular interferon beta-1a are consistent with outcomes on clinical and brain MRI lesion measures in DECIDE (NCT01064401). Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  13. Pregnancy outcomes during treatment with interferon beta-1a in patients with multiple sclerosis.

    PubMed

    Sandberg-Wollheim, M; Frank, D; Goodwin, T M; Giesser, B; Lopez-Bresnahan, M; Stam-Moraga, M; Chang, P; Francis, G S

    2005-09-27

    Although patients with multiple sclerosis (MS) are advised to stop interferon (IFN) beta-1a therapy before becoming pregnant, some patients become pregnant while on treatment. We examined individual patient data from eight clinical trials with IFNbeta-1a. Of 3,361 women in the studies, 69 pregnancies were reported, of which 41 were patients receiving (or who had stopped receiving within 2 weeks prior to conception) IFNbeta-1a (in utero exposure group), 22 were patients who discontinued IFNbeta-1a treatment more than 2 weeks before conception (previous exposure group), and six were patients receiving placebo. The 41 in utero exposure pregnancies resulted in 20 healthy full-term infants, one healthy premature infant, nine induced abortions, eight spontaneous abortions, one fetal death, and one congenital anomaly (hydrocephalus). One patient was lost to follow-up. The 22 previous exposure pregnancies resulted in 20 full-term healthy infants, one healthy premature infant, and one birth-related congenital anomaly (Erb palsy). The majority (21/31) of pregnancies that had the potential to go to full term produced healthy infants. The rate of spontaneous abortion was higher, but not significantly so, in the in utero exposure group compared to general population estimates. Until more exposure data become available, patients remain advised to stop IFNbeta therapy before becoming pregnant.

  14. A pilot study on the use of interferon beta-1a in early Alzheimer's disease subjects.

    PubMed

    Grimaldi, Luigi Maria Edoardo; Zappalà, Giuseppe; Iemolo, Francesco; Castellano, Anna Elisa; Ruggieri, Stefano; Bruno, Giuseppe; Paolillo, Andrea

    2014-02-13

    Despite the fact that multiple sclerosis (MS) and Alzheimer's disease (AD) share common neuroimmunological features, interferon beta 1a (IFNβ1a), the well-established treatment for the prevention of disease progression and cognitive decline in MS patients, has never been used in AD. We evaluated the safety and efficacy of IFNβ1a in subjects affected by mild-to-moderate AD in a double-blind, randomized, placebo-controlled, multicenter pilot study. Forty-two early Alzheimer's patients were randomized to receive either a 22 mcg subcutaneous injection of IFNβ1a or placebo three times per week. A treatment period of 28 weeks was followed by 24 weeks of observation. IFNβ1a was well tolerated and adverse events were infrequent and mild to moderate. Although not statistically significant, a reduction in disease progression during follow-up was measured in IFNβ1a-treated patients by the Alzheimer's Disease Assessment Scale cognitive subscale. Interestingly, the treatment group showed significant improvements in the Instrumental Activities of Daily Living and Physical Self-maintenance Scale. This study suggests that IFNβ1a is safe and well tolerated in early AD patients, and its possible beneficial role should be further investigated in larger studies.

  15. Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis.

    PubMed

    Radue, Ernst-Wilhelm; Stuart, William H; Calabresi, Peter A; Confavreux, Christian; Galetta, Steven L; Rudick, Richard A; Lublin, Fred D; Weinstock-Guttman, Bianca; Wynn, Daniel R; Fisher, Elizabeth; Papadopoulou, Athina; Lynn, Frances; Panzara, Michael A; Sandrock, Alfred W

    2010-05-15

    The SENTINEL study showed that the addition of natalizumab improved outcomes for patients with relapsing multiple sclerosis (MS) who had experienced disease activity while receiving interferon beta-1a (IFNbeta-1a) alone. Previously unreported secondary and tertiary magnetic resonance imaging (MRI) measures are presented here. Patients received natalizumab 300 mg (n=589) or placebo (n=582) intravenously every 4 weeks plus IFNbeta-1a 30 microg intramuscularly once weekly. Annual MRI scans allowed comparison of a range of MRI end points versus baseline. Over 2 years, 67% of patients receiving natalizumab plus IFNbeta-1a remained free of new or enlarging T2-lesions compared with 30% of patients receiving IFNbeta-1a alone. The mean change from baseline in T2 lesion volume over 2 years decreased in patients receiving natalizumab plus IFNbeta-1a and increased in those receiving IFNbeta-1a alone (-277.5mm(3) versus 525.6mm(3); p<0.001). Compared with IFNbeta-1a alone, add-on natalizumab therapy resulted in a smaller increase in mean T1-hypointense lesion volume after 2 years (1821.3mm(3) versus 2210.5mm(3); p<0.001), a smaller mean number of new T1-hypointense lesions over 2 years (2.3 versus 4.1; p<0.001), and a slower rate of brain atrophy during the second year of therapy (-0.31% versus -0.40%; p=0.020). Natalizumab add-on therapy reduced gadolinium-enhancing, T1-hypointense, and T2 MRI lesion activity and slowed brain atrophy progression in patients with relapsing MS who experienced disease activity despite treatment with IFNbeta-1a alone.

  16. Effects of Systemic and Local Interferon Beta-1a on Epidural Fibrosis

    PubMed Central

    Işık, Semra; Doğan, Şeref; Özgün, Gonca; Ocakoğlu, Gökhan; Uğraş, Nesrin

    2016-01-01

    Study Design Level 1 randomized controlled study. Purpose To investigate the effects of systemic and local interferon-beta-1a (IFN-β-1a) on prevention of epidural fibrosis using histopathological parameters. Overview of Literature Epidural fibrosis involves fibroblastic invasion of nerve roots into the epidural space. Formation of dense fibrous tissue causes lumbar and radicular pain. Many surgical techniques and several materials have been proposed in the literature, but no study has assessed the effect of IFN-β-1a on prevention of epidural fibrosis. Methods Forty-eight adult female Sprague-Dawley rats were divided into six groups of eight: sham group, control group, systemic 44 μg IFN-β-1a group and 22 μg IFN-β-1a group (after laminectomy and discectomy, 0.28 mL and 0.14 mL IFN-β-1a applied subcutaneously three times for a week, respectively), local 44 μg IFN-β-1a group (laminectomy and discectomy, followed by 0.28 mL IFN-β-1a on the surgical area), and local 22 μg IFN-β-1a group (laminectomy and discectomy, followed by 0.14 mL IFN-β-1a on the surgical area). All rats were sacrificed after 4 weeks and groups were evaluated histopathologically. Results Compared with sham and control groups, significantly less epidural fibrosis, dural adhesion, and fibroblast cell density were observed in the local and systemic 44 μg IFN-β-1a groups. No other differences were evident between the local and systemic groups. Conclusions IFN-β-1a is effective in preventing epidural fibrosis with systemic and local application. PMID:27340517

  17. Recombinant interferon-beta-1a: a review of its therapeutic efficacy in relapsing-remitting multiple sclerosis.

    PubMed

    Wagstaff, A J; Goa, K L

    1998-12-01

    This review focuses on Rebif, one of 2 available formulations of recombinant interferon-beta-1a, a molecule with the same molecular weight and primary structure as native interferon-beta. The product under review is intended for subcutaneous injection and contains 22 or 44microg of recombinant interferon-beta-1a. This molecule has the same antiviral, antiproliferative and immunomodulatory profile as native interferon-beta. Regulation of excessive immune responses in the inflamed lesions of patients with multiple sclerosis is thought to be important to its mode of action. In vivo studies indicate that the biological response to interferon-beta-1a is sustained with 3-times-weekly, in preference to once-weekly, administration. Subcutaneous interferon-beta-1a 22 and 44microg 3 times weekly for 2 years slowed sustained progression of disability (by 6.6 and 9.4 months; first quartile), decreased the mean number (by 27 and 33%) and severity of relapses, decreased the number of hospital visits and steroid courses, and decreased the acute activity [measured as the number of new or enlarging lesions seen with magnetic resonance imaging (MRI)] and burden (measured as the cumulative area or calculated volume of the lesions) of disease in patients with relapsing-remitting multiple sclerosis. All changes (except hospital visits: significant results were obtained with the higher dose only) were significant versus placebo with both doses. A recent study of once weekly interferon-beta-1a 22 or 44microg has confirmed the dose-dependency of the clinical and MRI effects. Patients with more severe disease appear to require the higher dosage regimen. Further studies of long term (>2 years) clinical efficacy, tolerability, and pharmacoeconomic aspects are required. Although injection site disorders and alterations in liver enzymes and lymphopenia are common, they rarely lead to withdrawal from treatment. As with other interferons, an influenza-like syndrome is often seen in patients

  18. INTERFERON BETA-1A TREATMENT IN HTLV-1-ASSOCIATED MYELOPATHY/TROPICAL SPASTIC PARAPARESIS: A CASE REPORT

    PubMed Central

    Viana, Graça Maria de Castro; da Silva, Marcos Antonio Custódio Neto; Souza, Victor Lima; Lopes, Natália Barbosa da Silva; da Silva, Diego Luz Felipe; Nascimento, Maria do Desterro Soares Brandão

    2014-01-01

    Here a young patient (< 21 years of age) with a history of infective dermatitis is described. The patient was diagnosed with myelopathy associated with HTLV-1/tropical spastic paraparesis and treated with interferon beta-1a. The disease was clinically established as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and laboratory tests confirmed the presence of antibodies to HTLV-1 in the cerebrospinal fluid (CSF). Mumps, cytomegalovirus, Epstein-Barr virus, schistosomiasis, herpes virus 1 and 2, rubella, measles, varicella-zoster toxoplasmosis, hepatitis, HIV, and syphilis were excluded by serology. The patient was diagnosed with neurogenic bladder and presented with nocturia, urinary urgency, paresthesia of the lower left limb, a marked reduction of muscle strength in the lower limbs, and a slight reduction in upper limb strength. During the fourth week of treatment with interferon beta-1a, urinary urgency and paresthesia disappeared and clinical motor skills improved. PMID:25229227

  19. Effect of intramuscular interferon beta-1a on gray matter atrophy in relapsing-remitting multiple sclerosis: A retrospective analysis.

    PubMed

    Fisher, E; Nakamura, K; Lee, J-C; You, X; Sperling, B; Rudick, R A

    2016-04-01

    Changes in gray matter (GM) volume may be a useful measure of tissue loss in multiple sclerosis (MS). To investigate the rate, patterns, and disability correlates of GM volume change in an MS treatment clinical trial. Patients (n=140) with relapsing-remitting MS were randomized to intramuscular (IM) interferon (IFN) beta-1a or placebo. Treatment effects on GM fraction (GMF) and white matter (WM) fraction (WMF) changes, differences in rates of GMF and WMF change in year one and two on treatment, and differences in atrophy rates by disease progression status were assessed retrospectively. Significantly less GM atrophy (during year two), but not WM atrophy (at any point), was observed with IM IFN beta-1a compared with placebo. Pseudoatrophy effects were more apparent in WM than in GM; in year one, greater WM volume loss was observed with IM IFN beta-1a than with placebo, whereas GM volume loss was similar between groups. Risk of sustained disability progression was significantly associated with GM, but not WM, atrophy. These results suggest that GMF change is more meaningful than WMF as a marker of tissue loss and may be useful to augment whole brain atrophy measurements in MS clinical trials. © The Author(s), 2015.

  20. Cost-effectiveness analysis of peginterferon beta-1a compared with interferon beta-1a and glatiramer acetate in the treatment of relapsing-remitting multiple sclerosis in the United States.

    PubMed

    Hernandez, Luis; Guo, Shien; Kinter, Elizabeth; Fay, Monica

    2016-07-01

    Objective Peginterferon beta-1a 125 mcg, administered subcutaneously (SC) every 2 weeks, a new disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS), was approved by the US Food and Drug Administration in 2014. This study assesses the cost-effectiveness of peginterferon beta-1a vs interferon beta-1a (44 mcg SC 3 times per week) and glatiramer acetate (20 mg SC once-daily) in the treatment of RRMS from the perspective of a US payer over 10 years. Methods A Markov cohort economic model was developed for this analysis. The model predicts disability progression, occurrence of relapses and other adverse events and translates them into quality-adjusted life years (QALYs) and costs. Natural history data were obtained from the placebo arm of the ADVANCE trial of peginterferon beta-1a, the London Ontario (Canada) database and a large population-based MS survey. Comparative efficacy of each DMT vs placebo was obtained from a network meta-analysis. Costs (in 2014 US dollars) were sourced from public databases and literature. Clinical and economic outcomes were discounted at 3% per year. Results Over 10 years, peginterferon beta-1a was dominant (i.e., more effective and less costly), with cost-savings of $22,070 and additional 0.06 QALYs when compared with interferon beta-1a 44 mcg and with cost-savings of $19,163 and 0.07 QALYs gained when compared with glatiramer acetate 20 mg. Results were most sensitive to variations in the treatment effect of each DMT, treatment acquisition costs of each DMT and the time horizon. Probabilistic sensitivity analyses indicated that peginterferon beta-1a remains dominant in >90% of 5,000 replications compared with either DMTs. Conclusion This analysis suggests that long-term treatment with peginterferon beta-1a improves clinical outcomes at reduced costs compared with interferon beta-1a 44 mcg and glatiramer acetate 20 mg and should be a valuable addition to managed care formularies for treating

  1. Severe Dermatomyositis Triggered by Interferon Beta-1a Therapy and Associated With Enhanced Type I Interferon Signaling

    PubMed Central

    Somani, Ally-Khan; Swick, Alan R.; Cooper, Kevin D.; McCormick, Thomas S.

    2013-01-01

    Background Type I interferons (IFNs) are common therapeutics for several diseases, including viral infections and multiple sclerosis (MS). Although numerous studies have implicated type I INFs with the production of autoantibodies and the development of certain autoimmune disorders, interferon beta has not previously been described in association with dermatomyositis, to our knowledge. Previous microarray studies of muscle biopsy specimens from patients with dermatomyositis disclosed a type I IFN–induced gene expression profile. The central role of plasmacytoid dendritic cell precursors, together with increased type IIFN production, suggests a pivotal role for type I IFNs in dermatomyositis. We report a case of dermatomyositis exacerbated or induced by interferon beta therapy for MS and provide evidence that demonstrates enhanced type I IFN signaling in this patient. Observations We observed new-onset dermatomyositis in a 57-year-old patient treated with interferon beta for MS. His symptoms were exacerbated temporally by interferon beta injections. Immunohistochemical staining of skin biopsy specimens for myxovirus-resistance protein A (a surrogate marker for cutaneous type I IFN signaling) showed increased staining that correlated temporally with interferon beta treatment and subsequent disease activity. In vitro treatment with interferon beta of peripheral blood mononuclear cells isolated from our patient revealed enhanced type I IFN signaling assessed by interferon-induced gene expression profiles. Conclusions To our knowledge, this is the first description of dermatomyositis exacerbated or induced by interferon beta treatment. Our results demonstrate enhanced type I IFN signaling following interferon beta treatment in our patient with dermatomyositis. PMID:18936398

  2. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.

    PubMed

    Cohen, Jeffrey A; Coles, Alasdair J; Arnold, Douglas L; Confavreux, Christian; Fox, Edward J; Hartung, Hans-Peter; Havrdova, Eva; Selmaj, Krzysztof W; Weiner, Howard L; Fisher, Elizabeth; Brinar, Vesna V; Giovannoni, Gavin; Stojanovic, Miroslav; Ertik, Bella I; Lake, Stephen L; Margolin, David H; Panzara, Michael A; Compston, D Alastair S

    2012-11-24

    The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of first-line alemtuzumab compared with interferon beta 1a in a phase 3 trial. In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-50 years with previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00530348. 187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0·45 [95% CI 0·32-0·63]; p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (p<0·0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 [95% CI 0·40-1·23]; p=0·22). 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or

  3. Alemtuzumab improves quality-of-life outcomes compared with subcutaneous interferon beta-1a in patients with active relapsing-remitting multiple sclerosis.

    PubMed

    Arroyo González, Rafael; Kita, Mariko; Crayton, Heidi; Havrdova, Eva; Margolin, David H; Lake, Stephen L; Giovannoni, Gavin

    2017-09-01

    Alemtuzumab was superior on clinical and magnetic resonance imaging (MRI) outcomes versus subcutaneous interferon beta-1a in phase 3 trials in patients with relapsing-remitting multiple sclerosis. To examine quality-of-life (QoL) outcomes in the alemtuzumab phase 3 trials. Patients who were treatment naive (Comparison of Alemtuzumab and Rebif(®) Efficacy in Multiple Sclerosis I [CARE-MS I]) or had an inadequate response to prior therapy (CARE-MS II) received annual courses of alemtuzumab 12 mg/day at baseline (5 days) and Month 12 (3 days) or subcutaneous interferon beta-1a 44 µg three times/week. QoL was measured every 6 or 12 months using Functional Assessment of Multiple Sclerosis (FAMS), European Quality of Life-5 Dimensions (EQ-5D) and its visual analog scale (EQ-VAS), and 36-Item Short-Form Survey (SF-36). Statistically significant improvements from baseline with alemtuzumab were observed on all three QoL instruments at the earliest post-baseline assessment and sustained through Year 2. Statistically significant greater QoL improvements over subcutaneous interferon beta-1a were seen at all time points in CARE-MS II with FAMS, EQ-VAS and SF-36 physical component summary, and in CARE-MS I with FAMS. Patients treated with alemtuzumab had improvements in physical, mental, and emotional QoL regardless of treatment history. Improvements were significantly greater with alemtuzumab versus subcutaneous interferon beta-1a on both disease-specific and general measures of QoL.

  4. Interferon beta-1a for the maintenance of remission in patients with Crohn's disease: results of a phase II dose-finding study

    PubMed Central

    2009-01-01

    Background Crohn's disease (CD) and multiple sclerosis (MS) share common pathogenic processes. Interferon (IFN) beta-1a is effective and generally well tolerated in patients with MS and has been shown to down-regulate the expression of interleukin-12, a cytokine that is thought to be involved in mucosal degeneration in CD. IFN beta-1a therefore offers promise as a treatment for CD. Methods In this multicentre, double-blind, placebo-controlled, phase II, dose-finding study, patients with steroid-induced clinical remissions of CD were randomized 1:1:1:1 to subcutaneous IFN beta-1a: 66 mcg three times weekly (tiw), 44 mcg tiw, 44 mcg twice weekly (biw), or matching placebo tiw with steroid tapering. The primary endpoint was the proportion of patients relapse-free at Week 26. Safety was also assessed. Results This study was terminated early following a planned interim analysis at 26 weeks. Of the planned 192 patients, 67 were randomized to treatment: placebo (n = 16), or IFN beta-1a 44 mcg biw (n = 17), 44 mcg tiw (n = 16) or 66 mcg tiw (n = 18). In total, 20/67 patients (29.9%) completed 26 weeks and 7 patients (10.4%) completed 52 weeks. The proportion of patients who remained relapse-free at Week 26 did not differ significantly between the placebo group (5/16, 31%) and the IFN beta-1a 44 mcg biw (6/17, 35%; p = 0.497), 44 mcg tiw (7/16, 44%; p = 0.280) or 66 mcg tiw (2/18, 11%; p = 0.333) groups. There was little difference between treatment groups in secondary efficacy endpoints. IFN beta-1a was generally well tolerated at all doses. Adverse events (AEs) were generally mild or moderate in IFN beta-1a-treated patients, with the most common AEs (influenza-like symptoms, headache, injection-site reactions) being similar to those reported with IFN beta-1a in MS. Conclusion There was no difference in efficacy between patients with CD receiving IFN beta-1a or placebo. However, these results should be considered in the context of the low patient numbers and high dropout

  5. Impact of adherence on subcutaneous interferon beta-1a effectiveness administered by Rebismart® in patients with multiple sclerosis

    PubMed Central

    Edo Solsona, María Dolores; Monte Boquet, Emilio; Casanova Estruch, Bonaventura; Poveda Andrés, José Luis

    2017-01-01

    Background Adherence to disease-modifying drugs (DMDs) is one of the key factors for achieving optimal clinical outcomes. Rebismart® is an injection device for subcutaneous administration of interferon beta-1a (INF β-1a) that is also able to monitor adherence objectively. The aim of this study was to describe adherence to INF β-1a using the said electronic autoinjection device and to explore the relationship between adherence and relapses in a Spanish cohort. Methods This is a retrospective observational study in which 110 Spanish patients self-administered INF β-1a subcutaneously using an electronic autoinjection device between June 2010 and June 2015. The primary end point was the percentage of adherence measured by Rebismart® to subcutaneous INF β-1a injections calculated as number of injections received in time period versus number of injections scheduled in time period. Other variables recorded were demographic and clinical data. Statistical analysis was performed using SPSS 19.0 software. Results Median adherence for the total study period was 96.5% (interquartile range [IQR]: 91.1–99.1). Similar values were observed during the first 6 months: 98.7% (IQR: 91.3–100), and the last 6 months: 97.6% (IQR: 91.1–99.8). Median duration of treatment was 979 days (IQR: 613.8–1,266.8). During the entire treatment period, 77.3% of patients were relapse free and mean annualized relapse rate was 0.14 (standard deviation: 0.33). Increased adherence was associated with better clinical outcomes, leading to lower relapse risk (odds ratio: 0.953; 95% confidence interval: 0.912–0.995). Specifically, every percentage unit increase in adherence resulted in a 4.7% decrease in relapse. Conclusion Patients with multiple sclerosis who self-injected INF β-1a with Rebismart® had excellent adherence, correlating with a high proportion of relapse-free patients and very low annualized relapse rate. PMID:28280313

  6. Neopterin production and tryptophan degradation during 24-months therapy with interferon beta-1a in multiple sclerosis patients

    PubMed Central

    2011-01-01

    Background Increased synthesis of neopterin and degradation of tryptophan to kynurenine, measured as kynurenine/tryptophan ratio (kyn/trp ratio), are considered in vitro markers of interferon beta-1a (IFNβ-1a) activity. The aim of the study was to investigate the dynamic profile of neopterin and kyn/trp ratio in patients with relapsing remitting multiple sclerosis (RRMS) treated with two different doses of IFNβ-1a over a period of 24 months. Methods RRMS patients (n = 101) received open-label IFNβ-1a 22 mcg (low dose, LD) or 44 mcg (high dose, HD) subcutaneously (sc), three times weekly for 24 months. Serum measurements of neopterin, kyn/trp ratio and neutralizing antibodies (NAbs) were obtained before treatment (i.e., at baseline) and 48 hours post-injection every 3 months thereafter. Clinical assessments were performed at baseline and every 6 months. Changes in biomarkers over time were compared between LD- and HD-group as well as between patients with/without relapses and with/without NAbs using Analysis of Variance and Mann-Whitney tests. Results Neopterin (p < 0.001) and kyn/trp ratio (p = 0.0013) values increased over time vs baseline in both treatment groups. Neopterin values were higher (p = 0.046) in the HD-compared to the LD-group at every time point with the exclusion of months 21 and 24 of therapy. Conversely, there were no differences between the two doses groups in the kyn/trp ratio with the exclusion of month 6 of therapy (p < 0.05). Neopterin levels were significantly reduced in NAb-positive patients starting from month 9 of therapy (p < 0.05); the same result was observed for kyn/trp ratio but only at month 9 (p = 0.02). Clinical status did not significantly affect neopterin production and tryptophan degradation. Conclusions Although differences in serum markers concentration were found following IFNβ administration the clinical relevance of these findings needs to be confirmed with more detailed studies. PMID:21501517

  7. Pulmonary administration of interferon Beta-1a-fc fusion protein in non-human primates using an immunoglobulin transport pathway.

    PubMed

    Vallee, Sebastien; Rakhe, Swapnil; Reidy, Thomas; Walker, Sandra; Lu, Qi; Sakorafas, Paul; Low, Susan; Bitonti, Alan

    2012-04-01

    Currently, products containing interferon beta (IFNβ) are injected either intramuscularly or subcutaneously. To avoid the necessity of injection, we developed a novel monomeric Fc fusion protein of IFNβ (IFNβFc) that is absorbed via an immunoglobulin transport system present in the upper and central airways upon administration of the drug as an inhaled aerosol. The systemic absorption of IFNβFc through the lung in non-human primates, at deposited doses of 1, 3, and 10 μg/kg, was compared to the absorption of a single 3 μg/kg dose of IFNβ-1a (Avonex®) subcutaneously administered. IFNβFc was well absorbed through the lung, displaying dose proportional increases in serum concentrations, and was biologically active, as shown by increases in plasma neopterin levels. The circulating half-life of IFNβFc was ∼3 times longer (∼30 h) than that of IFNβ-1a, (8-9 h). At approximately equimolar doses of IFNβFc (10 μg/kg) and IFNβ-1a (3 μg/kg), the stimulation of neopterin over background levels was approximately equivalent, demonstrating that the longer half-life of IFNβFc compensated for the lower relative specific antiviral activity of IFNβFc measured in vitro. In conclusion, IFNβFc was efficiently absorbed after pulmonary delivery in non-human primates, retained its biological activity, and may offer a convenient alternative to injectable IFNβ.

  8. Magnetic resonance imaging changes with recombinant human interferon-beta-1a: a short term study in relapsing-remitting multiple sclerosis.

    PubMed Central

    Pozzilli, C; Bastianello, S; Koudriavtseva, T; Gasperini, C; Bozzao, A; Millefiorini, E; Galgani, S; Buttinelli, C; Perciaccante, G; Piazza, G; Bozzao, L; Fieschi, C

    1996-01-01

    OBJECTIVE: To evaluate whether recombinant human interferon-beta-1a significantly affects disease activity as measured by a reduction in the number and volume of Gd enhancing lesions on monthly MRI. The study also evaluated the effect on six-monthly T2 weighted abnormality and relapse frequency. METHODS: After a baseline scan and a six month pretreatment period, 68 patients were randomly assigned to receive either 3 MIU or 9 MIU of interferon-beta-1a by subcutaneous injection three times a week for six months. All patients were examined by Gd enhanced MRI every month in both pretreatment and treatment periods. The evaluation of Gd enhancing lesions was performed blind at the end of the study. RESULTS: The mean number of Gd enhancing lesions was higher during the pretreatment period than during treatment. This difference was statistically significant for the two different dose subgroups (3.5 v 1.8, P < 0.001 for the 3 MIU group and 2.4 v 0.9, P < 0.001 for the 9 MIU group, corresponding to a reduction of 49% and 64% respectively). The mean volume of Gd enhancing lesions also significantly decreased by 61% (3 MIU group) and 73% (9 MIU group). These reductions were evident only after the first month of treatment. The six-monthly rate of new lesions as seen in T2 weighted images showed a similar trend of reduction with treatment (65% and 70% respectively). Lesion volume on T2 scans significantly increased during the pretreatment period whereas it remained almost stable during the treatment period in both groups. Clinical relapse rate was significantly reduced by treatment (53% for the 3 MIU group, P < 0.001; 69% for the 9 MIU group, P < 0.001). CONCLUSION: Interferon-beta-1a seemed effective in reducing disease activity in relapsing-remitting multiple sclerosis at both the doses used. PMID:8795595

  9. Postmarketing Safety Profile of Subcutaneous Interferon Beta-1a Given 3 Times Weekly: A Retrospective Administrative Claims Analysis.

    PubMed

    Smith, Meredith Y; Sabidó-Espin, Meritxell; Trochanov, Anton; Samuelson, Mark; Guedes, Sandra; Corvino, Frank A; Richy, Florent F

    2015-08-01

    Health insurance administrative claims databases represent a valuable source of information regarding the safety profile of marketed products as used in actual clinical practice in a broader range of patients than that assessed in clinical trials. Interferon beta-1a administered subcutaneously 3 times weekly (IFN β-1a SC tiw), which was approved in 2002 by the FDA for the treatment of relapsing-remitting multiple sclerosis (MS), has over a decade of postmarketing experience. To date, however, its postmarketing safety profile has not been described using a real-world evidence source such as administrative claims data. To describe the safety profile of IFN β-1a SC tiw as presented in its U.S. prescribing information (PI) for patients with MS initiating IFN β-1a SC tiw therapy using data from U.S. health care administrative claims databases. This study featured an observational and retrospective "new start" cohort design using data from the Truven MarketScan Commercial and Medicare Supplemental health care administrative claims databases. Patients were eligible for inclusion if they were aged ≥ 18 years; had ≥ 1 diagnosis for MS recorded between January 1, 2006, and December 31, 2012; had ≥ 2 prescriptions for IFN β-1a SC tiw; and had ≥ 90 days of continuous eligibility pre-index date and ≥ 180 days of continuous eligibility post-index date. Patients with a prescription for IFN β-1a SC tiw without a MS diagnosis were excluded. Patients were followed from first prescription for IFN β-1a SC tiw (index date) until date of therapy switch or discontinuation, end of insurance eligibility, or end of observation period. Adverse events (AEs) examined were those listed in the Warnings and Precautions, Adverse Reactions, and Postmarketing Experience sections of the 2014 U.S. PI. Outcomes of interest were identified at the Medical Dictionary for Regulatory Activities (version 17.1) Preferred Term level and then coded to the corresponding ICD-9-CM

  10. Persistence on Therapy and Propensity Matched Outcome Comparison of Two Subcutaneous Interferon Beta 1a Dosages for Multiple Sclerosis

    PubMed Central

    Kalincik, Tomas; Spelman, Timothy; Trojano, Maria; Duquette, Pierre; Izquierdo, Guillermo; Grammond, Pierre; Lugaresi, Alessandra; Hupperts, Raymond; Cristiano, Edgardo; Van Pesch, Vincent; Grand’Maison, Francois; La Spitaleri, Daniele; Rio, Maria Edite; Flechter, Sholmo; Oreja-Guevara, Celia; Giuliani, Giorgio; Savino, Aldo; Amato, Maria Pia; Petersen, Thor; Fernandez-Bolanos, Ricardo; Bergamaschi, Roberto; Iuliano, Gerardo; Boz, Cavit; Lechner-Scott, Jeannette; Deri, Norma; Gray, Orla; Verheul, Freek; Fiol, Marcela; Barnett, Michael; van Munster, Erik; Santiago, Vetere; Moore, Fraser; Slee, Mark; Saladino, Maria Laura; Alroughani, Raed; Shaw, Cameron; Kasa, Krisztian; Petkovska-Boskova, Tatjana; den Braber-Moerland, Leontien; Chapman, Joab; Skromne, Eli; Herbert, Joseph; Poehlau, Dieter; Needham, Merrilee; Bacile, Elizabeth Alejandra Bacile; Arruda, Walter Oleschko; Paine, Mark; Singhal, Bhim; Vucic, Steve; Cabrera-Gomez, Jose Antonio; Butzkueven, Helmut; Roger, Elaine; Despault, Pierre; Marriott, Mark; Van der Walt, Anneke; King, John; Kilpatrick, Trevor; Buzzard, Katherine; Jokubaitis, Vilija; Byron, Jill; Morgan, Lisa; Skibina, Olga; Haartsen, Jodi; De Luca, Giovanna; Di Tommaso, Valeria; Travaglini, Daniela; Pietrolongo, Erika; di Ioia, Maria; Farina, Deborah; Mancinelli, Luca; Paolicelli, Damiano; Iaffaldano, Pietro; Ignacio Rojas, Juan; Patrucco, Liliana; Roullet, Etienne; Correale, Jorge; Ysrraelit, Celica; Elisabetta, Cartechini; Pucci, Eugenio; Williams, David; Dark, Lisa; Shaygannejad, Vahid; Zwanikken, Cees; Vella, Norbert; Sirbu, Carmen-Adella

    2013-01-01

    Objectives To compare treatment persistence between two dosages of interferon β-1a in a large observational multiple sclerosis registry and assess disease outcomes of first line MS treatment at these dosages using propensity scoring to adjust for baseline imbalance in disease characteristics. Methods Treatment discontinuations were evaluated in all patients within the MSBase registry who commenced interferon β-1a SC thrice weekly (n = 4678). Furthermore, we assessed 2-year clinical outcomes in 1220 patients treated with interferon β-1a in either dosage (22 µg or 44 µg) as their first disease modifying agent, matched on propensity score calculated from pre-treatment demographic and clinical variables. A subgroup analysis was performed on 456 matched patients who also had baseline MRI variables recorded. Results Overall, 4054 treatment discontinuations were recorded in 3059 patients. The patients receiving the lower interferon dosage were more likely to discontinue treatment than those with the higher dosage (25% vs. 20% annual probability of discontinuation, respectively). This was seen in discontinuations with reasons recorded as “lack of efficacy” (3.3% vs. 1.7%), “scheduled stop” (2.2% vs. 1.3%) or without the reason recorded (16.7% vs. 13.3% annual discontinuation rate, 22 µg vs. 44 µg dosage, respectively). Propensity score was determined by treating centre and disability (score without MRI parameters) or centre, sex and number of contrast-enhancing lesions (score including MRI parameters). No differences in clinical outcomes at two years (relapse rate, time relapse-free and disability) were observed between the matched patients treated with either of the interferon dosages. Conclusions Treatment discontinuations were more common in interferon β-1a 22 µg SC thrice weekly. However, 2-year clinical outcomes did not differ between patients receiving the different dosages, thus replicating in a registry dataset derived from

  11. A novel needle for subcutaneous injection of interferon beta-1a: effect on pain in volunteers and satisfaction in patients with multiple sclerosis.

    PubMed

    Jaber, Amer; Bozzato, Gian B; Vedrine, Lionel; Prais, Wes A; Berube, Julie; Laurent, Philippe E

    2008-10-10

    To reduce injection pain and improve satisfaction, a thinner (29-gauge [29G]), sharper (5-bevel) needle than the 27G/3-bevel needle used previously to inject interferon (IFN) beta-1a, 44 or 22 mcg subcutaneously (sc) three times weekly (tiw), was developed for use in multiple sclerosis (MS). Two clinical trials in healthy volunteers and five surveys of patients with MS were conducted to assess whether the 29G/5-bevel needle with a Thermo Plastic Elastomer (TPE) needle shield (a sleeve that houses the tip of the needle in a secure location) is an improvement over the 27G/3-bevel needle with a rubber shield for injection of IFN beta-1a, 44 or 22 mcg sc tiw. Parameters assessed were: pain and ease of insertion (healthy volunteer and nurse responses on subjective pain measurement scales); and patient satisfaction (surveys of patients with MS). In healthy volunteers, the 29G/5-bevel needle with TPE shield was associated with the least perceived pain on the Visual Analog Scale (VAS) and Verbal VAS (VB-VAS); mean VAS pain scores decreased by 40% and skin penetration improved by 69% compared with the 27G/3-bevel needle with standard rubber shield (p < 0.01). Pooled results from surveys of patients with MS indicated that 63% of patients thought that injections were less painful with the 29G/5-bevel needle than the 27G/3-bevel needle. Results from individual surveys indicated that the 29G/5-bevel needle was an improvement over the 27G/3-bevel needle for ease of insertion, injection-site reactions, bruising, burning and stinging. Together these studies indicate that the 29G/5-bevel needle with the TPE shield is an improvement over the 27G/3-bevel needle with standard rubber shield in terms of pain, ease of insertion and patient satisfaction. These improvements are expected to result in improved compliance in patients with MS treated with IFN beta-1a, 44 or 22 mcg sc tiw.

  12. Deciphering the Biophysical Effects of Oxidizing Sulfur-Containing Amino Acids in Interferon-beta-1a using MS and HDX-MS

    NASA Astrophysics Data System (ADS)

    Houde, Damian J.; Bou-Assaf, George M.; Berkowitz, Steven A.

    2017-02-01

    Introduction of a chemical change to one or more amino acids in a protein's polypeptide chain can result in various effects on its higher-order structure (HOS) and biophysical behavior (or properties). These effects range from no detectable change to significant structural or conformational alteration that can greatly affect the protein's biophysical properties and its resulting biological function. The ability to reliably detect the absence or presence of such changes is essential to understanding the structure-function relationship in a protein and in the successful commercial development of protein-based drugs (biopharmaceuticals). In this paper, we focus our attention on the latter by specifically elucidating the impact of oxidation on the HOS, structural dynamics, and biophysical properties of interferon beta-1a (IFNβ-1a). Oxidation is a common biochemical modification that occurs in many biopharmaceuticals, specifically in two naturally-occurring sulfur-containing amino acids, methionine and cysteine. To carry out this work, we used combinations of hydrogen peroxide and pH to differentially oxidize IFNβ-1a (to focus on only methionine oxidation versus methionine and cysteine oxidation). We then employed several analytical and biophysical techniques to acquire information about the differential impact of these two oxidation scenarios on IFNβ-1a. In particular, the use of MS-based techniques, especially HDX-MS, play a dominant role in revealing the differential effects.

  13. Deciphering the Biophysical Effects of Oxidizing Sulfur-Containing Amino Acids in Interferon-beta-1a using MS and HDX-MS

    NASA Astrophysics Data System (ADS)

    Houde, Damian J.; Bou-Assaf, George M.; Berkowitz, Steven A.

    2017-05-01

    Introduction of a chemical change to one or more amino acids in a protein's polypeptide chain can result in various effects on its higher-order structure (HOS) and biophysical behavior (or properties). These effects range from no detectable change to significant structural or conformational alteration that can greatly affect the protein's biophysical properties and its resulting biological function. The ability to reliably detect the absence or presence of such changes is essential to understanding the structure-function relationship in a protein and in the successful commercial development of protein-based drugs (biopharmaceuticals). In this paper, we focus our attention on the latter by specifically elucidating the impact of oxidation on the HOS, structural dynamics, and biophysical properties of interferon beta-1a (IFNβ-1a). Oxidation is a common biochemical modification that occurs in many biopharmaceuticals, specifically in two naturally-occurring sulfur-containing amino acids, methionine and cysteine. To carry out this work, we used combinations of hydrogen peroxide and pH to differentially oxidize IFNβ-1a (to focus on only methionine oxidation versus methionine and cysteine oxidation). We then employed several analytical and biophysical techniques to acquire information about the differential impact of these two oxidation scenarios on IFNβ-1a. In particular, the use of MS-based techniques, especially HDX-MS, play a dominant role in revealing the differential effects.

  14. Adverse events of interferon beta-1a: a prospective multi-centre international ICH-GCP-based CRO-supported external validation study in daily practice.

    PubMed

    Jongen, Peter Joseph; Sindic, Christian; Sanders, Evert; Hawkins, Stanley; Linssen, Wim; van Munster, Erik; Frequin, Stephan; Borm, George

    2011-01-01

    Due to methodological shortcomings the available post-registration data on the adverse events (AEs) occurring in interferon beta-1a (INFb-1a)-treated patients fail to adequately validate phase III data and only partially inform on safety in daily practice. We assessed AEs in relapsing remitting multiple sclerosis (RRMS) patients treated with intramuscular (IM) INFb-1a in daily practice using data quality assurance measures similar to those in phase III trials. A prospective, International Conference on Harmonization (ICH) - Good Clinical Practice (GCP)-based, clinical research organization (CRO)-supported study in 36 practices in the Netherlands, Belgium, the United Kingdom and Luxembourg. During 24 months after start of IM INFb-1a treatment 275 RRMS patients were assessed for AEs' severity (mild, moderate, severe) and relationship to treatment (not, unlikely, likely, definite). Data were compared with those reported in the pivotal phase III trial. 75.3% of the patients experienced one or more AEs that were likely or definitely related to INFb-1a. Of all AEs 40.5% were likely or definitely treatment-related; 68.5% of these were mild, and 3% severe. 6.6% of the patients discontinued treatment because of an AE. Compared to the pivotal phase III trial, we found statistically significantly lower incidences for most of the common AEs: headache, muscle ache, fatigue, fever, chills, nausea. One patient died following two cerebral vascular events in study month 22, both AEs were assessed as not related to INFb-1a. Three out of four RRMS patients treated with IM INFb-1a in daily practice experience treatment-related AEs, most of these being mild. Our data externally validate the favorable phase III safety profile of IM INFb-1a and suggest that the real-life incidence of treatment-related AEs is less than reported in the pivotal phase III trial. Larger studies are needed to detect rare, potentially hazardous AEs of IM INFb-1a.

  15. Impact of exposure to interferon beta-1a on outcomes in patients with relapsing-remitting multiple sclerosis: exploratory analyses from the PRISMS long-term follow-up study.

    PubMed

    Uitdehaag, Bernard; Constantinescu, Cris; Cornelisse, Peter; Jeffery, Douglas; Kappos, Ludwig; Li, David; Sandberg-Wollheim, Magnhild; Traboulsee, Anthony; Verdun, Elisabetta; Rivera, Victor

    2011-01-01

    To explore the effects of exposure to subcutaneous (sc) interferon (IFN) beta-1a on efficacy in patients with relapsing-remitting multiple sclerosis (RRMS) enrolled in the PRISMS (Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) study. Patients with RRMS received IFN beta-1a, 44 or 22 µg sc three times weekly (tiw), or placebo, for 2 years, at which point placebo recipients were re-randomized to IFN beta-1a, 44 or 22 µg sc tiw, for a further 2-4 years. Long-term follow-up visits occurred 7-8 years after enrolment and allowed participation of patients who had previously discontinued treatment. Post hoc descriptive analyses were conducted within the lower (MIN) and upper (MAX) quartiles of patients divided according to cumulative dose of IFN beta-1a and cumulative time on treatment. Outcomes were explored in patients initially randomized to IFN beta-1a, 44 µg sc tiw, who had received continuous or noncontinuous therapy during the study. For both cumulative dose and time analyses, the MIN and MAX groups comprised 96 and 95 patients, respectively. The continuous and noncontinuous groups included 45 and 91 patients, respectively. The MAX DOSE and MAX TIME groups had lower annualized relapse rates, lower rates of conversion to secondary progressive MS, lower percentages of patients with Expanded Disability Status Scale progression, higher percentages of relapse-free patients, and less T2 burden of disease than the MIN groups. The continuous therapy group had a lower annualized relapse rate and lower percentages of patients with Expanded Disability Status Scale progression or conversion to secondary progressive MS than the noncontinuous therapy group. The findings of these post hoc analyses suggest that high exposure to sc IFN beta-1a may be associated with better clinical outcomes than low exposure, and also highlight the importance of maximizing adherence. Additional prospective investigation is warranted to

  16. An observational, retrospective, UK and Ireland audit of patient adherence to subcutaneous interferon beta-1a injections using the RebiSmart(®) injection device.

    PubMed

    Willis, Helen; Webster, Julie; Larkin, Anne Marie; Parkes, Laura

    2014-01-01

    Poor adherence to disease-modifying drugs is associated with an increased risk of relapse in patients with multiple sclerosis. However, adherence is difficult to assess objectively. RebiSmart(®) (Merck Serono SA, Geneva, Switzerland), a device for subcutaneous (sc) injection of interferon (IFN) β-1a, features an electronic injection log that can assist in objective monitoring of adherence. To assess adherence to sc IFN β-1a injections using data from RebiSmart(®). This was a single-group, observational, retrospective audit. Adherence data were collected from patients with relapsing multiple sclerosis in the United Kingdom and Ireland who had been prescribed sc IFN β-1a and had been using RebiSmart(®) for a minimum of 24 months. In total, 225 patients were included in the full analysis set; 72% were in the United Kingdom, and 28% were in Ireland. Overall, the mean age was 44.1 years, and 73% were women. Patients received sc IFN β-1a 44 µg (68%) or 22 µg (32%) three times per week. Mean adherence over the course of 24 months was 95.0% (median, 99.4%), and similar values were observed across all periods. The proportion of patients with 80% or higher adherence was 92.0% at 12 months and 91.1% at 24 months. High adherence to sc IFN β-1a was observed across all patient groups using RebiSmart(®), according to 2-year treatment adherence data. This may be partly attributed to the expert support patients received, supplemented by routine and regular contact from the MySupport patient-support program, as well as the self-motivation of patients who persisted with treatment for 2 or more years.

  17. Dose titration of intramuscular interferon beta-1a reduces the severity and incidence of flu-like symptoms during treatment initiation.

    PubMed

    Matson, Mark A; Zimmerman, Thomas R; Tuccillo, Dianne; Tang, Yongqiang; Deykin, Aaron

    2011-12-01

    Flu-like symptoms (FLS) are common side effects of interferon beta (IFNβ) therapy and can negatively affect the willingness of patients with multiple sclerosis to initiate therapy. Although dose titration is commonly used to reduce the severity and incidence of IFNβ-related FLS during treatment initiation, these benefits have not been confirmed in a well controlled study. The objective of this randomized, dose-blinded, parallel-group study was to assess the effect of dose titration on the severity and incidence of FLS during the initial 8 weeks of once-weekly intramuscular (IM) IFNβ-1a administration. Healthy volunteers were randomized 1:1:1 to one of three IM IFNβ-1a regimens: 3-week titration (weekly quarter-dose increments over 3 weeks to full dose [30 µg]); 6-week titration (biweekly quarter-dose increments over 6 weeks to full dose); or no titration (full dose over 8 weeks). At weekly clinic visits, the severity of each FLS was rated 1 hour pre-injection and 4-6 hours and 12-15 hours post-injection. Study endpoints included post-injection change in FLS severity and post-injection FLS incidence (percentage of subjects with a ≥2-point increase in total FLS severity score) at each time point. Clinicaltrials.gov identifier: NCT01119677. Of 234 subjects enrolled, 194 (83%) completed the study. At 8 weeks, FLS severity was significantly reduced at both post-injection time points with 3-week titration (76% reduction at 4-6 hours, p < 0.001; 37% reduction at 12-15 hours; p < 0.001) and 6-week titration (50% reduction at 4-6 hours, p < 0.001; 32% reduction at 12-15 hours; p = 0.002) compared with no titration. The incidence of FLS was also significantly reduced at both time points with both titration regimens. Safety profiles for both titration regimens were consistent with the current IM IFNβ-1a label. Study limitations included that there is currently no validated assessment tool for evaluating the severity of FLS, that the study enrolled

  18. Two recombinant human interferon-beta 1a pharmaceutical preparations produce a similar transcriptional response determined using whole genome microarray analysis.

    PubMed

    Prync, A E Sterin; Yankilevich, P; Barrero, P R; Bello, R; Marangunich, L; Vidal, A; Criscuolo, M; Benasayag, L; Famulari, A L; Domínguez, R O; Kauffman, M A; Diez, R A

    2008-02-01

    Recombinant human interferon-beta (IFN-b) is a well-established treatment for multiple sclerosis (MS). The regulatory process for marketing authorization of biosimilars is currently under debate in certain countries. In the EU, EMEA has clearly defined the process including overarching and product-specific guidelines, which includes clinical testing. Biosimilarity needs to be based on comparability criteria, including at least molecular characterization, biological activity relevant for the therapeutic effect and relative bioavailability ("bioequivalence"). In the case of such complex diseases as MS, where the effect of treatment is not so directly measurable, in vitro tools can provide additional data to support comparability. Genomic microarrays assays might be useful to compare multisource biopharmaceuticals. The aim of the present study was to compare the pharmacodynamic genomic effects (in terms of transcriptional regulation) of two recombinant human IFN-I(2)1a preparations on lymphocytes of multiple sclerosis patients using a whole genome microarray assay. We performed an ex vivo whole genome expression profiling of the effect of two preparations of IFN-I(2)1a on non-adherent mononuclears from five relapsing-remitting MS patients analyzing microarrays (CodeLink Human Whole Genome). Patients blood was drawn, PBMCs isolated and cultured in three different conditions: culture medium (control), 1,000 U/ml of IFN-I(2)1a (BLA- (STOFERON, Bio Sidus) and 1,000 U/ml of IFN-I(2)1a (REBIF, Serono) RNA was purified from non-adherent cells (mostly lymphocytes), amplified and hybridized. Raw data were generated by CodeLink proprietary software. Data normalization, quality control and analysis of differential gene expression between treatments were done using linear model for microarray data. Functional annotation analysis of IFN-I(2)1a MS treatment transcription was done using DAVID. Out of the approximately 45,000 human sequences examined, no evidence of differential

  19. Patient-rated suitability of a novel electronic device for self-injection of subcutaneous interferon beta-1a in relapsing multiple sclerosis: an international, single-arm, multicentre, Phase IIIb study

    PubMed Central

    2010-01-01

    Background Multiple sclerosis (MS) currently requires long-term treatment with disease-modifying drugs, administered parenterally up to once daily. The need for regular self-injection can be a barrier to treatment for many patients. Autoinjectors can help patients overcome problems or concerns with self-injection and could, therefore, improve treatment adherence. This study was performed to assess the suitability of a new electronic device for the subcutaneous (sc) administration of interferon (IFN) beta-1a, 44 mcg three times weekly, for relapsing MS. Methods In this Phase IIIb, multicentre, single-arm study, patients with relapsing MS who had been consistently self-injecting sc IFN beta-1a using an autoinjector for at least 6 weeks were taught to use the new device and self-administered treatment for 12 weeks thereafter. Patient-rated suitability of the device was assessed at the end of Week 12 using the Patient User Trial Questionnaire. Patient satisfaction with, and evaluation of, the injection process was assessed using the MS Treatment Concern Questionnaire. Trainers evaluated the device using the Trainer User Trial Questionnaire. Results At Week 12, 71.6% (73/102) of patients considered the device 'very suitable' or 'suitable' for self-injection; 92.2% (94/102) reported some degree of suitability and only 7.8% (8/102) found the device 'not at all suitable'. At Weeks 4, 8 and 12, most patients reported that injection preparation and clean-up, performing injections and ease of device use in the previous 4 weeks compared favourably with, or was equivalent to, their previous experience of self-injection. Injection-related pain, injection reactions and 'flu-like' symptoms remained stable over the 12 weeks. Each device feature was rated 'very useful' or 'useful' by at least 80% of patients. All trainers and 95.2% (99/104) of patients found device functions 'very easy' or 'easy' to use. Overall convenience was considered the most important benefit of the device

  20. Interferon beta and multiple sclerosis: look at the evidence.

    PubMed

    Patti, F; Reggio, A

    2002-09-01

    Recent advances in therapy for multiple sclerosis (MS) have centred on the use of the disease-modifying drugs glatiramer acetate (GA) and interferon (IFN) beta. Several large-scale clinical trials have been carried out on the use of these compounds, but there have been few studies that have directly compared their efficacy in MS. Furthermore, there has been controversy and confusion over the IFN beta therapy regimen that will achieve the best possible clinical outcome for MS patients. This review focuses principally on clinical trials of IFN beta-1a, where data that allow direct comparison of different treatment regimens are now available. Current data indicate that IFN beta, and in particular IFN beta-1a, has important advantages over GA in the treatment of relapsing-remitting MS (RRMS). Additionally, IFN beta-1a (Rebif, Serono), 44 microg administered subcutaneously (s.c.) three times weekly (t.i.w.), is significantly more effective than IFN beta-1a (Avonex, Biogen), 30 microg administered intramuscularly once weekly. For optimal management of RRMS, treatment with IFN beta-1a, 44 microg s.c. t.i.w., should begin as early as possible after diagnosis.

  1. The cross-reactivity of binding antibodies with different interferon beta formulations used as disease-modifying drugs in multiple sclerosis patients

    PubMed Central

    Wencel-Warot, Agnieszka; Michalak, Slawomir; Warot, Marcin; Kalinowska-Lyszczarz, Alicja; Kazmierski, Radoslaw

    2016-01-01

    Abstract Interferon beta (IFNb) preparations are commonly used as first-line therapy in relapsing-remitting multiple sclerosis (RRMS). They are, however, characterized by limited efficacy, partly due to the formation of anti-IFNb antibodies in patients. In this pilot study, we assessed with the ELISA method the presence of the binding antibodies (BAbs) against interferon beta after 2 years of therapy with subcutaneous interferon beta 1a (Rebif) in 49 RRMS patients. Antibody levels were established again within 1 year after treatment withdrawal. We used 3 interferons that are commercially available for MS therapy, namely Avonex (Biogen Idec Limited), Rebif (Merck Serono), and Betaferon (Bayer Pharma AG), as antigens. BAbs reacting with Rebif were found in 24.4% to 55% of patients, depending on the units of their expression. The levels of anti-Rebif antibodies remained high in 8 patients and in 4 patients they dropped significantly. Strong correlations were obtained in all assays (anti-Rebif-anti-Avonex, anti-Rebif-anti-Betaferon, and anti-Betaferon-anti-Avonex) and the existence of cross-reactivity in the formation of antibodies against all the tested formulations of interferon beta was confirmed. The levels of BAbs remain significant in the clinical context, and their assessment is the first choice screening; however, methods of BAbs evaluation can be crucial for further decisions. More studies are needed to confirm our results; specifically it would be of interest to evaluate methods of neutralizing antibodies identification, as we only assessed the binding antibodies. Nevertheless, our results support the concept that in interferon nonresponders, that are positive for binding antibodies, switching the therapy to alternative disease-modifying agent (for example glatiramer acetate, fingolimod, or natalizumab) is justified, whereas the switch to another interferon formulation will probably be of no benefit. PMID:27828855

  2. The cross-reactivity of binding antibodies with different interferon beta formulations used as disease-modifying drugs in multiple sclerosis patients.

    PubMed

    Wencel-Warot, Agnieszka; Michalak, Slawomir; Warot, Marcin; Kalinowska-Lyszczarz, Alicja; Kazmierski, Radoslaw

    2016-11-01

    Interferon beta (IFNb) preparations are commonly used as first-line therapy in relapsing-remitting multiple sclerosis (RRMS). They are, however, characterized by limited efficacy, partly due to the formation of anti-IFNb antibodies in patients.In this pilot study, we assessed with the ELISA method the presence of the binding antibodies (BAbs) against interferon beta after 2 years of therapy with subcutaneous interferon beta 1a (Rebif) in 49 RRMS patients. Antibody levels were established again within 1 year after treatment withdrawal. We used 3 interferons that are commercially available for MS therapy, namely Avonex (Biogen Idec Limited), Rebif (Merck Serono), and Betaferon (Bayer Pharma AG), as antigens.BAbs reacting with Rebif were found in 24.4% to 55% of patients, depending on the units of their expression. The levels of anti-Rebif antibodies remained high in 8 patients and in 4 patients they dropped significantly. Strong correlations were obtained in all assays (anti-Rebif-anti-Avonex, anti-Rebif-anti-Betaferon, and anti-Betaferon-anti-Avonex) and the existence of cross-reactivity in the formation of antibodies against all the tested formulations of interferon beta was confirmed. The levels of BAbs remain significant in the clinical context, and their assessment is the first choice screening; however, methods of BAbs evaluation can be crucial for further decisions. More studies are needed to confirm our results; specifically it would be of interest to evaluate methods of neutralizing antibodies identification, as we only assessed the binding antibodies. Nevertheless, our results support the concept that in interferon nonresponders, that are positive for binding antibodies, switching the therapy to alternative disease-modifying agent (for example glatiramer acetate, fingolimod, or natalizumab) is justified, whereas the switch to another interferon formulation will probably be of no benefit.

  3. Effect of Treatment with Interferon Beta-1a on Changes in Voxel-Wise Magnetization Transfer Ratio in Normal Appearing Brain Tissue and Lesions of Patients with Relapsing–Remitting Multiple Sclerosis: A 24-Week, Controlled Pilot Study

    PubMed Central

    Zivadinov, Robert; Dwyer, Michael G.; Markovic-Plese, Silva; Kennedy, Cheryl; Bergsland, Niels; Ramasamy, Deepa P.; Durfee, Jacqueline; Hojnacki, David; Hayward, Brooke; Dangond, Fernando; Weinstock-Guttman, Bianca

    2014-01-01

    Background This pilot study investigated changes in remyelinating and demyelinating activity in normal appearing brain tissue (NABT) and lesions, by using voxel-wise magnetization transfer ratio (VW-MTR), in patients with relapsing–remitting multiple sclerosis (RRMS) receiving interferon beta-1a 44 mcg subcutaneously (IFN β-1a SC) three times weekly versus healthy controls (HCs) (NCT01085318). Methods Increasing (suggestive of remyelination) and decreasing (suggestive of demyelination) VW-MTR changes in NABT and in T2, T1 and gadolinium (Gd)-enhancing lesion volume were measured over 24 weeks in 23 patients treated with IFN β-1a SC and in 15 HCs (where applicable). VW-MTR changes were tested using the Wilcoxon signed–rank or Wilcoxon rank–sum test. Results A trend for greater volume of NABT with increasing VW-MTR at 24 weeks was observed for patients versus HCs (median [range] 1206 [0–15278]; 342 [0–951] mm3; p = 0.061). NABT volume with increasing VW-MTR at 12 weeks was significantly greater in patients than in HCs (852 [6–11577]; 360 [0–1755] mm3; p = 0.028). Similar findings were detected for lesion volumes. Two patients with notably high numbers of Gd-enhancing lesions at baseline had a markedly greater volume of tissue with increasing VW-MTR compared with other patients. Volume of NABT tissue with decreasing VW-MTR was significantly greater in patients versus HCs at 24 weeks (942 [0–6141]; 297 [0–852] mm3; p<0.001). Conclusions The significant change in NABT volume with increasing VW-MTR at 12 weeks suggests that active remyelination in patients with RRMS may occur during treatment with IFN β-1a SC. Findings from two patients with the highest number of Gd-enhancing lesions at baseline suggest that extensive remyelination in NABT may occur in patients with high disease activity. Tissue volume with decreasing VW-MTR was greater in patients than in HCs, despite treatment, validating the sensitivity of this technique for detecting MS

  4. 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

  5. EVASEP: A Noninterventional Study Describing the Perception of Neurologists, Patients, and Caregivers on Caregivers' Role in the Support of Patients Suffering from Multiple Sclerosis Treated with Subcutaneous Interferon Beta 1a

    PubMed Central

    Donzé, Cécile; Lenne, Bruno; Jean Deleglise, Anne-Sophie; Bellili, Yasmine; Hautecoeur, Patrick

    2016-01-01

    Background. The perception of the role of caregivers for people with multiple sclerosis (MS) is important but poorly studied, particularly in patients with low levels of disability. Objectives. To describe the perceptions of the role of caregivers from the perspective of the caregiver, the patient, and neurologists. Methods. This observational study was conducted in France on patients with relapsing remitting MS treated with subcutaneous (SC) interferon-β-1a (IFN-β-1a) for more than 24 months. Results. Caregiver, patients, and neurologists all considered providing moral support and fighting against the disease as the most important role of the care provider. Moral support was considered significantly more important by caregivers than the patients and neurologists (p = 0.002) and caregivers considered their role in helping patients to fight disease more important than did the neurologists (p = 0.006). Knowledge of disease and available treatments were less important among support providers than patients (p = 0.007 and p = 0.001). Conclusion. There are many unmet needs in the perception of the role of caregivers for people with MS which need to be addressed to deliver the most effective care package for patients and to support the needs of the support provider. PMID:27563466

  6. Less Frequent and Less Severe Flu-Like Syndrome in Interferon Beta-1a Treated Multiple Sclerosis Patients with at Least One Allele Bearing the G>C Polymorphism at Position -174 of the IL-6 Promoter Gene

    PubMed Central

    Bertoli, Diego; Serana, Federico; Sottini, Alessandra; Cordioli, Cinzia; Maimone, Davide; Amato, Maria Pia; Centonze, Diego; Florio, Ciro; Puma, Elisa; Capra, Ruggero; Imberti, Luisa

    2015-01-01

    One of the most common adverse event of interferon beta (IFNβ) therapy for multiple sclerosis is flu-like syndrome (FLS), which has been reportedly related to increased levels of cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Average cytokine levels can be affected by single nucleotide polymorphism in the gene promoter regions. To investigate whether IL-6 -174 G>C and TNF-α -376 G>A polymorphisms could be correlated to the incidence of FLS, and whether an anti-inflammatory/antipyretic therapy may influence FLS development, a prospective observational study was performed in 190 treatment naïve, multiple sclerosis patients who started IM IFNβ-1a 30mcg once weekly. The identification of IL-6 -174 G>C and TNF-α -376 G>A polymorphisms was achieved by performing an amplification-refractory mutation system. Serum IL-6 levels were measured using enzyme-linked immunosorbent assay in blood samples taken before therapy and then after the first and last IFNβ-1a injection of the follow-up. FLS-related symptoms were recorded by patients once per week during the first 12 weeks of therapy into a self-reported diary. We found that patients carrying at least one copy of the C allele at position -174 in the promoter of IL-6 gene produced lower levels of IL-6 and were less prone to develop FLS, which was also less severe. On the contrary, the polymorphism of TNF-α had no effect on FLS. Patients taking the first dose of anti-inflammatory/antipyretic therapy in the peri-injection period (within 1 hour) experienced a reduced FLS severity. In conclusion, the study of IL-6 -174 G>C polymorphism would allow the identification of patients lacking the C nucleotide on both alleles who are at risk of a more severe FLS, and may be addressed to a timely and stronger anti-inflammatory/antipyretic therapy for a more effective FLS prevention. PMID:26285213

  7. Differential effects of three interferon betas on neutralising antibodies in patients with multiple sclerosis: a follow up study in an independent laboratory

    PubMed Central

    Bertolotto, A; Malucchi, S; Sala, A; Orefice, G; Carrieri, P; Capobianco, M; Milano, E; Melis, F; Giordana, M

    2002-01-01

    Objective: To evaluate the incidence and the prevalence of neutralising antibodies (NABs) to three interferon beta (IFNß) products in patients with multiple sclerosis (MS). Methods: Sera were tested from 125 patients with relapsing-remitting MS. Patients were treated with IFNß-1b (Betaferon, n = 29) 8 MIU subcutaneously every other day, IFNß-1a (Avonex, n = 44) 30 µg intramuscularly once weekly, or IFNß-1a (Rebif, n = 36) 22 µg subcutaneously three times weekly for 6 to 18 months. An additional 16 patients were treated with Rebif 22 µg intramuscularly once or twice weekly. NABs were assessed using the cytopathic effect assay before treatment and every three months during treatment. Patients with two or more consecutive positive samples were considered to be persistent NAB positive (NAB+). Results: At baseline, no patients were NAB+. NABs developed during the first three months of treatment and continued to develop until month 18. Over 18 months of treatment, the risk of being persistent NAB+ was 31% for Betaferon, 15% for Rebif, and 2% for Avonex (Betaferon versus Avonex, p = 0.001; Betaferon versus Rebif, p = 0.19; Rebif versus Avonex, p = 0.04). In all patients with one or more NAB+ samples, the risk of becoming NAB+ was 38% for Betaferon, 18% for Rebif, and 7% for Avonex (Betaferon versus Avonex, p = 0.0007; Betaferon versus Rebif, p = 0.10; Rebif versus Avonex, p = 0.07). At month 18, the prevalence of persistent NAB+ patients was 31.6% for Betaferon, 18.7% for Rebif, and 4% for Avonex. Numbers of NAB+ patients observed were similar with intramuscular Rebif and with subcutaneous Rebif. Conclusion: The three IFNß preparations have different degrees of immunogenicity, with Betaferon producing the highest incidence of NABs and Avonex the lowest. These differences should be considered by neurologists when selecting treatment for their patients with MS because NABs can reduce both bioavailability and clinical efficacy of IFNß. PMID:12122172

  8. IFN beta 1a as Glucocorticoids-Sparing Therapy in a Patient with CLIPPERS

    PubMed Central

    Rico, María; Villafani, Javier; Tuñón, Alberto; Mateos, Valentín; Oliva-Nacarino, Pedro

    2016-01-01

    Patient: Male, 31 Final Diagnosis: CLIPPERS Symptoms: Ataxia • diplopia Medication: IFNbeta 1a Clinical Procedure: — Specialty: Neurology Objective: Rare disease Background: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently described inflammatory disease of the central nervous system, distinguished by brainstem- and spinal cord-centered lesions with a characteristic contrast enhancement on MRI, a lymphocytic perivascular infiltrate on pathological exam, and a dramatic response to and dependence on steroids therapy. Since its initial description in 2010, different glucocorticoid-sparing agents, mostly immunosuppressant drugs, have been used to minimize the dosage, but these therapies also carry the risk of important secondary effects. We present the first reported case of CLIPPERS treated with interferon beta 1a as add-on therapy. Case Report: A previously healthy 31-year-old man presented with gait ataxia and dysarthria. MRI showed pons-centered hyperintense patchy lesions on T2-weighted images. Additional tests ruled out other possible diagnoses and symptoms reversed with intravenous methylprednisolone. Over the years the patient presented with several episodes of deterioration each year, which were partly reversed with glucocorticoid therapy, but leaving him with growing sequelae. Four years after the initial event, treatment with interferon-beta-1a was initiated, achieving reduced frequency of the relapses to 1 every 4 years, which were no longer associated to increasing disability. This allowed reducing glucocorticoids to 30 mg of Deflazacort every other day. Conclusions: Interferon beta-1a could be an alternative to corticosteroid-combined therapy in CLIPPERS and its more benign profile of secondary effects compared to immunosuppressants could make it an attractive choice. PMID:26813773

  9. Quality Assessment in Multiple Sclerosis Therapy (QUASIMS): a comparison of interferon beta therapies for relapsing-remitting multiple sclerosis.

    PubMed

    Limmroth, Volker; Malessa, Rolf; Zettl, Uwe Klaus; Koehler, Jürgen; Japp, Gudrun; Haller, Peter; Elias, Wolfgang; Obhof, Winfried; Viehöver, Andrea; Meier, Uwe; Brosig, Arne; Hasford, Joerg; Putzki, Norman; Kalski, Gabriele; Wernsdörfer, Colin

    2007-01-01

    Interferon beta (IFN beta) preparations are the most frequently prescribed therapies for patients with relapsing multiple sclerosis (MS). Several open-label observational studies report similar efficacy among IFN beta preparations. The Quality Assessment in Multiple Sclerosis Therapy (QUASIMS) study is a large, open-label observational study designed to compare the effectiveness and tolerability of available IFN beta preparations as disease-modifying therapies for relapsing MS across a wide range of clinical practice settings. This retrospective, controlled cohort study was conducted by chart review at 510 sites in Germany, Austria, and Switzerland. Enrolled patients had received one of the four available IFN beta preparations/dosing regimens (intramuscular IFN beta-1a 30 microg 1x/week [Avonex], subcutaneous (SC) IFN beta-1a 22 or 44 microg 3 x/week [Rebif], or SC IFN beta-1b 250 microg 3.5x/week [Betaferon/Betaseron]) for >or= 2 years. Pre-planned outcomes at 1 and 2 years included change from baseline Expanded Disability Status Scale (EDSS) score, percentage of progression-free patients (< 1.0 EDSS point), annualised relapse rate (RR), percentage of relapse-free patients, and reasons for therapy change. Of 4754 evaluable patients, 3991 (84%) received IFN beta as initial therapy. There were no significant differences among IFN betas when used as initial or follow-up therapy on almost all outcome variables. Relapse rate was consistently higher and percentage of relapse-free patients consistently lower for all products used as follow-up versus initial therapy. Results of QUASIMS showed similar effectiveness among IFN beta products. Benefits were consistently superior when IFN beta was used as initial rather than follow-up therapy. Our results suggest that patients do not benefit in terms of disease outcome from switching between IFN beta preparations/dosing regimens.

  10. Incidence, characterization, and clinical impact analysis of peginterferon beta1a immunogenicity in patients with multiple sclerosis in the ADVANCE trial

    PubMed Central

    White, Joleen T.; Newsome, Scott D.; Kieseier, Bernd C.; Bermel, Robert A.; Cui, Yue; Seddighzadeh, Ali; Hung, Serena; Crossman, Mary; Subramanyam, Meena

    2016-01-01

    Background: Efficacy of interferon beta in multiple sclerosis (MS) can be dampened in patients who develop neutralizing antidrug antibodies (NAbs). Peginterferon beta1a is an interferon conjugated with a polyethylene glycol (PEG) moiety. Pegylation increases a drug’s half life and exposure, and may also reduce immunogenicity. Objective: The objective of this study was to characterize the incidence and impact of immunogenicity to peginterferon beta1a over 2 years in patients with MS. Methods: Patients with relapsing–remitting MS (N = 1512) were randomized to subcutaneous peginterferon beta1a 125 μg every 2 or 4 weeks, or placebo, for 1 year; patients in the placebo group were rerandomized to active treatment in year 2. The incidence and titers of binding antibodies (BAbs) and NAbs to interferon and antibodies to PEG (anti-PEG) were assessed in analytically validated assays. The clinical impact of immunogenicity on relapse and magnetic resonance imaging endpoints was evaluated. Results: Over 2 years, 6%, less than 1%, and 7% of patients developed anti-interferon BAbs, NAbs, and anti-PEG antibodies, respectively. There was no discernible clinically meaningful effect of antibody status on the pharmacodynamic, efficacy, or safety parameters evaluated, although these analyses were limited by the low incidence of treatment-emergent antibodies. Conclusion: The treatment effect of peginterferon beta1a in patients with relapsing–remitting MS is not expected to be attenuated by immunogenicity. PMID:27366230

  11. Peginterferon Beta-1a Shows Antitumor Activity as a Single Agent and Enhances Efficacy of Standard of Care Cancer Therapeutics in Human Melanoma, Breast, Renal, and Colon Xenograft Models.

    PubMed

    Boccia, Antonio; Virata, Cyrus; Lindner, Daniel; English, Nicki; Pathan, Nuzhat; Brickelmaier, Margot; Hu, Xiao; Gardner, Jennifer L; Peng, Liaomin; Wang, Xinzhong; Zhang, Xiamei; Yang, Lu; Perron, Keli; Yco, Grace; Kelly, Rebecca; Gamez, James; Scripps, Thomas; Bennett, Donald; Joseph, Ingrid B; Baker, Darren P

    2017-01-01

    Because of its tumor-suppressive effect, interferon-based therapy has been used for the treatment of melanoma. However, limited data are available regarding the antitumor effects of pegylated interferons, either alone or in combination with approved anticancer drugs. We report that treatment of human WM-266-4 melanoma cells with peginterferon beta-1a induced apoptotic markers. Additionally, peginterferon beta-1a significantly inhibited the growth of human SK-MEL-1, A-375, and WM-266-4 melanoma xenografts established in immunocompromised mice. Peginterferon beta-1a regressed large, established WM-266-4 xenografts in nude mice. Treatment of SK-MEL-1 tumor-bearing mice with a combination of peginterferon beta-1a and the MEK inhibitor PD325901 ((R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzamide) significantly improved tumor growth inhibition compared with either agent alone. Examination of the antitumor activity of peginterferon beta-1a in combination with approved anticancer drugs in breast and renal carcinomas revealed improved antitumor activity in these preclinical xenograft models, as did the combination of peginterferon beta-1a and bevacizumab in a colon carcinoma xenograft model.

  12. A randomized open label study of pain medications (naproxen, acetaminophen and ibuprofen) for controlling side effects during initiation of IFN beta-1a therapy and during its ongoing use for relapsing-remitting multiple sclerosis.

    PubMed

    Leuschen, M Patricia; Filipi, Mary; Healey, Kathleen

    2004-12-01

    Multiple sclerosis (MS) patients initiating IFN beta-1a, Avonex, therapy (Group 1, n = 30) or experiencing side effects after 6 months on therapy (Group 2, n = 30) were randomized for 5 weeks open label adjunct therapy to naproxen (Aleve), acetaminophen (Tylenol) or ibuprofen (Advil). Our hypothesis was that non-prescription pain medications are effective in decreasing or alleviating the side effects associated with IFN beta-1a therapy. Contrary to the hypothesis, most patients in both groups continued to report side effects on all pain medications. After 5 weeks, headache, fever, chills and injection site pain were low in < or = 50% of patients. Moderate to significant fatigue, muscle or joint pain continued in most patients. As a quality of life measure, the Modified Fatigue Impact Scale (mFIS) improved for Group 1 on naproxen or ibuprofen with greatest improvement in physical subset (P = 0.002 for naproxen and P<0.01 for ibuprofen). Total mFIS for Group 1 on acetaminophen improved (P = 0.04) due to improved cognitive subset rather than physical subset. Group 2, with side effects initially, reported less significant fatigue (severity 5-10) but more moderate fatigue (severity 2-4) at study end for all three medications. All medications improved cognitive subset (P = 0.05). Physical mFIS subset did not improve for Group 2 on acetaminophen, but did with naproxen (P = 0.05) or ibuprofen (P = 0.03). Naproxen and ibuprofen were more effective than acetaminophen in minimizing physical side effects of IFN beta-1a. None of the three pain medications tested were as effective as hypothesized for minimizing fatigue or muscle and joint pain.

  13. Adherence and cost in multiple sclerosis patients treated with IM IFN beta-1a: impact of the CARE patient management program.

    PubMed

    Katsarava, Zaza; Ehlken, Birgit; Limmroth, Volker; Taipale, Kirsi; Patel, Sarita Noemi; Niemczyk, Gabriele; Rehberg-Weber, Karin; Wernsdörfer, Colin

    2015-09-22

    Disease modifying treatments (DMT) for MS such as interferon beta (IFNβ) have been shown to reduce the risk for disease progression. Therefore adherence to treatment is essential for treatment outcome.Here we want to evaluate if participation in a patient management program (PMP) improves adherence to DMT as well as health and cost outcomes associated with MS. In this open-label multicentre prospective observational study, German MS patients treated with once weekly intramuscular (IM) IFNβ-1a (Avonex), were offered participation in a PMP and followed for up to 12 months. The PMP included injection trainings, support and quarterly visits for up to 12 months after initiation of therapy. Utilisation of health care services was evaluated. The primary endpoint was to evaluate the direct and indirect cost associated with MS from payer, patient and societal perspective, in patients who participate in the PMP. Secondary endpoint was the clinical outcome in patients who participate in the PMP (differentiated in adherent versus non-adherent patients). In total 731 patients (mean age: 38.2, 73.7% female) were enrolled, 640 (88%) were observed for twelve months. After six months 34% of patients had participated in the PMP continuously and 21% temporarily; 39% had not participated. After twelve months, the proportions of participants were: 37% continuously and 19% temporarily; 40% had not participated. After 6 months, mean reduction in cost per patient in the participants group (€ 2151) was almost twice as high as the cost reduction amongst non-participants (€ 1131). After twelve months, the annual relapse rate was reduced by 58% compared to baseline in both the participant and non-participant groups. In a real-world-setting, participation in a patient management program was associated with improved medication adherence and lower total MS-related direct and indirect cost over time.

  14. Exploratory analysis of predictors of patient adherence to subcutaneous interferon beta-1a in multiple sclerosis: TRACER study.

    PubMed

    Paolicelli, Damiano; Cocco, Eleonora; Di Lecce, Valentina; Direnzo, Vita; Moiola, Lucia; Lanzillo, Roberta; Perini, Paola; Malucchi, Simona; Borriello, Giovanna; Portaccio, Emilio; Panetta, Valentina; Fenu, Giuseppe; Sangalli, Francesca; Cacciaguerra, Laura; Trojano, Maria

    2016-06-01

    The TRACER multicenter retrospective study aimed to collect data on treatment adherence in a real-life setting, in order to identify predictors of adherence at baseline. We recruited 384 relapsing-remitting (RR) multiple sclerosis patients with at least 12 months of use of RebiSmart®. This electronic device records the performed injections and assesses adherence as the percentage of 'not missing doses', through the connection to the iMed database. Subjects with at least 80% of completed doses at the 12 month of therapy were defined 'treatment adherents'. After 12 months, 89.3% of patients were adherent; 93.2% of patients aged 26-40 years at baseline were adherent (vs 79% of the ≤25 and 87.5% of the ≥41 year olds; p = 0.006). Furthermore, 90.5% of patients with a baseline Expanded Disability Status Scale (EDSS) score <4 showed ≥80% adherence (vs 71.4% in those with EDSS score ≥4; p = 0.016). Fifty-four percent of the patients who were not adherent after 3 months were also not adherent after 12 months (OR 16.8; CI 95%:7.1-39.8). Patients aged 26-40 years and with an EDSS score <4 at baseline were the most adherent. The status of 'treatment adherent' in the first 3 months was predictive of higher adherence in the long term.

  15. The therapeutic effect of Avonex, Rebif and Betaferon on EDSS and relapse in multiple sclerosis: a comparative study.

    PubMed

    Mazdeh, Mehrdokht; Afzali, Saeed; Jaafari, Mahmood Reza

    2010-01-01

    We aimed to compare the therapeutic effect of Avonex (Av), Betaferon (Be) & Rebif (Re) on the Expanded Disability Status Scale (EDSS) in Multiple Sclerosis (MS). Ninety patients referring to Farshchian Hospital were entered in this study. The patients were divided into three equal groups: group 1 received Av, group 2 received Re and group 3 received Be, and after 24 months, comparison was done by calculating primary and final EDSS and the relapse rate. For comparison of the primary and final EDSS in each group, the relapse rate between the groups and side effects between the drugs, the paired samples t.test, the One-Way ANOVA test and the Pearson- chi-square were used. Average age was 31.11 +/- 8.62 years, 80% being female. Comparison of the average primary and final EDSS using the paired samples t.test showed a significant statistical difference (P < 0.05). Motor and visual disturbances (respectively 68.3% and 60.3%) were the most common signs and relapsing- remitting form was the most common form (42.1%). The average EDSS change of groups Av, Be and Re was respectively, 1.28 (29.76%), 1.30 (24.30%) and 1.26 (26.63%), showing no significant statistical difference in reducing EDSS. Groups Av and Be, showed no significant statistical difference in the average relapse rate before and after treatment, but in group Re there was a significant difference (P < 0.05). Treatment with these drugs reduces motor disability, with no significant difference between them. Also in comparison, Re has a greater effect in reducing the relapse rate, but again with no significant statistical difference among them.

  16. Management Strategies for Flu-Like Symptoms and Injection-Site Reactions Associated with Peginterferon Beta-1a

    PubMed Central

    Centonze, Diego; Newsome, Scott D.; Huang, DeRen; Robertson, Christopher; You, Xiaojun; Sabatella, Guido; Evilevitch, Vladimir; Leahy, Leslie

    2016-01-01

    Background: Flu-like symptoms (FLSs) and injection-site reactions (ISRs) have been reported with interferon beta treatments for multiple sclerosis (MS). We sought to obtain consensus on the characteristics/management of FLSs/ISRs in patients with relapsing-remitting MS based on experiences from the randomized, placebo-controlled ADVANCE study of peginterferon beta-1a. Methods: ADVANCE investigators with a predefined number of enrolled patients were eligible to participate in a consensus-generating exercise using a modified Delphi method. An independent steering committee oversaw the development of two sequential Delphi questionnaires. An average rating (AR) of 2.7 or more was defined as consensus a priori. Results: Thirty and 29 investigators (ie, responders) completed questionnaires 1 and 2, respectively, representing 374 patients from ADVANCE. Responders reported that the incidence/duration of FLSs/ISRs in their typical patient generally declined after 3 months of treatment. Responders reached consensus that FLSs typically last up to 24 hours (AR = 3.17) and have mild/moderate effects on activities of daily living (AR = 3.34). Patients should initiate acetaminophen/nonsteroidal anti-inflammatory drug treatment on a scheduled basis (AR = 3.31) and change the timing of injection (AR = 3.28) to manage FLSs. Injection-site rotation/cooling and drug administration at room temperature (all AR ≥ 3.10) were recommended for managing ISRs. Patient education on FLSs/ISRs was advocated before treatment initiation. Conclusions: Delphi responders agreed on the management strategies for FLSs/ISRs and agreed that patient education is critical to set treatment expectations and promote adherence. PMID:27551246

  17. Biological activity of interferon betas in patients with multiple sclerosis is affected by treatment regimen and neutralising antibodies

    PubMed Central

    Bertolotto, A; Sala, A; Malucchi, S; Marnetto, F; Caldano, M; Di, S; Capobianco, M; Gilli, F

    2004-01-01

    Background: MxA gene expression is one of the most appropriate markers of biological activity of exogenous interferon (IFN) beta. Methods: We quantified MxA mRNA for five consecutive days in 62 patients treated with IFN beta (16, Avonex; 10, Betaferon; 24, Rebif 22; 12, Rebif 44), by quantitative-competitive polymerase chain reaction. Every three months, IFN beta induced neutralising antibodies (NAbs) were evaluated in sera using a cytopathic effect assay. Results: Two categories of patients were identified: one group (49/62) had a sharp post-injection increase in MxA expression (defined as "IFN beta biological responder"), whereas the other group (13/62) had no MxA induction after IFN beta administrations (defined as "IFN beta biological non-responder"). In 11/13 biological non-responders, the persistent presence of NAbs correlated with abolished biological activity, independently of treatment regimen. The two remaining IFN beta biological non-responders were NAb–. Among the 49 IFN beta biological responders, biological activity was comparable between the four preparations on day 2 and 3 (+12 and +36 hours post-injection), but it was greater in Betaferon and both Rebif preparations on day 1, 4, and 5. In biological responders treated three times a week, only 82% (59/72) of injections were considered effective, compared with 100% (13/13) of Avonex injections. Conclusion: Our results suggest that an optimal IFN beta regimen is not yet available: Avonex, given once a week, shows lower cumulative biological activity. On the other hand, both Betaferon and Rebif, given three times a week, show 18% biologically ineffective injections and higher risk of developing NAbs, which abolish biological activity. PMID:15314118

  18. Peginterferon beta-1a reduces disability worsening in relapsing–remitting multiple sclerosis: 2-year results from ADVANCE

    PubMed Central

    Newsome, Scott D.; Kieseier, Bernd C.; Liu, Shifang; You, Xiaojun; Kinter, Elizabeth; Hung, Serena; Sperling, Bjoern

    2016-01-01

    Background: In the pivotal phase III 2-year ADVANCE study, subcutaneous peginterferon beta-1a 125 mcg every 2 weeks demonstrated significant improvements in clinical outcomes, including disability endpoints, in patients with relapsing–remitting multiple sclerosis (RRMS). Here, we aim to further evaluate disability data from ADVANCE, and explore associations between confirmed disability progression (CDP), functional status, and health-related quality of life (HRQoL). Methods: In total, 1512 patients were randomized to placebo or peginterferon beta-1a 125 mcg every 2 or 4 weeks. After 1 year, patients on placebo were re-randomized to peginterferon beta-1a every 2 or 4 weeks. CDP was defined as ⩾1.0 point increase from a baseline Expanded Disability Status Scale (EDSS) score ⩾ 1.0, or ⩾1.5-point increase from baseline 0, confirmed 12 or 24 weeks after onset. Results: Peginterferon beta-1a every 2 weeks significantly reduced risk of 12- and 24-week CDP at 1 year compared with placebo (12-week CDP: 6.8% versus 10.5%, p = 0.038; 24-week CDP: 4% versus 8.4%, p = 0.0069, peginterferon beta-1a every 2 weeks versus placebo, respectively). Benefits were maintained over 2 years (11.2% and 7.7%, peginterferon beta-1a every 2 weeks in 12- and 24-week CDP, respectively). Approximately 90% of patients with 24-week CDP had simultaneous worsening by ⩾1 point in at least one functional system score, most commonly pyramidal. Displaying a 24-week CDP was associated with worse scores on the Multiple Sclerosis Functional Composite (MSFC) scale and several HRQoL instruments; the impact of CDP was attenuated by treatment with peginterferon beta-1a every 2 weeks. Conclusions: Peginterferon beta-1a has the potential to prevent/delay worsening of disability in patients with relapsing–remitting multiple sclerosis. Furthermore, improved benefits in disability status with peginterferon beta-1a were also associated with improved functional status and HRQoL [Clinical

  19. Peginterferon beta-1a reduces disability worsening in relapsing-remitting multiple sclerosis: 2-year results from ADVANCE.

    PubMed

    Newsome, Scott D; Kieseier, Bernd C; Liu, Shifang; You, Xiaojun; Kinter, Elizabeth; Hung, Serena; Sperling, Bjoern

    2017-01-01

    In the pivotal phase III 2-year ADVANCE study, subcutaneous peginterferon beta-1a 125 mcg every 2 weeks demonstrated significant improvements in clinical outcomes, including disability endpoints, in patients with relapsing-remitting multiple sclerosis (RRMS). Here, we aim to further evaluate disability data from ADVANCE, and explore associations between confirmed disability progression (CDP), functional status, and health-related quality of life (HRQoL). In total, 1512 patients were randomized to placebo or peginterferon beta-1a 125 mcg every 2 or 4 weeks. After 1 year, patients on placebo were re-randomized to peginterferon beta-1a every 2 or 4 weeks. CDP was defined as ⩾1.0 point increase from a baseline Expanded Disability Status Scale (EDSS) score ⩾ 1.0, or ⩾1.5-point increase from baseline 0, confirmed 12 or 24 weeks after onset. Peginterferon beta-1a every 2 weeks significantly reduced risk of 12- and 24-week CDP at 1 year compared with placebo (12-week CDP: 6.8% versus 10.5%, p = 0.038; 24-week CDP: 4% versus 8.4%, p = 0.0069, peginterferon beta-1a every 2 weeks versus placebo, respectively). Benefits were maintained over 2 years (11.2% and 7.7%, peginterferon beta-1a every 2 weeks in 12- and 24-week CDP, respectively). Approximately 90% of patients with 24-week CDP had simultaneous worsening by ⩾1 point in at least one functional system score, most commonly pyramidal. Displaying a 24-week CDP was associated with worse scores on the Multiple Sclerosis Functional Composite (MSFC) scale and several HRQoL instruments; the impact of CDP was attenuated by treatment with peginterferon beta-1a every 2 weeks. Peginterferon beta-1a has the potential to prevent/delay worsening of disability in patients with relapsing-remitting multiple sclerosis. Furthermore, improved benefits in disability status with peginterferon beta-1a were also associated with improved functional status and HRQoL [ClinicalTrials.gov identifier: NCT00906399].

  20. Transient laminin beta 1a Induction Defines the Wound Epidermis during Zebrafish Fin Regeneration.

    PubMed

    Chen, Chen-Hui; Merriman, Alexander F; Savage, Jeremiah; Willer, Jason; Wahlig, Taylor; Katsanis, Nicholas; Yin, Viravuth P; Poss, Kenneth D

    2015-08-01

    The first critical stage in salamander or teleost appendage regeneration is creation of a specialized epidermis that instructs growth from underlying stump tissue. Here, we performed a forward genetic screen for mutations that impair this process in amputated zebrafish fins. Positional cloning and complementation assays identified a temperature-sensitive allele of the ECM component laminin beta 1a (lamb1a) that blocks fin regeneration. lamb1a, but not its paralog lamb1b, is sharply induced in a subset of epithelial cells after fin amputation, where it is required to establish and maintain a polarized basal epithelial cell layer. These events facilitate expression of the morphogenetic factors shha and lef1, basolateral positioning of phosphorylated Igf1r, patterning of new osteoblasts, and regeneration of bone. By contrast, lamb1a function is dispensable for juvenile body growth, homeostatic adult tissue maintenance, repair of split fins, or renewal of genetically ablated osteoblasts. fgf20a mutations or transgenic Fgf receptor inhibition disrupt lamb1a expression, linking a central growth factor to epithelial maturation during regeneration. Our findings reveal transient induction of lamb1a in epithelial cells as a key, growth factor-guided step in formation of a signaling-competent regeneration epidermis.

  1. The interferons.

    PubMed Central

    Toy, J L

    1983-01-01

    An overview of the interferons is presented. A description of something of what is known about them is given, including: their genes; their protein structures and characteristics; their mechanisms of actions; and their varied biological effects emphasising particularly their immunomodulatory actions. Finally, a brief summary is made of the current status of human clinical studies that have been conducted with interferons in the oncological and viral fields, mentioning also recent findings in patients who have the acquired immunodeficiency syndrome (AIDS). PMID:6193915

  2. Peripheral Vasculitis, Intermediate Uveitis and Interferon Use in Multiple Sclerosis

    PubMed Central

    Kinyas, Şeref; Esgin, Haluk

    2016-01-01

    Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. A 40-year-old female patient with a 12-year history of MS was admitted to our clinic with blurred vision and floaters in her right eye for about 1 month. Here, we share the findings and the management of intermediate uveitis and retinal periphlebitis in an MS case being treated with interferon beta-1a for 7 years. PMID:27800257

  3. Interferon 7, 1986

    SciTech Connect

    Gresser, I.

    1986-01-01

    This book contains seven sections. Some of the section titles are: Interferon Analogues from Synthetic Genes: An Approach to Protein Structure--Activity Studies; Interferon and Major Histocompatibility Complex Genes: A Model to Analyse Eukaryotic Gene Regulation; Interferons and the Regulations of Oncogenes; and AIDS and Kaposi's Sarcoma: Interferons in Pathogenesis and Treatment.

  4. [Interferons and autoimmune diseases].

    PubMed

    Niino, Masaaki; Miyazaki, Yusei

    2013-11-01

    Interferons are widely expressed cytokines that have potent antiviral, antiproliferative, and immunomodulatory effects. Type I interferons show complex biology; in some cases, they promote autoimmunity and inflammation, and in other cases, exhibit homeostatic functions by controlling inflammation and tissue destruction. This complexity is exemplified in the 2 major autoimmune diseases: systemic lupus erythematosus, in which type I interferons play an important role in the pathogenesis, and multiple sclerosis, in which interferon beta, a type I interferon, exhibits protective and therapeutic roles. This article reviews the basic clinical data on type I interferons in autoimmune diseases and type I interferons as potential targets for therapies in autoimmune diseases.

  5. Interferons and autoimmune disorders.

    PubMed

    Meyer, Olivier

    2009-10-01

    Interferons are ubiquitous cytokines produced by all mononuclear cell types in response to infection by a DNA or RNA virus. There are three major classes of interferons: type I or nonimmune interferons consist chiefly of interferons alpha produced by leukocytes and of interferon beta produced by fibroblasts, although there are several other less important variants; type II or immune interferon is interferon gamma, which is mainly produced by NK cells and T cells; and type III consists of the lambda interferons. Each type is characterized by a specific receptor and signal transduction pathway. Toll-like receptors (TLRs) on the cell membrane and endosomes recognize viruses and other microorganisms. Binding of DNA or RNA to endosomal TLRs generates a signal whose transduction pathways lead to molecules capable of binding to genes for various interferons, interleukin-1, and TNFalpha. Interferons can stimulate or inhibit up to 300 different genes encoding proteins involved in antiviral defense mechanisms, inflammation, adaptive immunity, angiogenesis, and other processes. The properties of interferons are used to treat a number of viral infections (e.g., hepatitis B and hepatitis C), inflammatory diseases (interferon beta for multiple sclerosis and interferon gamma for systemic sclerosis), and malignancies. Overactivation of the interferon pathways has been demonstrated in patients with systemic lupus erythematosus. The result is a characteristic pattern of mRNA expression known as the interferon signature. Interferon overactivation is related to inadequate clearance of apoptotic particles with accumulation of apoptosis products (DNA-CpG motifs and U-RNA). Similar abnormalities have been found in patients with primary Sjögren's syndrome, systemic sclerosis, and polymyositis, as well as in some cases of rheumatoid arthritis. Immunomodulation strategies designed to decrease interferon overactivity are being evaluated in patients with systemic lupus erythematosus.

  6. [Gamma (or immune) interferon].

    PubMed

    Maniu, H

    1987-01-01

    Research on interferon progressed very much during the last years, especially studies on the gamma type of interferon. Historical data about the research conducted on the gamma interferon, its inductors, its physical, chemical and biological properties, the methods of preparation and purification, as well as the perspective of therapeutical utilisation of this type of interferon, in spite of some reversible side effects, are presented and discussed.

  7. Clinical uses of interferons

    PubMed Central

    Friedman, Robert M

    2008-01-01

    Interferons were first described by Isaacs & Lindenmann working at the National Institute for Medical Research, Mill Hill in 1957 [1]. Thus, the fiftieth year of their discovery is being celebrated this year at Oxford in a meeting of the International Society for Interferon and Cytokine Research. This then is an appropriate time to review the clinical applications of the interferons. To accomplish this coherently it is necessary also to review briefly what led to the discovery of interferons, why their clinical applications were so slow in coming, and the impact of interferon research on the biomedical sciences. PMID:18070219

  8. [Development of binding antibodies to interferon-beta during treatment of multiple sclerosis with different types of interferon-beta].

    PubMed

    Bartosik-Psujek, Halina; Mitosek-Szewczyk, Krystyna; Belniak, Ewa; Stelmasiak, Zbigniew

    2004-07-01

    Interferon beta (IFN-beta) is generally considered an effective treatment for multiple sclerosis (MS). Importance of binding antibodies (BAb), which are created during the treatment of MS by the use of IFN-beta, hasn't been completely explained, however it is generally reckoned that they might be one of the factors diminishing treatment efficacy. The aim of the study was the appreciation of BAb occurrence during the treatment of MS by the use of different types of interferon beta and their impact on clinical efficacy. The study included 47 patients with relapsing-remitting MS. Within 24 months 37 patients were given two different preparations of IFN-beta 1-a and 10 patients were given IFN-beta 1-b. Every 6 months clinical parameters and BAb level in serum by EIA method were estimated. All preparations of IFN-beta induced appearance of BAb, but frequency of developing BAb to IFN-beta varied according to the IFN beta given. The high levels of BAb appeared significant frequently in patients treated with IFN-beta 1-b than in patients treated with both preparations of IFN-beta 1-a. After 2 years of treatment greater disability, measured by EDSS scale was encountered in patients with high levels of BAb but differences weren't statistically significant. As well, it wasn't stated significant correlation between exacerbation numbers during the treatment.

  9. Beta 1D integrin displaces the beta 1A isoform in striated muscles: localization at junctional structures and signaling potential in nonmuscle cells.

    PubMed

    Belkin, A M; Zhidkova, N I; Balzac, F; Altruda, F; Tomatis, D; Maier, A; Tarone, G; Koteliansky, V E; Burridge, K

    1996-01-01

    The cytoplasmic domains of integrins provide attachment of these extracellular matrix receptors to the cytoskeleton and play a critical role in integrin-mediated signal transduction. In this report we describe the identification, expression, localization, and initial functional characterization of a novel form of beta 1 integrin, termed beta 1D. This isoform contains a unique alternatively spliced cytoplasmic domain of 50 amino acids, with the last 24 amino acids encoded by an additional exon. Of these 24 amino acids, 11 are conserved when compared to the beta 1A isoform, but 13 are unique (Zhidkova, N. I., A. M. Belkin, and R. Mayne. 1995. Biochem. Biophys. Res. Commun. 214:279-285; van der Flier, A., I. Kuikman, C. Baudoin, R, van der Neuf, and A. Sonnenberg. 1995. FEBS Lett. 369:340-344). Using an anti-peptide antibody against the beta 1D integrin subunit, we demonstrated that the beta 1D isoform is synthesized only in skeletal and cardiac muscles, while very low amounts of beta 1A were detected by immunoblot in striated muscles. Whereas beta 1A could not be detected in adult skeletal muscle fibers and cardiomyocytes by immunofluorescence, beta 1D was localized to the sarcolemma of both cell types. In skeletal muscle, beta 1D was concentrated in costameres, myotendinous, and neuromuscular junctions. In cardiac muscle this beta 1 isoform was found in costamers and intercalated discs. beta 1D was associated with alpha 7A and alpha 7B in adult skeletal muscle. In cardiomyocytes of adult heart, alpha 7B was the major partner for the beta 1D isoform. beta 1D could not be detected in proliferating C2C12 myoblasts, but it appeared immediately after myoblast fusion and its amount continued to rise during myotube growth and maturation. In contrast, expression of the beta 1A isoform was downregulated during myodifferentiation in culture and it was completely displaced by beta 1D in mature differentiated myotubes. We also analyzed some functional properties of the beta 1D

  10. [Side-effects of the treatment with disease modifying drugs in patients with multiple sclerosis: an analysis of register data in the Yaroslavl region].

    PubMed

    Spirin, N N; Kasatkin, D S; Stepanov, I O; Shipova, E G; Baranova, N S

    2012-01-01

    Authors have followed up 230 patients with multiple sclerosis treated with disease modifying drugs (DMD) using the data of the Multiple sclerosis register of the Yaroslavl oblast during 2009-2011. Original drugs and their generics registered in Russia are used. Patients received interferon-beta 1a for intramuscular introduction (avonex - 3.0%), interferon-beta 1a for hypodermic injection (rebif - 19.2%, genfakson - 8.5%), interferon-beta 1b (betaferon - 16.5%, extavia - 18.2%, ronbetal - 18.0%), glatimer acetate (copaxone - 16.7%). Adverse effects were recorded and subjective tolerability of the drug by the patient was assessed. Statistically significant differences in the safety profile between some bioanalogues and original DMD were identified. This finding suggests that effects of different DMD should be studied in depth in clinical and post marketing trials.

  11. Peginterferon beta-1a reduces the evolution of MRI lesions to black holes in patients with RRMS: a post hoc analysis from the ADVANCE study.

    PubMed

    Arnold, Douglas L; You, Xiaojun; Castrillo-Viguera, Carmen

    2017-08-01

    The presence of chronic black holes, i.e., chronic lesions that are hypointense on T1-weighted images and are indicative of more severe tissue injury, has been increasingly utilized as a surrogate marker of therapeutic outcome in multiple sclerosis. The ADVANCE study was a 2-year, double-blind, pivotal trial evaluating the safety and efficacy of subcutaneous peginterferon beta-1a 125 mcg in 1512 patients with relapsing-remitting multiple sclerosis (RRMS). This report describes the correlation of clinical outcomes with the evolution of acute lesions into chronic black holes in ADVANCE, and the efficacy of peginterferon beta-1a in reducing this evolution. Treatment with peginterferon beta-1a significantly reduced the mean number of new/enlarging T2-weighted (NET2) lesions (0.76 vs. 1.03 from week 24, p = 0.0037; 0.44 vs. 0.99 from week 48, p < 0.0001) and new gadolinium-enhancing (Gd+) lesions (0.15 vs. 0.32 from week 24, p < 0.0001; 0.09 vs. 0.19 from week 48) that evolved into chronic black holes by 2 years. Patients with NET2 or Gd+ lesions at 24 weeks that evolved into chronic black holes showed significantly worse clinical outcomes, including a greater proportion with 12-week (14.9 vs. 8.4%; p = 0.0167) and 24-week (12.3 vs. 7.0%; p = 0.0333) confirmed disability worsening and higher mean annualized relapse rate (0.62 vs. 0.43; p = 0.0118), compared with patients with lesions that did not evolve into black holes. The correlation was independent of treatment. Reduced risk of evolution of new lesions into chronic black holes with peginterferon beta-1a treatment suggests potential to reduce long-term disability in RRMS by preventing irreversible tissue damage.

  12. Interferons and interferon regulatory factors in malaria.

    PubMed

    Gun, Sin Yee; Claser, Carla; Tan, Kevin Shyong Wei; Rénia, Laurent

    2014-01-01

    Malaria is one of the most serious infectious diseases in humans and responsible for approximately 500 million clinical cases and 500 thousand deaths annually. Acquired adaptive immune responses control parasite replication and infection-induced pathologies. Most infections are clinically silent which reflects on the ability of adaptive immune mechanisms to prevent the disease. However, a minority of these can become severe and life-threatening, manifesting a range of overlapping syndromes of complex origins which could be induced by uncontrolled immune responses. Major players of the innate and adaptive responses are interferons. Here, we review their roles and the signaling pathways involved in their production and protection against infection and induced immunopathologies.

  13. Interferon Beta-1b Injection

    MedlinePlus

    Interferon beta-1b injection is used to reduce episodes of symptoms in patients with relapsing-remitting (course ... and problems with vision, speech, and bladder control). Interferon beta-1b is in a class of medications ...

  14. Interferon Gamma-1b Injection

    MedlinePlus

    Interferon gamma-1b injection is used to reduce the frequency and severity of serious infections in people ... with severe, malignant osteopetrosis (an inherited bone disease). Interferon gamma-1b is in a class of medications ...

  15. Contradictory results in interferon research

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, G.

    1984-01-01

    Several reports on immunologically related interferon research, both in the areas of basic science and clinical research, are briefly reviewed, and it is noted that in many cases the results obtained are contradictory. It is argued, however, that the contradictory results are not surprising since interferon is a biological response modifier and has been known to produce opposite results even when the same interferon prepartion is used. It is emphasized that dosage, timing, route, and other experimental conditions are essential factors in planning immunological studies with interferon. Careful planning of future experiments with interferon should be required to prevent the possible generation of effects that are opposite to those expected.

  16. Peginterferon Beta-1a Injection

    MedlinePlus

    ... a solution (liquid) in a dosing pen or prefilled syringe to inject subcutaneously (under the skin). It is ... how to inject the medication.Use a new prefilled syringe or dosing pen each time you inject your ...

  17. Interferons and Interferon Regulatory Factors in Malaria

    PubMed Central

    Claser, Carla; Tan, Kevin Shyong Wei; Rénia, Laurent

    2014-01-01

    Malaria is one of the most serious infectious diseases in humans and responsible for approximately 500 million clinical cases and 500 thousand deaths annually. Acquired adaptive immune responses control parasite replication and infection-induced pathologies. Most infections are clinically silent which reflects on the ability of adaptive immune mechanisms to prevent the disease. However, a minority of these can become severe and life-threatening, manifesting a range of overlapping syndromes of complex origins which could be induced by uncontrolled immune responses. Major players of the innate and adaptive responses are interferons. Here, we review their roles and the signaling pathways involved in their production and protection against infection and induced immunopathologies. PMID:25157202

  18. Interferon, a growing cytokine family: 50 years of interferon research.

    PubMed

    Chelbi-Alix, Mounira K; Wietzerbin, Juana

    2007-01-01

    The establishment of an antiviral state in cells is the defining activity of interferons (IFNs) as well as the property that permitted their discovery in 1957 by Isaacs and Lindenmann. In addition, interferons have other cellular functions that have potential clinical applications. Today, interferons are used for the treatment of a variety of malignancies and viral diseases. The publication of this special issue of Biochimie gives us a great opportunity to review the state of the art in knowledge about interferons and to explore possible future directions. This commentary text will introduce the reviews written by colleagues who are experts in different aspects of interferon research, to mark the 50th anniversary of the discovery of interferon.

  19. Absence of regulation of the T-type calcium current by Cav1.1, beta1a and gamma1 dihydropyridine receptor subunits in skeletal muscle cells.

    PubMed

    Strube, Caroline

    2008-02-01

    The subunit structure of low voltage activated T-type Ca2+ channels is still unknown. Co-expression of dihydropyridine receptor (DHPR) auxiliary subunits with T-type alpha1 subunits in heterologous systems has produced conflicting results. In developing foetal skeletal muscle fibres which abundantly express DHPR subunits, Cav3.2 (alpha1H) subunits are believed to underlie T-type calcium currents which disappear 2 to 3 weeks after birth. Therefore, a possible regulation of foetal skeletal muscle T-type Ca2+ channels by DHPR subunits was investigated in freshly isolated foetal skeletal muscle using knockout mice, which provide a powerful tool to address this question. The possible involvement of alpha1S (Cav1.1), beta1 and gamma1 DHPR subunits was tested using dysgenic (alpha1S-null), beta1a and gamma1 knockout mice. The results show that the absence of alpha1S, beta1 or gamma1 DHPR subunits does not significantly affect the electrophysiological properties of T-type Ca2+ currents in skeletal muscle, suggesting that (1) native Cav3.2 is not regulated by beta1 or gamma1 DHPR subunits; (2) T-type and L-type currents have distinct and not interchangeable roles.

  20. Evolution of Interferons and Interferon Receptors

    PubMed Central

    Secombes, Chris J.; Zou, Jun

    2017-01-01

    The earliest jawed vertebrates (Gnathostomes) would likely have had interferon (IFN) genes, since they are present in extant cartilaginous fish (sharks and rays) and bony fish (lobe-finned and ray-finned fish, the latter consisting of the chondrostei, holostei, and teleostei), as well as in tetrapods. They are thought to have evolved from a class II helical cytokine ancestor, along with the interleukin (IL)-10 cytokine family. The two rounds of whole genome duplication (WGD) that occurred between invertebrates and vertebrates (1) may have given rise to additional loci, initially containing an IL-10 ancestor and IFN ancestor, which have duplicated further to give rise to the two loci containing the IL-10 family genes, and potentially the IFN type I and IFN type III loci (2). The timing of the divergence of the IFN type II gene from the IL-10 family genes is not clear but was also an early event in vertebrate evolution. Further WGD events at the base of the teleost fish, and in particular teleost lineages (cyprinids, salmonids), have duplicated the loci further, giving rise to additional IFN genes, with tandem gene duplication within a locus a common occurrence. Finally, retrotransposition events have occurred in different vertebrate lineages giving rise to further IFN loci, with large expansions of genes at these loci in some cases. This review will initially explore the likely IFN system present in the earliest Gnathostomes by comparison of the known cartilaginous fish genes with those present in mammals and will then explore the changes that have occurred in gene number/diversification, gene organization, and the encoded proteins during vertebrate evolution. PMID:28303139

  1. Evolution of Interferons and Interferon Receptors.

    PubMed

    Secombes, Chris J; Zou, Jun

    2017-01-01

    The earliest jawed vertebrates (Gnathostomes) would likely have had interferon (IFN) genes, since they are present in extant cartilaginous fish (sharks and rays) and bony fish (lobe-finned and ray-finned fish, the latter consisting of the chondrostei, holostei, and teleostei), as well as in tetrapods. They are thought to have evolved from a class II helical cytokine ancestor, along with the interleukin (IL)-10 cytokine family. The two rounds of whole genome duplication (WGD) that occurred between invertebrates and vertebrates (1) may have given rise to additional loci, initially containing an IL-10 ancestor and IFN ancestor, which have duplicated further to give rise to the two loci containing the IL-10 family genes, and potentially the IFN type I and IFN type III loci (2). The timing of the divergence of the IFN type II gene from the IL-10 family genes is not clear but was also an early event in vertebrate evolution. Further WGD events at the base of the teleost fish, and in particular teleost lineages (cyprinids, salmonids), have duplicated the loci further, giving rise to additional IFN genes, with tandem gene duplication within a locus a common occurrence. Finally, retrotransposition events have occurred in different vertebrate lineages giving rise to further IFN loci, with large expansions of genes at these loci in some cases. This review will initially explore the likely IFN system present in the earliest Gnathostomes by comparison of the known cartilaginous fish genes with those present in mammals and will then explore the changes that have occurred in gene number/diversification, gene organization, and the encoded proteins during vertebrate evolution.

  2. Interferon induced thyroiditis.

    PubMed

    Tomer, Yaron; Menconi, Francesca

    2009-12-01

    Interferon-alpha (IFNalpha) is used for the treatment of various disorders, most notable chronic hepatitis C virus (HCV) infection. One of the commonest side effects of IFNalpha therapy is thyroiditis, with up to 40% of HCV patients on IFNalpha developing clinical or subclinical disease. In some cases interferon induced thyroiditis (IIT) may result in severe symptomatology necessitating discontinuation of therapy. IIT can manifest as clinical autoimmune thyroiditis, presenting with symptoms of classical Hashimoto's thyroiditis or Graves' disease, or as non-autoimmune thyroiditis. Non-autoimmune thyroiditis can manifest as destructive thyroiditis, with early thyrotoxicosis and later hypothyroidism, or as non-autoimmune hypothyroidism. While the epidemiology and clinical presentation of IIT have been well characterized the mechanisms causing IIT are still poorly understood. It is likely that the hepatitis C virus (HCV) itself plays a role in the disease, as the association between HCV infection and thyroiditis is well established. It is believed that IFNalpha induces thyroiditis by both immune stimulatory effects and by direct effects on the thyroid. Early detection and therapy of this condition are important in order to avoid complications of thyroid disease such as cardiac arrhythmias.

  3. Interferon Induced Focal Segmental Glomerulosclerosis

    PubMed Central

    Bayram Kayar, Nuket; Alpay, Nadir; Hamdard, Jamshid; Emegil, Sebnem; Bag Soydas, Rabia; Baysal, Birol

    2016-01-01

    Behçet's disease is an inflammatory disease of unknown etiology which involves recurring oral and genital aphthous ulcers and ocular lesions as well as articular, vascular, and nervous system involvement. Focal segmental glomerulosclerosis (FSGS) is usually seen in viral infections, immune deficiency syndrome, sickle cell anemia, and hyperfiltration and secondary to interferon therapy. Here, we present a case of FSGS identified with kidney biopsy in a patient who had been diagnosed with Behçet's disease and received interferon-alpha treatment for uveitis and presented with acute renal failure and nephrotic syndrome associated with interferon. PMID:27847659

  4. Chicken interferons, their receptors and interferon-stimulated genes.

    PubMed

    Goossens, Kate E; Ward, Alister C; Lowenthal, John W; Bean, Andrew G D

    2013-11-01

    The prevalence of pathogenic viruses is a serious issue as they pose a constant threat to both the poultry industry and to human health. To prevent these viral infections an understanding of the host-virus response is critical, especially for the development of novel therapeutics. One approach in the control of viral infections would be to boost the immune response through administration of cytokines, such as interferons. However, the innate immune response in chickens is poorly characterised, particularly concerning the interferon pathway. This review will provide an overview of our current understanding of the interferon system of chickens, including their cognate receptors and known interferon-stimulated gene products. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Impact of a switch to fingolimod versus staying on glatiramer acetate or beta interferons on patient- and physician-reported outcomes in relapsing multiple sclerosis: post hoc analyses of the EPOC trial.

    PubMed

    Calkwood, Jonathan; Cree, Bruce; Crayton, Heidi; Kantor, Daniel; Steingo, Brian; Barbato, Luigi; Hashmonay, Ron; Agashivala, Neetu; McCague, Kevin; Tenenbaum, Nadia; Edwards, Keith

    2014-11-26

    The Evaluate Patient OutComes (EPOC) study assessed physician- and patient-reported outcomes in individuals with relapsing multiple sclerosis who switched directly from injectable disease-modifying therapy (iDMT; glatiramer acetate, intramuscular or subcutaneous interferon beta-1a, or interferon beta-1b) to once-daily, oral fingolimod. Post hoc analyses evaluated the impact of a switch to fingolimod versus staying on each of the four individual iDMTs. Overall, 1053 patients were randomized 3:1 to switch to fingolimod or remain on iDMT. The primary endpoint was the change in Treatment Satisfaction Questionnaire for Medication (TSQM) Global Satisfaction score. Secondary endpoints included changes in scores for TSQM Effectiveness, Side Effects and Convenience subscales, Beck Depression Inventory-II (BDI-II), Fatigue Severity Scale (FSS), Patient-Reported Outcome Indices for Multiple Sclerosis (PRIMUS) Activities, 36-item Short-Form Health Survey (SF-36) Mental Component Summary (MCS) and Physical Component Summary (PCS) and mean investigator-reported Clinical Global Impressions of Improvement (CGI-I). All outcomes were evaluated after 6 months of treatment. Changes in TSQM Global Satisfaction scores were superior after a switch to fingolimod when compared with scores in patients remaining on any of the iDMTs (all p <0.001). Likewise, all TSQM subscale scores improved following a switch to fingolimod (all p <0.001), except when compared with glatiramer acetate for the TSQM Side Effects subscale (p = 0.111). FSS scores were found to be superior for fingolimod versus remaining on subcutaneous interferon beta-1a and interferon beta-1b, BDI-II scores were significantly improved for fingolimod except for the comparison with intramuscular interferon beta-1a, and SF-36 scores were superior with fingolimod compared with remaining on interferon beta-1b (MCS and PCS; p = 0.030 and p = 0.022, respectively) and subcutaneous interferon beta-1a (PCS only; p = 0

  6. Interferons and hepatitis C virus.

    PubMed

    Heim, Markus H

    2012-05-09

    Interferons are not only the first line of defence against viral infections such as hepatitis C virus infections, but they also have important roles during the chronic phase of viral infections. For over 20 years now, recombinant interferon alpha has been used for the treatment of chronic hepatitis C. The molecular mechanisms responsible for non-response to interferon are still not completely understood, but systematic analysis of liver biopsies revealed that the spontaneous activation of the endogenous interferon system in the liver of patients with chronic hepatitis C prevented response to interferon-based therapies. Moreover, recent genomewide association studies found a highly significant and strong association between genetic variants near the IFNλ3 gene, designated the IL28B genotype, with spontaneous clearance of hepatitis C virus as well as with response to treatment of chronic hepatitis C with pegylated interferon alpha and ribavirin. The molecular pathways that link the IL28B genotype with antiviral effector systems of the innate and adaptive immune system are not known. However, substantial progress has been made in basic understanding of the induction of interferons through toll-like receptor and RIG-I/MDA5 pathways, and of interferon-induced signalling pathways and antiviral effector systems. Over the last two decades, hepatitis C virus has been an important tool for study of the fundamental aspects of host-virus interactions in a chronic viral infection. Further insights into the viral escape strategies that allow hepatitis C virus to persist for decades despite an ongoing innate and adaptive immune response will eventually allow the rational development of preventive vaccines.

  7. [Interferons: between structure and function].

    PubMed

    Bandurska, Katarzyna; Król, Izabela; Myga-Nowak, Magdalena

    2014-05-06

    Interferons are a family of proteins that are released by a variety of cells in response to infections caused by viruses. Currently, we distinguish three types of interferons. They are classified based on the nucleotide sequence, interaction with specific receptors, chromosomal location, structure and physicochemical properties. The following interferons are classified as type I: α, β, ω, κ, ε, ζ, τ, δ, ν. They are recognized and bound by a receptor formed by two peptides, IFN-αR1 and IFN-αR2. Representative of type II interferons is interferon-γ. It binds to a receptor composed of chains IFNGR-1 and IFNGR-2. The recently classified type III interferons comprise IFN-λ1, IFN-λ2, and IFN-λ3. They act on receptors formed by λR1 IFN-and IL-10R2 subunits. A high level of antiviral protection is achieved by IFN-α, IFN-β and IFN-λ. Antiviral activity of interferons is based on the induction and regulation of innate and acquired immune mechanisms. By binding to transmembrane receptors, IFN interacts with target cells mainly by activating the JAK/STAT, but also other signaling pathways. This leads to induction and activation of many antiviral agents, such as protein kinase RNA-activated (PKR), ribonuclease 2-5A pathway, and Mx proteins, as well as numerous apoptotic pathways. As a result of the protective effect of interferons, the virus binding to cells and viral particles penetration into cells is stopped, and the release of the nucleocapsid from an envelope is suppressed. Disruption of transcription and translation processes of the structural proteins prevents the formation of virions or budding of viruses, and as a result degradation of the viral mRNA; the started processes inhibit the chain synthesis of viral proteins and therefore further stimulate the immune system cells.

  8. NK cells and interferons.

    PubMed

    Paolini, Rossella; Bernardini, Giovanni; Molfetta, Rosa; Santoni, Angela

    2015-04-01

    The role of Natural Killer cells in host defense against infections as well as in tumour surveillance has been widely appreciated for a number of years. Upon recognition of "altered" cells, NK cells release the content of cytolytic granules, leading to the death of target cells. Moreover, NK cells are powerful producers of chemokines and cytokines, particularly Interferon-γ (IFN-γ), of which they are the earliest source upon a variety of infections. Despite being armed to fight against pathogens, NK cells become fully functional upon an initial phase of activation that requires the action of several cytokines, including type I IFNs. Type I IFNs are now recognized as key players in antiviral defense and immune regulation, and evidences from both mouse models of disease and in vitro studies support the existence of an alliance between type I IFNs and NK cells to ensure effective protection against viral infections. This review will focus on the role of type I IFNs in regulating NK cell functions to elicit antiviral response and on NK cell-produced IFN-γ beneficial and pathological effects. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Long-Term Adherence to IFN Beta-1a Treatment when Using RebiSmart® Device in Patients with Relapsing-Remitting Multiple Sclerosis

    PubMed Central

    Fernández, O.; Arroyo, R.; Martínez-Yélamos, S.; Marco, M.; Merino, J. A. García; Muñoz, D.; Merino, E.; Roque, A.

    2016-01-01

    The effectiveness of disease-modifying drugs in the treatment of multiple sclerosis is associated with adherence. RebiSmart® electronic device provides useful information about adherence to the treatment with subcutaneous (sc) interferon (IFN) β-1a (Rebif®). The aim of the study was to determine long-term adherence to this treatment in patients with relapsing-remitting multiple sclerosis (RRMS). This retrospective multicentre observational study analysed 258 patients with RRMS who were receiving sc IFN β-1a (Rebif®) treatment by using RebiSmart® until replacement (36 months maximum lifetime) or treatment discontinuation. Adherence was calculated with data (injection dosage, time, and date) automatically recorded by RebiSmart®. Patients in the study had a mean age of 41 years with a female proportion of 68%. Mean EDSS score at start of treatment was 1.8 (95% CI, 1.6–1.9). Overall adherence was 92.6% (95% CI, 90.6–94.5%). A total of 30.2% of patients achieved an adherence rate of 100%, 80.6% at least 90%, and only 13.2% of patients showed a suboptimal adherence (<80%). A total of 59.9% of subjects were relapse-free after treatment initiation. Among 106 subjects (41.1%) who experienced, on average, 1.4 relapses, the majority were mild (40.6%) or moderate (47.2%). Having experienced relapses from the beginning of the treatment was the only variable significantly related to achieving an adherence of at least 80% (OR = 3.06, 1.28–7.31). Results of this study indicate that sc IFN β-1a administration facilitated by RebiSmart® could lead to high rates of adherence to a prescribed dose regimen over 36 months. PMID:27526201

  10. Cost-effectiveness of different interferon beta products for relapsing-remitting and secondary progressive multiple sclerosis: Decision analysis based on long-term clinical data and switchable treatments

    PubMed Central

    2013-01-01

    Background Multiple sclerosis (MS) is a highly debilitating immune mediated disorder and the second most common cause of neurological disability in young and middle-aged adults. Iran is amongst high MS prevalence countries (50/100,000). Economic burden of MS is a topic of important deliberation in economic evaluations study. Therefore determining of cost-effectiveness interferon beta (INF β) and their copied biopharmaceuticals (CBPs) and biosimilars products is significant issue for assessment of affordability in Lower-middle-income countries (LMICs). Methods A literature-based Markov model was developed to assess the cost-effectiveness of three INF βs products compared with placebo for managing a hypothetical cohort of patients diagnosed with relapsing remitting MS (RRMS) in Iran from a societal perspective. Health states were based on the Kurtzke Expanded Disability Status Scale (EDSS). Disease progression transition probabilities for symptom management and INF β therapies were obtained from natural history studies and multicenter randomized controlled trials and their long term follow up for RRMS and secondary progressive MS (SPMS). A cross sectional study has been developed to evaluate cost and utility. Transitions among health states occurred in 2-years cycles for fifteen cycles and switching to other therapies was allowed. Calculations of costs and utilities were established by attachment of decision trees to the overall model. The incremental cost effectiveness ratio (ICER) of cost/quality adjusted life year (QALY) for all available INF β products (brands, biosimilars and CBPs) were considered. Both costs and utilities were discounted. Sensitivity analyses were done to assess robustness of model. Results ICER for Avonex, Rebif and Betaferon was 18712, 11832, 15768 US Dollars ($) respectively when utility attained from literature review has been considered. ICER for available CBPs and biosimilars in Iran was $847, $6964 and $11913. Conclusions The Markov

  11. Dermatomyositis and Type 1 Interferons

    PubMed Central

    2010-01-01

    Dermatomyositis is a poorly understood multisystem disease predominantly affecting skin and muscle. This review focuses on the potential role of a group of related cytokines, the type 1 interferons, in the pathogenesis of dermatomyositis. Type 1 interferon–inducible transcripts and proteins are uniquely elevated in dermatomyositis muscle compared with all other muscle diseases studied to date. The endothelial cell tubuloreticular inclusions present in affected dermatomyositis muscle are biomarkers of type 1 interferon exposure. The cell-poor lichenoid reaction in skin with predominant involvement of the basal epidermal cell layer and its topologic equivalent in muscle, perifascicular atrophy, may be lesions that develop directly in response to type 1 interferon signaling. PMID:20425524

  12. Interferons and uterine receptivity.

    PubMed

    Bazer, Fuller W; Spencer, Thomas E; Johnson, Gregory A

    2009-01-01

    This article focuses on the potential roles of interferons (IFNs) in establishing uterine receptivity to implantation. A common feature of the peri-implantation period of pregnancy in most mammals is production of type I and/or type II IFNs by trophoblasts that induce and/or stimulate expression of an array of IFN-stimulate genes (ISGs). These effects range from pregnancy recognition signaling in ruminants through IFN tau to effects on cellular functions of the uterus and uterine vasculature. For actions of IFNs, progesterone (P4) is permissive to the expression of many effects and to the expression of ISGs that are induced directly by an IFN or induced by P4 and stimulated by an IFN in a temporal and/or cell-specific manner. Uterine receptivity to implantation is P4 dependent; however, implantation events are preceded by loss of expression of progesterone (PGR) and estrogen (ESR1) receptors by uterine epithelia. Therefore, P4 likely acts via PGR-positive stromal cells to induce expression of fibroblast growth factors-7 and -10 and/or hepatocyte growth factor (progestamedins) that then act via their respective receptors on uterine epithelia and trophectoderm to affect expression of ISGs. The permissive effects of P4 on the expression of ISGs and the effects of P4 to induce and IFNs to stimulate gene expression raise the question of whether uterine receptivity to implantation requires P4 and IFN to activate unique, but complementary, cell signaling pathways. Uterine receptivity to implantation, depending on species, involves changes in the expression of genes for the attachment of trophectoderm to the uterine lumenal epithelium (LE) and superficial glandular epithelium (sGE), modification of the phenotype of uterine stromal cells, the silencing of PGR and ESR1 genes, the suppression of genes for immune recognition, alterations in membrane permeability to enhance conceptus-maternal exchange of factors, increased vascularity of the endometrium, activation of genes for

  13. Antiviral Actions of Interferons

    PubMed Central

    Samuel, Charles E.

    2001-01-01

    Tremendous progress has been made in understanding the molecular basis of the antiviral actions of interferons (IFNs), as well as strategies evolved by viruses to antagonize the actions of IFNs. Furthermore, advances made while elucidating the IFN system have contributed significantly to our understanding in multiple areas of virology and molecular cell biology, ranging from pathways of signal transduction to the biochemical mechanisms of transcriptional and translational control to the molecular basis of viral pathogenesis. IFNs are approved therapeutics and have moved from the basic research laboratory to the clinic. Among the IFN-induced proteins important in the antiviral actions of IFNs are the RNA-dependent protein kinase (PKR), the 2′,5′-oligoadenylate synthetase (OAS) and RNase L, and the Mx protein GTPases. Double-stranded RNA plays a central role in modulating protein phosphorylation and RNA degradation catalyzed by the IFN-inducible PKR kinase and the 2′-5′-oligoadenylate-dependent RNase L, respectively, and also in RNA editing by the IFN-inducible RNA-specific adenosine deaminase (ADAR1). IFN also induces a form of inducible nitric oxide synthase (iNOS2) and the major histocompatibility complex class I and II proteins, all of which play important roles in immune response to infections. Several additional genes whose expression profiles are altered in response to IFN treatment and virus infection have been identified by microarray analyses. The availability of cDNA and genomic clones for many of the components of the IFN system, including IFN-α, IFN-β, and IFN-γ, their receptors, Jak and Stat and IRF signal transduction components, and proteins such as PKR, 2′,5′-OAS, Mx, and ADAR, whose expression is regulated by IFNs, has permitted the generation of mutant proteins, cells that overexpress different forms of the proteins, and animals in which their expression has been disrupted by targeted gene disruption. The use of these IFN system

  14. Ticks Take Cues from Mammalian Interferon.

    PubMed

    de Silva, Aravinda M

    2016-07-13

    Interferons are considered a first line of immune defense restricted to vertebrates. In this issue of Cell Host & Microbe, Smith et al. (2016) demonstrate that mammalian interferon γ activates an antimicrobial response within ticks feeding on blood. The study suggests that arthropods have a parallel interferon-like defense system.

  15. Patient adherence to subcutaneous IFN beta-1a injections using the RebiSmart® injection device: a retrospective real-world study among Dutch and German patients with multiple sclerosis

    PubMed Central

    Krol, Marieke; de Voer, Gert; Osowski, Ulrike

    2017-01-01

    Purpose Long-term treatment adherence among patients with multiple sclerosis (MS) is a general concern, with an established correlation with clinical efficacy. Closely monitoring patients’ treatment behavior may have a beneficial effect on adherence. This study assessed adherence, in daily life, to subcutaneous (sc) IFN beta-1a, self-administered using the RebiSmart® electronic injection device (the IFN beta-Ia autoinjector device), in patients with MS. Patients and methods This was a retrospective observational study analyzing treatment adherence based on injection data, eg, injection date and dose, extracted from the IFN beta-Ia autoinjector devices collected from patients in Germany and the Netherlands. Results Data recorded in the period from 2007 to 2012 by the IFN beta-Ia autoinjector devices from 1,682 (79.7% from Germany, 20.3% from the Netherlands) patients were analyzed. A mean of 94.8% of the multi-dose cartridges (containing sc IFN beta-1a for three injections) were used completely, indicating a low incidence of application errors and drug wastage. The mean adherence rate was 90.7% and 82.9% over the entire observation period (mean treatment duration: 150.1 weeks). Median adherence rates were similar between German and Dutch patients (97.9% vs 99.0%). Conclusion In daily clinical practice, patients using the IFN beta-Ia autoinjector device were highly adherent to sc IFN beta-1a. The injection data stored electronically in the device may help patients to adhere to treatment regimens and, if viewed by physicians, promote discussion of adherence issues with patients. PMID:28744108

  16. Patient adherence to subcutaneous IFN beta-1a injections using the RebiSmart(®) injection device: a retrospective real-world study among Dutch and German patients with multiple sclerosis.

    PubMed

    Krol, Marieke; de Voer, Gert; Osowski, Ulrike

    2017-01-01

    Long-term treatment adherence among patients with multiple sclerosis (MS) is a general concern, with an established correlation with clinical efficacy. Closely monitoring patients' treatment behavior may have a beneficial effect on adherence. This study assessed adherence, in daily life, to subcutaneous (sc) IFN beta-1a, self-administered using the RebiSmart(®) electronic injection device (the IFN beta-Ia autoinjector device), in patients with MS. This was a retrospective observational study analyzing treatment adherence based on injection data, eg, injection date and dose, extracted from the IFN beta-Ia autoinjector devices collected from patients in Germany and the Netherlands. Data recorded in the period from 2007 to 2012 by the IFN beta-Ia autoinjector devices from 1,682 (79.7% from Germany, 20.3% from the Netherlands) patients were analyzed. A mean of 94.8% of the multi-dose cartridges (containing sc IFN beta-1a for three injections) were used completely, indicating a low incidence of application errors and drug wastage. The mean adherence rate was 90.7% and 82.9% over the entire observation period (mean treatment duration: 150.1 weeks). Median adherence rates were similar between German and Dutch patients (97.9% vs 99.0%). In daily clinical practice, patients using the IFN beta-Ia autoinjector device were highly adherent to sc IFN beta-1a. The injection data stored electronically in the device may help patients to adhere to treatment regimens and, if viewed by physicians, promote discussion of adherence issues with patients.

  17. Pegylated interferon β-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study.

    PubMed

    Calabresi, Peter A; Kieseier, Bernd C; Arnold, Douglas L; Balcer, Laura J; Boyko, Alexey; Pelletier, Jean; Liu, Shifang; Zhu, Ying; Seddighzadeh, Ali; Hung, Serena; Deykin, Aaron

    2014-07-01

    Subcutaneous pegylated interferon (peginterferon) beta-1a is being developed for treatment of relapsing multiple sclerosis, with less frequent dosing than currently available first-line injectable treatments. We assessed the safety and efficacy of peginterferon beta-1a after 48 weeks of treatment in the placebo-controlled phase of the ADVANCE trial, a study of patients with relapsing-remitting multiple sclerosis. We did this 2-year, double-blind, parallel group, phase 3 study, with a placebo-controlled design for the first 48 weeks, at 183 sites in 26 countries. Patients with relapsing-remitting multiple sclerosis (age 18-65 years, with Expanded Disability Status Scale score ≤5) were randomly assigned (1:1:1) via an interactive voice response or web system, and stratified by site, to placebo or subcutaneous peginterferon beta-1a 125 μg once every 2 weeks or every 4 weeks. The primary endpoint was annualised relapse rate at 48 weeks. This trial is registered with ClinicalTrials.gov, number NCT00906399. We screened 1936 patients and enrolled 1516, of whom 1512 were randomly assigned (500 to placebo, 512 to peginterferon every 2 weeks, 500 to peginterferon every 4 weeks); 1332 (88%) patients completed 48 weeks of treatment. Adjusted annualised relapse rates were 0·397 (95% CI 0·328-0·481) in the placebo group versus 0·256 (0·206-0·318) in the every 2 weeks group and 0·288 (0·234-0·355) in the every 4 weeks group (rate ratio for every 2 weeks group 0·644, 95% CI 0·500-0·831, p=0·0007; rate ratio for the every 4 weeks group 0·725, 95% CI 0·565-0·930, p=0·0114). 417 (83%) patients taking placebo, 481 (94%) patients taking peginterferon every 2 weeks, and 472 (94%) patients taking peginterferon every 4 weeks reported adverse events including relapses. The most common adverse events associated with peginterferon beta-1a were injection site reactions, influenza-like symptoms, pyrexia, and headache. 76 (15%) patients taking placebo, 55 (11%) patients

  18. Interferon-induced Raynaud's syndrome.

    PubMed

    Schapira, Daniel; Nahir, Abraham Menahem; Hadad, Nuhad

    2002-12-01

    To review the clinical features, diagnosis, treatment, and outcome of interferon-induced Raynaud's phenomenon. The medical literature was reviewed from 1967 to November 2001 with the assistance of a MEDLINE search using the key words: Raynaud, Interferon, ischemia, thrombosis and necrosis. A qualitative review was performed after the articles were abstracted and the relevant information was summarized. Twenty-four cases of interferon-induced Raynaud's phenomenon (including our patient) are described. Interpheron-alpha was the most common causative agent (14 cases). The symptoms appeared weeks to years after beginning treatment and varied from mild vasospasm to occlusion of digital arteries and tissue necrosis (14 cases), sometimes necessitating finger amputation (6 patients). Digital plethysmography, arteriography and capillaroscopy were valuable diagnostic tools. In 4 cases, cardiac, ophthalmic, or central nervous system drug-induced ischemia accompanied the peripheral Raynaud's phenomenon. Of the 15 cases with a documented outcome, withdrawal of the drug alone resulted in complete (6 patients) or partial (1 patient) recovery. In the others, supportive therapy was needed. The recovery period lasted from 2 weeks to 3 months. In 2 patients, continuation of treatment was possible. Raynaud's phenomenon and related complications must be recognized as possible side effects of interferon therapy. Early diagnosis and withdrawal of the drug may prevent unnecessary morbidity and disability. Copyright 2002, Elsevier Science (USA). All rights reserved.

  19. Effects of interferon on antibody formation

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, G.

    1984-01-01

    Studies of the effects of interferon on primary and secondary antibody responses and of the relationship of interferon to other cytokines, or cell products, are presented. Dosage- and timing-dependent immunoenhancing and immunosuppressive activities of interferon are documented for mouse spleen cell cultures and for mice infected with murine hepatitis virus (MHV-3). A possibility that altered interferon production might lead to immunopathological disorders, such as lupus erythematosus, AIDS, arthritis, etc., is discussed. Latest technological developments are presented that indicate that interferon does apparently play a major role in the regulation of antibody responses.

  20. Effects of interferon on antibody formation

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, G.

    1984-01-01

    Studies of the effects of interferon on primary and secondary antibody responses and of the relationship of interferon to other cytokines, or cell products, are presented. Dosage- and timing-dependent immunoenhancing and immunosuppressive activities of interferon are documented for mouse spleen cell cultures and for mice infected with murine hepatitis virus (MHV-3). A possibility that altered interferon production might lead to immunopathological disorders, such as lupus erythematosus, AIDS, arthritis, etc., is discussed. Latest technological developments are presented that indicate that interferon does apparently play a major role in the regulation of antibody responses.

  1. Trisomy 21 consistently activates the interferon response.

    PubMed

    Sullivan, Kelly D; Lewis, Hannah C; Hill, Amanda A; Pandey, Ahwan; Jackson, Leisa P; Cabral, Joseph M; Smith, Keith P; Liggett, L Alexander; Gomez, Eliana B; Galbraith, Matthew D; DeGregori, James; Espinosa, Joaquín M

    2016-07-29

    Although it is clear that trisomy 21 causes Down syndrome, the molecular events acting downstream of the trisomy remain ill defined. Using complementary genomics analyses, we identified the interferon pathway as the major signaling cascade consistently activated by trisomy 21 in human cells. Transcriptome analysis revealed that trisomy 21 activates the interferon transcriptional response in fibroblast and lymphoblastoid cell lines, as well as circulating monocytes and T cells. Trisomy 21 cells show increased induction of interferon-stimulated genes and decreased expression of ribosomal proteins and translation factors. An shRNA screen determined that the interferon-activated kinases JAK1 and TYK2 suppress proliferation of trisomy 21 fibroblasts, and this defect is rescued by pharmacological JAK inhibition. Therefore, we propose that interferon activation, likely via increased gene dosage of the four interferon receptors encoded on chromosome 21, contributes to many of the clinical impacts of trisomy 21, and that interferon antagonists could have therapeutic benefits.

  2. Results of space experiment program "interferon"

    NASA Astrophysics Data System (ADS)

    Tálas, Margarita; Bátkai, László; Stöger, Ivana; Nagy, Károly; Hiros, László; Konstantinova, Irina; Rykova, Marina; Mozgovaya, Irina; Guseva, Olga; Kozharinov, Valerii

    The results of the biological space experiment "Interferon" performed by two international cosmonaut teams (26 May 1980, and 16 May 1981) aboard space laboratory Solyut-6 are reported: (1) Human lymphocytes separated from blood of healthy donors and placed into "Interferon I" equipment could be kept for 7 days in suspension culture under spaceflight conditons. Interferon production could be induced in human lymphocytes by preparations of different origin: virus, synthetic polyribonucleotides, bacterial protein and plant pigment. An increased lymphocyte interferon production in space laboratory compared to ground control was observed. (2) Human interferon preparations and interferon inducers placed in space laboratory at room temperature for 7 days maintained their biological activity. (3) A decrease of induced interferon production and natural killer activity of lymphocytes isolated from peripheral blood of cosmonauts was observed on the 1st day on Earth after 7-days spaceflight.

  3. No Love Lost Between Viruses and Interferons.

    PubMed

    Fensterl, Volker; Chattopadhyay, Saurabh; Sen, Ganes C

    2015-11-01

    The interferon system protects mammals against virus infections. There are several types of interferons, which are characterized by their ability to inhibit virus replication and resultant pathogenesis by triggering both innate and cell-mediated immune responses. Virus infection is sensed by a variety of cellular pattern-recognition receptors and triggers the synthesis of interferons, which are secreted by the infected cells. In uninfected cells, cell surface receptors recognize the secreted interferons and activate intracellular signaling pathways that induce the expression of interferon-stimulated genes; the proteins encoded by these genes inhibit different stages of virus replication. To avoid extinction, almost all viruses have evolved mechanisms to defend themselves against the interferon system. Consequently, a dynamic equilibrium of survival is established between the virus and its host, an equilibrium that can be shifted to the host's favor by the use of exogenous interferon as a therapeutic antiviral agent.

  4. Quantification of neutralizing antibodies to human type I interferons using division-arrested frozen cells carrying an interferon-regulated reporter-gene.

    PubMed

    Lallemand, C; Meritet, J-F; Erickson, R; Grossberg, S E; Roullet, E; Lyon-Caen, O; Lebon, P; Tovey, M G

    2008-06-01

    Development of neutralizing antibodies (NAbs) to interferons (IFNs) can reduce the clinical response to IFN therapy. As current cell-based assays for quantifying NAbs have limitations, a highly sensitive and reproducible assay was developed, using division-arrested frozen human U937 cells transfected with the luciferase reportergene controlled by an IFN-responsive chimeric promoter, which allows IFN activity to be determined with precision within hours. Assay-ready PIL5 cells can be stored frozen for >3 years without loss of IFN sensitivity or the need for cell propagation. The assay is highly IFN sensitive (detecting <1.0 IU/mL), reproducible (SE +/- 15%) over concentrations from <1.0 to 100 IU/mL and able to measure different IFN subtypes and their pegylated variants. The use of this assay has shown that NAbs from patients treated with IFN-alpha2 exhibited markedly lower titers against 10 LU/mL of low specific activity IFNs, namely, IFN-alpha1, PEG-Intron(TM) (Schering-Plough, Levallois-Perret,France), or Pegasys(TM) (Hoffmann-La Roche, Neuilly-sur-Seine, France, than against 10 LU/mL IFN-alpha2. Similarly, NAbs from patients treated with IFN-beta1a exhibit lower titers against 10 LU/mL of low specific activity IFN-beta1b than against IFN-beta1a. The combination of the use of division-arrested, IFN-responsive human cells transfected with the luciferase reporter-gene makes the rapid PIL5 assay for NAbs highly advantageous.

  5. SnapShot: Interferon Signaling.

    PubMed

    Chow, Kwan T; Gale, Michael

    2015-12-17

    Interferons (IFNs) are crucial cytokines of antimicrobial, antitumor, and immunomodulatory activity. The three types of IFN (I, II, and III) are classified by their receptor specificity and sequence homology. IFNs are produced and secreted by cells in response to specific stimuli. Here, we review the subsequent IFN signaling events occurring through unique receptors leading to regulation of gene expression for modulation of innate and adaptive immunity. To view this SnapShot, open or download the PDF.

  6. Clinical application of interferons and their inducers: Second edition

    SciTech Connect

    Stringfellow, D.A.

    1986-01-01

    This book discusses the clinical uses of interferons, specifically discussed are: uses of interferons in viral diseases; double stranded RNA and its analogs for clinical applications; interferons uses in cancer patients in Europe; Recombinant DNA technology; Gamma interferon and its role as a lymphokine and clinical trials of interferon in Japan and U.S.A.

  7. [Interferon in the treatment of viral hepatitis. The interferon was discovered 50 years ago].

    PubMed

    Fehér, János; Lengyel, Gabriella

    2007-08-19

    The interferons are heterogenic glycoproteins which are produced on the effect of virus infection, as immune answer, by the living cells. They were discovered half a century ago. They have antineoplastic, antiviral and immunomodulator effect. The names of interferons used in the therapy are nominated with Greek letters. This nomination shows their origins: the interferon-alpha originates from leucocytes, the interferon-beta does from fibroblasts and the interferon-gamma is produced as immune interferon by lymphocytes. In human medicine both natural and recombinant interferons are applied. The connection of polyethyleneglycol to interferons ensures their sustained effect. Nowadays they are applied in the therapy of chronic hepatitis B or C as well as in oncology to inhibit the neoplasm progression.

  8. Recombinant human gamma interferon inhibits simian malaria.

    PubMed Central

    Maheshwari, R K; Czarniecki, C W; Dutta, G P; Puri, S K; Dhawan, B N; Friedman, R M

    1986-01-01

    Prophylactic treatment with 0.1 mg of human gamma interferon per kg (body weight) per day completely suppressed experimental infection with Plasmodium cynomolgi B sporozoites in rhesus monkeys. Treatment with lower doses partially suppressed this infection. Prophylactic treatment with human gamma interferon, however, had no protective effect against trophozoite-induced infection, suggesting that the interferon effect was limited to the exoerythrocytic stage of parasitic development. PMID:3091507

  9. Use of Interferon Systems in Immunotoxicology

    DTIC Science & Technology

    1983-08-01

    tumor cells( 3 ’ 4 ). As a result of these activities, the use of interferons in clinical anti- cancer trials is now being actively pursued(7). Since...methylcholanthrene of interferon formation in rat embryo cells infected with Sindbis virus, J. Natl. Cancer Inst.-, 32:1317. 9. DeMaeyer-Guignard, J and E...DeMaever (1965). Effect of car- cinogenic and noncarcinogenic hydrocarbons on interferon synthesis and virus plaque development, J. Natl. Cancer Inst., 34

  10. 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.

  11. Interferon Production by Human Cells In Vitro

    PubMed Central

    Spina, Celsa A.; Chang, R. Shihman; Mishra, L.; Golden, H. Dean

    1972-01-01

    The relative capacity of several types of human cells and tissue to produce interferon was studied. Types of cells and tissue included were fibroblasts from embryos, foreskins, and biopsied skins; amnion cells; peripheral leukocytes; established lymphoid cell lines; established heteroploid cell lines; and chorioamniotic membrane. When Newcastle disease virus was used as the inducer, fibroblasts and amnion cells produced more interferon per 106 cells than leukocytes, lymphoid cells, and heteroploid cells. Only minor variations in interferon-producing capacity were observed among fibroblasts from 36 persons. Culture passage level, cell concentration, and inducer were factors that significantly affected interferon production. PMID:4344957

  12. Interferon prophylaxis of hepatic carcinoma.

    PubMed

    Voiosu, R; Dimitriu, L; Dragomir, P; Eremia, L

    1999-01-01

    The present article reveals the importance of hepatic carcinoma among the other diseases in digestive oncology, and also the importance of a correct designation of these cases. Epidemiology and actual hypothesis on the mechanisms of oncogenesis are discussed. There are reviewed some studies in the literature concerning infection with hepatitis B virus, hepatitis C virus, coinfection (B and C viruses, B and D viruses), the role of interferon prophylaxis in such cases. Also there is present a statistics on chronic viral hepatits, cirrhosis of viral etiology and hepatic carcinoma, diagnosed in patients in "N.Gh.Lupu" Hospital, over two decades.

  13. Interferon Induced Transfer of Viral Resistance

    DTIC Science & Technology

    1980-02-01

    interferon: We decided that rather than first studying induction of tyrosinase in melanoma cells or plasminogen activator in ovarian granulosa cells as...177-184 (HP Publishing, New York). 14. Lockhart, R.Z. (1973). Criteria for acceptance of a viral inhibitor as an interferon and a general

  14. Inactivation of human interferon by body fluids

    NASA Technical Reports Server (NTRS)

    Cesario, T. C.; Mandell, A.; Tilles, J. G.

    1973-01-01

    Description of the effects of human feces, bile, saliva, serum, and cerebrospinal fluid on interferon activity. It is shown that crude interferon is inactivated by at least 50% more than with the control medium used, when incubated for 4 hr in vitro in the presence of serum, saliva, or cerebrospinal liquid, and by close to 100% when incubated with stool extract or bile.

  15. 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.

  16. Type 1 Diabetes and Interferon Therapy

    PubMed Central

    Nakamura, Kan; Kawasaki, Eiji; Imagawa, Akihisa; Awata, Takuya; Ikegami, Hiroshi; Uchigata, Yasuko; Kobayashi, Tetsuro; Shimada, Akira; Nakanishi, Koji; Makino, Hideichi; Maruyama, Taro; Hanafusa, Toshiaki

    2011-01-01

    OBJECTIVE Interferon therapy can trigger induction of several autoimmune diseases, including type 1 diabetes. To assess the clinical, immunologic, and genetic characteristics of type 1 diabetes induced by interferon therapy, we conducted a nationwide cross-sectional survey. RESEARCH DESIGN AND METHODS Clinical characteristics, anti-islet autoantibodies, and HLA-DR typing were examined in 91 patients for whom type 1 diabetes developed during or shortly after interferon therapy. RESULTS Median age at the onset of type 1 diabetes was 56 (interquartile range 48–63) years and mean ± SD BMI was 20.8 ± 2.7 kg/m2. The time period from the initiation of interferon therapy to type 1 diabetes onset in patients receiving pegylated interferon and ribavirin was significantly shorter than that in patients with nonpegylated interferon single therapy (P < 0.05). Anti-islet autoantibodies were detected in 94.5% of patients at diabetes onset. Type 1 diabetes susceptibility HLA-DRs in the Japanese population, DR4 and DR9, were also associated with interferon treatment–related type 1 diabetes. Furthermore, the prevalence of HLA-DR13 was significantly higher in interferon treatment–related type 1 diabetes than in healthy control subjects (odds ratio 3.80 [95% CI 2.20–7.55]; P < 0.0001) and classical type 1 diabetes (2.15 [1.17–3.93]; P < 0.05). CONCLUSIONS Anti-islet autoantibodies should be investigated before and during interferon therapy to identify subjects at high risk of type 1 diabetes. Stronger antiviral treatment may induce earlier development of type 1 diabetes. Furthermore, patients who develop interferon-induced type 1 diabetes are genetically susceptible. PMID:21775762

  17. Interferon-γ Inhibits Ebola Virus Infection

    PubMed Central

    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.

    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. PMID:26562011

  18. Trisomy 21 consistently activates the interferon response

    PubMed Central

    Sullivan, Kelly D; Lewis, Hannah C; Hill, Amanda A; Pandey, Ahwan; Jackson, Leisa P; Cabral, Joseph M; Smith, Keith P; Liggett, L Alexander; Gomez, Eliana B; Galbraith, Matthew D; DeGregori, James; Espinosa, Joaquín M

    2016-01-01

    Although it is clear that trisomy 21 causes Down syndrome, the molecular events acting downstream of the trisomy remain ill defined. Using complementary genomics analyses, we identified the interferon pathway as the major signaling cascade consistently activated by trisomy 21 in human cells. Transcriptome analysis revealed that trisomy 21 activates the interferon transcriptional response in fibroblast and lymphoblastoid cell lines, as well as circulating monocytes and T cells. Trisomy 21 cells show increased induction of interferon-stimulated genes and decreased expression of ribosomal proteins and translation factors. An shRNA screen determined that the interferon-activated kinases JAK1 and TYK2 suppress proliferation of trisomy 21 fibroblasts, and this defect is rescued by pharmacological JAK inhibition. Therefore, we propose that interferon activation, likely via increased gene dosage of the four interferon receptors encoded on chromosome 21, contributes to many of the clinical impacts of trisomy 21, and that interferon antagonists could have therapeutic benefits. DOI: http://dx.doi.org/10.7554/eLife.16220.001 PMID:27472900

  19. Interferon effects on protozoan infections

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, G.; Wirth, J.; Kierszenbaum, F.; Degee, A. L. W.; Mansfield, J. M.

    1985-01-01

    The effects of interferon (IFN) on mice infected with two different parasitic protozoans, Trypanosoma cruzi and Trypanosoma brucei rhodesiense, are investigated experimentally. The preparation of the cell cultures, IFN and assays, antibody, and the experimental procedures are described. It is observed that in cells treated with IFN-gamma there is an increased association of T. cruzi with murine macrophages and an increase in the killing of T. cruzi by IFN-gamma-treated murine macrophages. For spleen cells infected with T.b. rhodesiense in vitro, it is detected that live trypanosomes cannot induce IFN in cells from normal mice, but can in cells from immunized mice; and that trypanosome-lysates induce IFN in vitro in cells from normal mice. The data suggest that there is a two-step mechanism for mice against T. cruzi and T.b. rhodesiense.

  20. Interferons, immunity and cancer immunoediting.

    PubMed

    Dunn, Gavin P; Koebel, Catherine M; Schreiber, Robert D

    2006-11-01

    A clear picture of the dynamic relationship between the host immune system and cancer is emerging as the cells and molecules that participate in naturally occurring antitumour immune responses are being identified. The interferons (IFNs) - that is, the type I IFNs (IFNalpha and IFNbeta) and type II IFN (IFNgamma) - have emerged as central coordinators of tumour-immune-system interactions. Indeed, the decade-old finding that IFNgamma has a pivotal role in promoting antitumour responses became the focus for a renewed interest in the largely abandoned concept of cancer immunosurveillance. More recently, type I IFNs have been found to have distinct functions in this process. In this Review, we discuss the roles of the IFNs, not only in cancer immunosurveillance but also in the broader process of cancer immunoediting.

  1. Interferon effects on protozoan infections

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, G.; Wirth, J.; Kierszenbaum, F.; Degee, A. L. W.; Mansfield, J. M.

    1985-01-01

    The effects of interferon (IFN) on mice infected with two different parasitic protozoans, Trypanosoma cruzi and Trypanosoma brucei rhodesiense, are investigated experimentally. The preparation of the cell cultures, IFN and assays, antibody, and the experimental procedures are described. It is observed that in cells treated with IFN-gamma there is an increased association of T. cruzi with murine macrophages and an increase in the killing of T. cruzi by IFN-gamma-treated murine macrophages. For spleen cells infected with T.b. rhodesiense in vitro, it is detected that live trypanosomes cannot induce IFN in cells from normal mice, but can in cells from immunized mice; and that trypanosome-lysates induce IFN in vitro in cells from normal mice. The data suggest that there is a two-step mechanism for mice against T. cruzi and T.b. rhodesiense.

  2. Interferons in oncology: Current status and future directions

    SciTech Connect

    Smyth, J.F.

    1987-01-01

    This book contains eight papers. Some of the titles are: Reduction of Nuclear Oncogene Expression by Endogenous and Exogenous Interferons; Interferons Combined with Other Anti-Cancer Agents - Studies in Experimental Systems; Natural Alpha Interferon as Part of a Combined Treatment for Small Cell Lung Cancer; and Interferon in the Treatment of Hairy Cell Leukemia and Chromic Myelogenous Leukemia.

  3. INTERFEROME: the database of interferon regulated genes

    PubMed Central

    Samarajiwa, Shamith A.; Forster, Sam; Auchettl, Katie; Hertzog, Paul J.

    2009-01-01

    INTERFEROME is an open access database of types I, II and III Interferon regulated genes (http://www.interferome.org) collected from analysing expression data sets of cells treated with IFNs. This database of interferon regulated genes integrates information from high-throughput experiments with annotation, ontology, orthologue sequences from 37 species, tissue expression patterns and gene regulatory information to enable a detailed investigation of the molecular mechanisms underlying IFN biology. INTERFEROME fulfils a need in infection, immunity, development and cancer research by providing computational tools to assist in identifying interferon signatures in gene lists generated by high-throughput expression technologies, and their potential molecular and biological consequences. PMID:18996892

  4. INTERFEROME: the database of interferon regulated genes.

    PubMed

    Samarajiwa, Shamith A; Forster, Sam; Auchettl, Katie; Hertzog, Paul J

    2009-01-01

    INTERFEROME is an open access database of types I, II and III Interferon regulated genes (http://www.interferome.org) collected from analysing expression data sets of cells treated with IFNs. This database of interferon regulated genes integrates information from high-throughput experiments with annotation, ontology, orthologue sequences from 37 species, tissue expression patterns and gene regulatory information to enable a detailed investigation of the molecular mechanisms underlying IFN biology. INTERFEROME fulfils a need in infection, immunity, development and cancer research by providing computational tools to assist in identifying interferon signatures in gene lists generated by high-throughput expression technologies, and their potential molecular and biological consequences.

  5. 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.

  6. Interferons and systemic sclerosis: correlation between interferon gamma and interferon-lambda 1 (IL-29).

    PubMed

    Dantas, Andréa Tavares; Gonçalves, Sayonara Maria Calado; Pereira, Michelly Cristiny; de Almeida, Anderson Rodrigues; Marques, Cláudia Diniz Lopes; Rego, Moacyr Jesus Barreto de Melo; Pitta, Ivan da Rocha; Duarte, Angela Luzia Branco Pinto; Pitta, Maira Galdino da Rocha

    2015-01-01

    Interferon (IFN)-λ1 is a newly described cytokine, member of type III interferons family, which is known for its antiviral, anti-proliferative and antitumor activity. Recent studies indicated that this cytokine has also immune-regulatory function, but its role in the pathogenesis of autoimmune diseases is not established yet. We evaluated serum levels of IFN-λ1 in systemic sclerosis (SSc) patients and healthy controls and its association with IFN-γ and clinical manifestations. IFN-λ1 and IFN-γ serum levels were measured by ELISA from 52 patients with SSc and 53 healthy controls. Association of cytokines serum levels was sought with clinical parameters. IFN-λ1 and IFN-γ levels in SSc patients were significantly higher than those in healthy individuals (24.82 ± 8.78 and 11.04 ± 3.04 pg/ml, p < 0.0001; 34.11 ± 8.11 and 10.73 ± 2.77 pg/ml, p < 0.0001, respectively). We found a positive correlation between IFN-λ1 and IFN-γ levels in SSc patients (p = 0.0103, r = 0.3526). IFN-γ levels were associated with muscle involvement (p = 0.0483). We first showed raised IFN-λ1 levels in SSc patients. Furthermore, we found a correlation between IFN-λ1 and IFN-γ levels and an association between IFN-γ and myositis. Additional in vitro and in vivo studies are needed to understand IFN-λ1 role in SSc.

  7. Interferon beta for primary progressive multiple sclerosis.

    PubMed

    Rojas, Juan Ignacio; Romano, Marina; Ciapponi, Agustín; Patrucco, Liliana; Cristiano, Edgardo

    2009-01-21

    Therapeutic trials with ss-interferon in Multiple Sclerosis (MS) have mainly focused on remitting-relapsing multiple sclerosis (RRMS), demonstrating a reduction in relapse rate. However, there is not enough evidence about their efficacy in patients with primary progressive multiple sclerosis (PPMS). Identify and summarize the evidence that ss-interferon is beneficial and safe in patients with PPMS. We searched (until April 2008) the Cochrane MS Group Trials Register; The Cochrane Central Register of Controlled Trials (CENTRAL) The Cochrane Library, (2008, Issue 3,); MEDLINE (PubMed) (January 1966 to April 2008), EMBASE (January 1974 to April 2008); NICE (January 1999 to April 2008); LILACS (January 1986 to April 2008); Screening of reference lists of all primary studies found; Contact and inquiry of drug manufactures and multiple sclerosis experts. Randomized double or single blind, placebo-controlled trials of recombinant ss-interferon in patients with PPMS including trials of MS which report separate outcomes in subgroups of patients with PPMS. Two reviewers independently extracted and assessed trials' quality according to the criteria outlined in The Cochrane Handbook. Of 1280 potential studies evaluated, only two Randomized Control Trials (123 patients) were included. ss-interferon treatment compared to placebo did not show differences regarding the proportion of patients with progression of the disease (RR 0.89, 95% CI 0.55 to1.43), and it was associated with a greater frequency of treatment-related adverse events (RR 1.90, 95% CI 1.45-2.48). One of the trials evaluated the MRI secondary outcome pre-specified in the protocol. This trial showed that at two years the numbers of active lesions on brain MRI scan in ss-interferon arm were significantly lower than in placebo arm (weighted mean difference -1.3, 95% CI -2.15 to -0.45, P = 0.003); also, the number of participants with active lesions was significantly higher in placebo arm vs. ss-interferon arm at two

  8. Interferons, interferon-like cytokines, and their receptors.

    PubMed

    Pestka, Sidney; Krause, Christopher D; Walter, Mark R

    2004-12-01

    Recombinant interferon-alpha (IFN-alpha) was approved by regulatory agencies in many countries in 1986. As the first biotherapeutic approved, IFN-alpha paved the way for the development of many other cytokines and growth factors. Nevertheless, understanding the functions of the multitude of human IFNs and IFN-like cytokines has just touched the surface. This review summarizes the history of the purification of human IFNs and the key aspects of our current state of knowledge of human IFN genes, proteins, and receptors. All the known IFNs and IFN-like cytokines are described [IFN-alpha, IFN-beta, IFN-epsilon, IFN-kappa, IFN-omega, IFN-delta, IFN-tau, IFN-gamma, limitin, interleukin-28A (IL-28A), IL-28B, and IL-29] as well as their receptors and signal transduction pathways. The biological activities and clinical applications of the proteins are discussed. An extensive section on the evolution of these molecules provides some new insights into the development of these proteins as major elements of innate immunity. The overall structure of the IFNs is put into perspective in relation to their receptors and functions.

  9. Inhibited interferon production after space flight

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, G.; Gould, C. L.; Williams, J.; Mandel, A. D.

    1988-01-01

    Several studies have been performed in our laboratories indicating that interferon production may be impaired in rodents after space flight. Using an antiorthostatic suspension model that simulates some of the effects of microgravity seen during space flight, we have shown that interferon-alpha/beta production was inhibited. The inhibition was not due solely to the stress of suspension. The inhibited interferon production was transient, as suspended animals returned to normal caging recovered the ability to produce interferon. Antiorthostatic suspension of mice also resulted in a loss of resistance to infection with the diabetogenic strain of encephalomyocarditis virus, which correlated with the drop in interferon production. In rats flown in US Space Shuttle mission SL-3, interferon-gamma production was inhibited severely when spleen cells were challenged with concanavalin-A upon return to earth. In contrast, interleukin-3 production by these cells was normal. These results suggest that immune responses may be altered after antiorthostatic modeling or space flight, and the resistance to viral infections may be especially affected.

  10. Inhibited interferon production after space flight

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, G.; Gould, C. L.; Williams, J.; Mandel, A. D.

    1988-01-01

    Several studies have been performed in our laboratories indicating that interferon production may be impaired in rodents after space flight. Using an antiorthostatic suspension model that simulates some of the effects of microgravity seen during space flight, we have shown that interferon-alpha/beta production was inhibited. The inhibition was not due solely to the stress of suspension. The inhibited interferon production was transient, as suspended animals returned to normal caging recovered the ability to produce interferon. Antiorthostatic suspension of mice also resulted in a loss of resistance to infection with the diabetogenic strain of encephalomyocarditis virus, which correlated with the drop in interferon production. In rats flown in US Space Shuttle mission SL-3, interferon-gamma production was inhibited severely when spleen cells were challenged with concanavalin-A upon return to earth. In contrast, interleukin-3 production by these cells was normal. These results suggest that immune responses may be altered after antiorthostatic modeling or space flight, and the resistance to viral infections may be especially affected.

  11. [Interferons and thyroid abnormalities: literature review].

    PubMed

    Deghima, S; Chentli, F

    2012-03-01

    Interferons are a large family of glycoproteins known as cytokines or substances released by lymphocytes that interfere with viral replication within host cells and activate the immune system. Nowadays, interferons are used as immunomodulators to treat many diseases, especially hepatitis. Among their side effects thyroidopathies are the most important. Their frequency varies from a study to another, and may reach 20%. Thyroid disorders may be an increase in thyroid antibodies or an abnormal function. Interferons can reveal or induce thyroid diseases whose mechanisms are still not understood. It seems that cytokines modify the immune system leading to an increase in stimulating or inhibiting antibodies production. A direct thyroid cells cytolysis is also possible. When stimulating antibodies are prevailing, hyperthyroidism is the resulting disease. This last situation is rarer than hypothyroidism resulting from an increase in inhibiting antibodies and/or thyroid cells cytolysis. When thyroid disease occurs under interferon therapy, overt hyper or hypothyroidism should be treated symptomatically without stopping interferons prescribed for a severe disease. However, after stopping interferons, control of thyroid function should be done to check if there is an ad integrum thyroid recovery.

  12. Interferon α-targeted therapy.

    PubMed

    Hanaoka, Hironari; Takeuchi, Tsutomu

    2013-01-01

    Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies to various cellular components. Although many of therapies have shown great efficacy, they often associate with adverse effects. The development of safer therapies for SLE has led to recent emphasis on targeting selected pathways that can be important in the inflammatory process in SLE. The cytokine family of type I interferons (IFNs), and especially the IFNα subtypes, are implicated in pathogenesis of SLE. Genetic polymorphisms of several components of the IFN signaling pathway have been associated with an increased risk of SLE. Therefore, IFNα subtypes have been identified as a potential target for drug development in SLE. There have been developed three agents, IFNα-targeted therapy, Sifalimumab, Rontalizumab and NNC 0152-0000-0001. They are anti-IFNα monoclonal antibodies that bind to and specifically neutralizes most IFNα subtypes, preventing signaling through the type I IFN receptor. The safety and dose-proportional pharmacokinetics of those agents were demonstrated. A larger study is currently ongoing, further safety profile will be evaluated. This review provides an update on the ongoing clinical trials of anti-IFNα therapy and the promise and obstacles in the use of biologics in SLE.

  13. [Interferon inductor activity and interferon production under the action of acridonacetic acid salts].

    PubMed

    Kovalenko, A L; Grigorian, S S; Romantsov, M G; Petrov, A Iu; Muzykin, M A; Isaeva, E I

    2014-01-01

    Peculiarities of the kinetics of accumulation and duration of circulation of three types of interferon under the action of acridonacetic acid salts have been studied. Optimum doses of meglumine salt of acridonacetic acid are established, which ensure efficient and consistent induction of three interferon types, ensuring their prolonged circulation in the blood.

  14. Stable and unstable forms of human fibroblast interferon.

    PubMed Central

    Edy, V G; Desmyter, J; Billiau, A; De Somer, P

    1977-01-01

    There is a minor fraction of human fibroblast interferon that resembles human leukocyte interferon in being renaturable after treatment with guanidine hydrochloride. However, antigenically and in its low activity on heterologous cells, it resembles the bulk of human fibroblast interferon. Since the production of this stable interferon fraction is not greatly inhibited by glucosamine at concentrations that significantly reduce total interferon production, it is suggested that it differs from the bulk of human fibroblast interferon in the extent or nature of glycosylation. PMID:863511

  15. Interferon-alpha therapy of renal cancer.

    PubMed

    Neidhart, J A; Gagen, M M; Young, D; Tuttle, R; Melink, T J; Ziccarrelli, A; Kisner, D

    1984-09-01

    Thirty-three patients with renal cancer began treatment with human lymphoblastoid interferon (Wellferon) between August 1982 and February 1983. Interferon was administered as an i.m. injection at a dose of 5 X 10(6) units/sq m 3 times per week. Treatments were continued for at least 24 weeks in the absence of rapid disease progression or intolerable toxicity. Five patients demonstrated partial responses, which continued in two patients with durations of 239+ and 300+ days. Prolonged therapy was often required with a mean time to response of 99 days (22 to 190 days). Toxicity was substantial. Fever, chills, arthralgias, and myalgias occurred following most doses, but usually were well tolerated. Leukopenia and hepatic enzyme elevations were usually modest and always reversible. Dose-limiting side effects were progressive fatigue and anorexia which reversed within approximately 4 to 6 weeks after cessation of interferon therapy. There was no correlation between interferon levels, clinical toxicities, and response in this group of patients. We conclude that interferon has definite antitumor activity in renal cancer when given by this dose and schedule.

  16. Pegylated interferon alpha-associated optic neuropathy.

    PubMed

    Berg, Kathleen T; Nelson, Bruce; Harrison, Andrew R; McLoon, Linda K; Lee, Michael S

    2010-06-01

    A 52-year-old man with chronic hepatitis C presented with painless, bilateral, simultaneous nonarteritic anterior ischemic optic neuropathy (NAION) and peripheral neuropathy. Symptoms began 19 weeks after starting peginterferon alpha-2a. The peripheral neuropathy and vision of the right eye improved, but the vision of the left eye worsened after stopping interferon. We identified 23 additional cases of NAION during interferon alpha therapy. At least 12 of these patients suffered bilateral NAION. Patients lost vision 1-40 weeks after initiating therapy. Of 21 eyes that had documented initial and follow-up acuities, 8 improved, 1 worsened, and the rest remained stable. One patient had a painful peripheral neuropathy. Treatment with interferon alpha may result in NAION. Discontinuation of therapy deserves consideration after weighing individual risks and benefits.

  17. Interferon Induced Transfer of Viral Resistance

    DTIC Science & Technology

    1981-02-01

    interferon induction (27). Reaction kinetics plus the falure of soluble factors in the medium to induce interferon suggested that the inducing factor...staining. Only NDV infected lymphocytes stained with the anti-ACTHa (1-13) or anti-Y-endorphin sera. The staining reaction of the anti-ACTHa (1-13) sera was...reasons. First, a cross reaction between human immunoglobulin class IgGl, and O-endorphin and ACTH has been reported (46). It seems that this is not the

  18. Interferon induction of fibroblast proteins with guanylate binding activity.

    PubMed

    Cheng, Y S; Colonno, R J; Yin, F H

    1983-06-25

    Treatment of human diploid fibroblastic cells with interferon induces the synthesis of two guanylate binding proteins (GBP) with molecular weights of 67,000 and 56,000. The Mr = 67,000 protein (67K GBP) is synthesized upon treatment with either alpha-, beta-, or gamma-interferon. Among these interferons, gamma-interferon induces a higher level of 67K GBP synthesis. The 67K GBP synthesized in either beta- or gamma-interferon-treated cells has two charge forms with isoelectric points of 6.0 and 5.8, respectively. The synthesis of the Mr = 56,000 protein is induced by the treatment using either alpha- or beta-interferon, but its synthesis in gamma-interferon-treated cells is undetectable. The amounts of the radioactive GBPs synthesized in human fibroblasts are proportional to the amounts of the purified beta-interferon used for the inductions. Syntheses of GBPs require the transcription of cellular genes because their syntheses are completely blocked by actinomycin D treatments. The mRNA for the 67K GBP is found in fibroblasts that are treated by either alpha-, beta-, or gamma-interferon, but it is not detected in untreated cells. More 67K GBP mRNA is accumulated in the gamma-interferon-treated than in alpha- or beta-interferon-treated fibroblasts. This is consistent with more 67K GBP synthesis found in gamma-interferon-treated fibroblasts.

  19. [Effects of neuropeptides on interferon production in vitro].

    PubMed

    Kul'chikov, A E; Makarenko, A N

    2008-01-01

    The study of an interferon-inducing action of neuropeptides (a cerebrolysin model) on production of interferons by human blood leukocytes has shown that neuropeptides induce gamma-interferon production in the titer 267 IU/ml that determines one of the mechanisms of a neuroimmunocorrecting effect of cerebrolysin (Ebewe, Austria) in many neurological diseases (acute stroke, brain traumas and different neuroinfectious diseases).

  20. Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study.

    PubMed

    Kalincik, Tomas; Brown, J William L; Robertson, Neil; Willis, Mark; Scolding, Neil; Rice, Claire M; Wilkins, Alastair; Pearson, Owen; Ziemssen, Tjalf; Hutchinson, Michael; McGuigan, Christopher; Jokubaitis, Vilija; Spelman, Tim; Horakova, Dana; Havrdova, Eva; Trojano, Maria; Izquierdo, Guillermo; Lugaresi, Alessandra; Prat, Alexandre; Girard, Marc; Duquette, Pierre; Grammond, Pierre; Alroughani, Raed; Pucci, Eugenio; Sola, Patrizia; Hupperts, Raymond; Lechner-Scott, Jeannette; Terzi, Murat; Van Pesch, Vincent; Rozsa, Csilla; Grand'Maison, François; Boz, Cavit; Granella, Franco; Slee, Mark; Spitaleri, Daniele; Olascoaga, Javier; Bergamaschi, Roberto; Verheul, Freek; Vucic, Steve; McCombe, Pamela; Hodgkinson, Suzanne; Sanchez-Menoyo, Jose Luis; Ampapa, Radek; Simo, Magdolna; Csepany, Tunde; Ramo, Cristina; Cristiano, Edgardo; Barnett, Michael; Butzkueven, Helmut; Coles, Alasdair

    2017-04-01

    Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years. In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6·5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models. Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0·19 [95% CI 0·14-0·23] vs 0·53 [0·46-0·61], p<0·0001) and fingolimod (0·15 [0·10-0·20] vs 0·34 [0·26-0·41], p<0·0001), and was associated with a similar annualised relapse rate as natalizumab (0·20 [0·14-0·26] vs 0·19 [0·15-0·23], p=0·78). For the disability outcomes

  1. Interferon Beta for primary progressive multiple sclerosis.

    PubMed

    Rojas, Juan Ignacio; Romano, Marina; Ciapponi, Agustín; Patrucco, Liliana; Cristiano, Edgardo

    2010-01-20

    This is an updated Cochrane review of the previous version published (Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD006643. DOI: 10.1002/14651858.CD006643.pub2).Therapeutic trials with ss-interferon in Multiple Sclerosis (MS) have mainly focused on remitting-relapsing multiple sclerosis (RRMS), demonstrating a reduction in relapse rate. However, there is not enough evidence about their efficacy in patients with primary progressive multiple sclerosis (PPMS). Identify and summarize the evidence that ss-interferon is beneficial and safe in patients with PPMS. We searched the Cochrane MS Group Trials Register (May 2009); The Cochrane Central Register of Controlled Trials (CENTRAL) The Cochrane Library, (2009, Issue 2); MEDLINE (PubMed) (January 1966 to May 2009), EMBASE (January 1974 to May 2009); NICE (January 1999 to May 2009); LILACS (January 1986 to May 2009); Screening of reference lists of all primary studies found; Contact and inquiry of drug manufactures and multiple sclerosis experts. Randomized double or single blind, placebo-controlled trials of recombinant ss-interferon in patients with PPMS including trials of MS which report separate outcomes in subgroups of patients with PPMS. Two reviewers independently extracted and assessed trials' quality according to the criteria outlined in The Cochrane Handbook. Of 1777 potential studies evaluated, only two Randomized Control Trials (123 patients) were included. ss-interferon treatment compared to placebo did not show differences regarding the proportion of patients with progression of the disease (RR 0.89, 95% CI 0.55 to1.43), and it was associated with a greater frequency of treatment-related adverse events (RR 1.90, 95% CI 1.45-2.48). One of the trials evaluated the MRI secondary outcome pre-specified in the protocol. This trial showed that at two years the numbers of active lesions on brain MRI scan in ss-interferon arm were significantly lower than in placebo arm (weighted mean difference

  2. Antiviral effects of interferon on a somatic cell hybrid between two Burkitt's lymphoma cell lines of different interferon sensitivities.

    PubMed Central

    Lidin, B; Lamon, E W

    1982-01-01

    A somatic cell hybrid between two human Burkitt's lymphoma cell lines, Raji and Daudi, was infected with either Epstein-Barr virus or vesicular stomatitis virus after interferon treatment. Raji cells are resistant to the antiviral effects of exogenously added interferon, whereas Daudi cells are interferon sensitive. The Raji-Daudi hybrid showed an interferon sensitivity that was intermediary to that of the parental cells against both viruses. PMID:6177642

  3. [Fundamentals of interferon system function in pathology and molecular biological peculiarities of interferon production].

    PubMed

    Spivak, M Ia; Didenko, L F; Lazarenko, L M; Zholobak, N M

    2008-01-01

    Molecular biological peculiarities of interferon system function in PV-infected persons have been found. It is evident that the interferon production, anti-inflammatory cytokines and their receptors and also defensines play an important role in the mechanism of virus interaction with sensitive cells of macroorganism with development of pathological process. The new conception of expediency for the use of interferons and their inducers as the polyfunctional regulators with a broad spectrum of activity for the treatment of PV-infected patients was suggested. Patents for the method of treatment of PV-infected patients were obtained. New inducers of interferon as well as recombinant IFN-alpha-2b was developed. Our results were introduced in the medical practice.

  4. 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

  5. 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.

  6. Digital Vasculitis Associated With Interferon Therapy

    DTIC Science & Technology

    1992-06-01

    Rheumatoid fac- rheumatoid arthritis [5], and with increasing fre- tor, antinuclear antibody , VDRL, antibody to the quency in hematologic...Goldsweig (Hoffmann-La Roche) nia. In addition, numbness, paresthesias, and sen- and Ms. D. Davis (Genentecn) in the interferon antibody assays. sory

  7. Interferon-alpha induced Raynaud's syndrome.

    PubMed

    Kruit, W H; Eggermont, A M; Stoter, G

    2000-11-01

    The cytokine interferon-alpha (IFN-alpha) is increasingly prescribed for a number of indications, especially viral hepatitis and several malignancies. Two patients are described who developed Raynaud's syndrome during treatment with IFN-alpha as adjuvant therapy for high-risk melanoma. With a review of the available literature the symptomatology, possible pathophysiologic mechanisms and treatment options are discussed.

  8. Differential Inhibition of Type I Interferon Induction by Arenavirus Nucleoproteins▿

    PubMed Central

    Martínez-Sobrido, Luis; Giannakas, Panagiotis; Cubitt, Beatrice; García-Sastre, Adolfo; de la Torre, Juan Carlos

    2007-01-01

    We have documented that the nucleoprotein (NP) of the prototypic arenavirus lymphocytic choriomeningitis virus is an antagonist of the type I interferon response. In this study we tested the ability of NPs encoded by representative arenavirus species from both Old World and New World antigenic groups to inhibit production of interferon. We found that, with the exception of Tacaribe virus (TCRV), all NPs tested inhibited activation of beta interferon and interferon regulatory factor 3 (IRF-3)-dependent promoters, as well as the nuclear translocation of IRF-3. Consistent with this observation, TCRV-infected cells also failed to inhibit interferon production. PMID:17804508

  9. Novel interferons for treatment of hepatitis C virus.

    PubMed

    Clark, Virginia; Nelson, David R

    2009-08-01

    The current standard of care for treatment of hepatitis C is pegylated interferon and ribavirin. Despite the large number of new oral agents under development, interferon will likely remain the backbone of future therapy. Interferon has unique antiviral and immunomodulatory properties, which have been critical in limiting resistance to protease inhibitors and improving efficacy. Hence, optimizing pharmacokinetics and promoting adherence to interferon dosing regimens will become even more critical as new regimens enter the clinical arena. This review highlights novel interferons under development that may offer therapeutic advantages over the formulations currently available.

  10. Induction and properties of guinea pig serum interferon. Preliminary report.

    PubMed

    Nolewajka, E; Mikolajski, K; Kapp-Burzyńska, Z; Trzeciak, J; Wrona, M

    1977-01-01

    Guinea pigs, 250-350 g body weight, both sexes, were injected with 5X10(8.5) EID50 NDV (Radom strain) intracardially and intraperitoneally simultaneously. The animals were bled by cardiac puncture 0, 3, 6, 12, 24 and 48 hours after injection. After virus inactivation, serum interferon titration was performed in cultures of guinea pig embryo kidney cells with 50 percent plaque inhibition test using VSV. The highest interferon titer (64 u./ml) was found after 6 hours of inductor injection. Interferon titer decreased quickly and after 12 hours it was lower than 16 u./ml. Guinea pig serum interferon induced by NDV was resistant to pH 2 and 56 degrees C during 1 hour. Interferon was inactivated by trypsin. The decribed interferon did not protect heterologous species cells (swine) against Teschen Disease Virus infection. Other properties of this interferon are being studied.

  11. Interferon responses in HIV infection: from protection to disease.

    PubMed

    Sivro, Aida; Su, Ruey-Chyi; Plummer, Francis A; Ball, T Blake

    2014-01-01

    Interferons, induced early during viral infections, represent important regulators of both innate and adaptive immune responses, and provide protective effects against a wide range of pathogens, including HIV. Several in vitro studies and some in vivo data from HIV-exposed seronegative cohorts indicate that interferons and interferon-mediated immune responses are crucial in preventing early HIV replication. Following establishment of HIV infection, the uncontrolled (aberrant) activation of the immune system, in part regulated by interferon levels, contributes to HIV-1-induced immune activation and disease progression. Modulation of interferon responses prior to and during HIV infection shows promise for development of novel therapeutics to prevent HIV transmission, clear HIV infection, and dampen chronic immune activation. In this review we discuss the role that interferons play in protection from HIV infection, acute infection, and their role in HIV pathogenesis and disease progression. Lastly, we review recent advances in modulating interferon responses for purposes of developing novel HIV therapeutic approaches.

  12. Mechanisms underlying the inhibition of interferon signaling by viruses

    PubMed Central

    Devasthanam, Anand S

    2014-01-01

    A hallmark of the antiviral response is the induction of interferons. First discovered in 1957 by Issac and Lindeman, interferons are noted for their ability to interfere with viral replication. Interferons act via autocrine and paracrine pathways to induce an antiviral state in infected cells and in neighboring cells containing interferon receptors. Interferons are the frontline defenders against viral infection and their primary function is to locally restrict viral propagation. Viruses have evolved mechanisms to escape the host interferon response, thus gaining a replicative advantage in host cells. This review will discuss recent findings on the mechanisms viruses use to evade the host interferon response. This knowledge is important because the treatment of viral infections is a challenge of global proportions and a better understanding of the mechanisms viruses use to persist in the host may uncover valuable insights applicable to the discovery of novel drug targets. PMID:24504013

  13. Mechanisms underlying the inhibition of interferon signaling by viruses.

    PubMed

    Devasthanam, Anand S

    2014-02-15

    A hallmark of the antiviral response is the induction of interferons. First discovered in 1957 by Issac and Lindeman, interferons are noted for their ability to interfere with viral replication. Interferons act via autocrine and paracrine pathways to induce an antiviral state in infected cells and in neighboring cells containing interferon receptors. Interferons are the frontline defenders against viral infection and their primary function is to locally restrict viral propagation. Viruses have evolved mechanisms to escape the host interferon response, thus gaining a replicative advantage in host cells. This review will discuss recent findings on the mechanisms viruses use to evade the host interferon response. This knowledge is important because the treatment of viral infections is a challenge of global proportions and a better understanding of the mechanisms viruses use to persist in the host may uncover valuable insights applicable to the discovery of novel drug targets.

  14. Diverse intracellular pathogens activate type III interferon expression from peroxisomes.

    PubMed

    Odendall, Charlotte; Dixit, Evelyn; Stavru, Fabrizia; Bierne, Helene; Franz, Kate M; Durbin, Ann Fiegen; Boulant, Steeve; Gehrke, Lee; Cossart, Pascale; Kagan, Jonathan C

    2014-08-01

    Type I interferon responses are considered the primary means by which viral infections are controlled in mammals. Despite this view, several pathogens activate antiviral responses in the absence of type I interferons. The mechanisms controlling type I interferon-independent responses are undefined. We found that RIG-I like receptors (RLRs) induce type III interferon expression in a variety of human cell types, and identified factors that differentially regulate expression of type I and type III interferons. We identified peroxisomes as a primary site of initiation of type III interferon expression, and revealed that the process of intestinal epithelial cell differentiation upregulates peroxisome biogenesis and promotes robust type III interferon responses in human cells. These findings highlight the importance of different intracellular organelles in specific innate immune responses.

  15. Molecular mechanisms of the anti-inflammatory functions of interferons

    PubMed Central

    Kovarik, Pavel; Sauer, Ines; Schaljo, Barbara

    2014-01-01

    Interferons are pleiotropic cytokines with important proinflammatory functions required in defence against infections with bacteria, viruses and multicellular parasites. In recent years, fundamental functions of interferons in other processes such as cancer immunosurveillance, immune homeostasis and immunosuppression have been established. In addition, anti-inflammatory roles of interferons are well-documented in several inflammatory disease models in the mouse, most importantly in experimental autoimmune encephalomyelitis that resembles multiple sclerosis in humans. While the beneficial effects of interferons in such disease models are known, the molecular mechanisms remain poorly understood. Only recently a few molecular principles for the anti-inflammatory properties of interferons at the cellular level have been revealed. They include the ability of interferons to reduce the expression of the receptors for the inflammation-related cytokines IL-1 and IL-4, or to increase the expression of the potent anti-inflammatory genes tristetraprolin and Twist. However, the individual contribution of these anti-inflammatory responses to the overall beneficial effects of interferons in inflammatory diseases is still an open question. Also, the reason for the apparently limited number of tissues that are susceptible to the anti-inflammatory functions of interferons remains enigmatic. This review summarizes the present knowledge of the anti-inflammatory effects of interferons, and describes the currently known molecular mechanisms that may help explain the benefits of interferon signalling in several inflammatory diseases. PMID:18086388

  16. A post-marketing study on interferon ß 1b and 1a treatment in relapsing-remitting multiple sclerosis: different response in drop-outs and treated patients

    PubMed Central

    Milanese, C; La Mantia, L; Palumbo, R; Martinelli, V; Murialdo, A; Zaffaroni, M; Caputo, D; Capra, R; Bergamaschi, R

    2003-01-01

    Objectives: To evaluate the effectiveness of these agents on the basis of clinical experience in northern Italian multiple sclerosis centres. Design: Clinical data on patients with relapsing-remitting multiple sclerosis were collected on an appropriate form from 65 centres in northern Italy. Intention to treat analysis was not possible, so patients who discontinued treatment (drop-outs) and who continued treatment (treated) were analysed separately. The main outcome measures were annual relapse frequency, number of relapse-free patients, mean change in extended disability status scale score (EDSS), and number of patients who worsened. Results: 1481 patients were included; 834 were treated with Betaferon and 647 with Avonex for mean periods of 21.4 and 12.0 months, respectively. Basal EDSS was 2.37 and 2.17, respectively, and relapse frequency was 1.62 and 1.45. The annual relapse rate decreased by more than 60% with Betaferon and 55% with Avonex. The proportions of relapse-free, improved, and worsened patients were similar in the two groups. More patients interrupted treatment with Betaferon (41.1%) than with Avonex (15.3%); such patients showed more active disease at baseline and during treatment. The incidence of side effects was higher in Betaferon treated patients. Conclusions: The effectiveness of Betaferon and Avonex is confirmed. There was a more marked effect than expected from the experimental trial results. This might reflect differences in inclusion criteria, or, more likely, loss of drop-outs, favouring selective retention of responders. PMID:14638892

  17. SUMOylation of p53 mediates interferon activities

    PubMed Central

    Marcos-Villar, Laura; Pérez-Girón, José V; Vilas, Jéssica M; Soto, Atenea; de la Cruz-Hererra, Carlos F; Lang, Valerie; Collado, Manuel; Vidal, Anxo; Rodríguez, Manuel S; Muñoz-Fontela, César; Rivas, Carmen

    2013-01-01

    There is growing evidence that many host proteins involved in innate and intrinsic immunity are regulated by SUMOylation, and that SUMO contributes to the regulatory process that governs the initiation of the type I interferon (IFN) response. The tumor suppressor p53 is a modulator of the IFN response that plays a role in virus-induced apoptosis and in IFN-induced senescence. Here we demonstrate that IFN treatment increases the levels of SUMOylated p53 and induces cellular senescence through a process that is partially dependent upon SUMOylation of p53. Similarly, we show that vesicular stomatitis virus (VSV) infection induces p53 SUMOylation, and that this modification favors the control of VSV replication. Thus, our study provides evidence that IFN signaling induces p53 SUMOylation, which results in the activation of a cellular senescence program and contributes to the antiviral functions of interferon. PMID:23966171

  18. [Local cutaneous side effects of interferons].

    PubMed

    Charron, A; Bessis, D; Dereure, O; Guilhou, J J; Guillot, B

    2001-10-27

    UNDERESTIMATED SIDE EFFECTS: Skin reactions to interferon (INF) treatment are uncommon in the larger series in the literature and are usually considered to be minor. They account for 5 to 12% of adverse effects to IFN and are encountered increasingly in patients with active chronic hepatitis C. Reactions may be local, occurring exclusively at the site of injection, or general. We reviewed the literature on local skin reactions at the site of injection of the different interferons to study the underlying pathophysiological mechanisms and management schemes used. Local skin reactions can be divided into two types depending on the potential gravity and management. Minor reactions (transient erythema, eczema, depilation) have few clinical or therapeutic implications. More serious reactions, necrosis, vasculitis or injection can be potentially severe and require definitive interruption of treatment. Preventive measures include careful education concerning self-injections using proper asepsia, variation of injection sites, and self-assessment of persistent skin reactions.

  19. (PCG) Protein Crystal Growth Gamma-Interferon

    NASA Technical Reports Server (NTRS)

    1989-01-01

    (PCG) Protein Crystal Growth Gamma-Interferon. Stimulates the body's immune system and is used clinically in the treatment of cancer. Potential as an anti-tumor agent against solid tumors as well as leukemia's and lymphomas. It has additional utility as an anti-ineffective agent, including antiviral, anti-bacterial, and anti-parasitic activities. Principal Investigator on STS-26 was Charles Bugg.

  20. (PCG) Protein Crystal Growth Gamma-Interferon

    NASA Technical Reports Server (NTRS)

    1989-01-01

    (PCG) Protein Crystal Growth Gamma-Interferon. Stimulates the body's immune system and is used clinically in the treatment of cancer. Potential as an anti-tumor agent against solid tumors as well as leukemia's and lymphomas. It has additional utility as an anti-ineffective agent, including antiviral, anti-bacterial, and anti-parasitic activities. Principal Investigator on STS-26 was Charles Bugg.

  1. [The role of interferons in the socially important human viral diseases].

    PubMed

    Ospel'nikova, T P

    2013-01-01

    The role of interferon in influenza and herpes infections, general patterns of the interferon system in these diseases, the identification of interferon deficiency, the possibility of their correction with the immune active drugs, including interferon inducers combining antiviral immunomodulatory interferon effects with etiopathogenic corrective mode of action, are discussed. Clinical values of faster recovery confirm the suitability of their application in the immunocompromised patients.

  2. Protein kinase C and the antiviral effect of human interferon.

    PubMed

    Cernescu, C; Constantinescu, S N; Baltă, F; Popescu, L M; Cajal, N

    1989-01-01

    Protein kinase C (PKC) inhibitors: Hidaka's compounds H-7 (10 microM) and H-8 (20 microM), palmitoyl-carnitine (10 microM) and phloretin (50 microM), did not modify the antiviral effect of human natural or recombinant interferon alpha and of natural interferon beta. The tumor promoter 12-o-tetradecanoyl-phorbol-13-acetate (TPA) (200 nM), known as activator of PKC induced an antiviral state when tested on human embryo fibroblasts challenged with the vesicular stomatitis virus. The battery of PKC inhibitors used inhibited the antiviral effect induced by TPA. Palmitoyl-carnitine (10 microM) exerted a toxic effect that was reversed by interferon treatment (2,000 IU/ml interferon alpha). These results suggest that PKC, possibly activated by interferon-receptor interaction, is not essential for inducing the antiviral effect of interferon, but, probably, mediates the antiviral effect of TPA.

  3. The roles of interferons in osteoclasts and osteoclastogenesis.

    PubMed

    Xiong, Qi; Zhang, Lihai; Ge, Wei; Tang, Peifu

    2016-05-01

    Interferons (IFNs) play essential roles in regulating osteoclast differentiation and bone resorption. Over the last decade, we have seen tremendous developments in our understanding of the mechanisms by which interferons regulate osteoclastogenesis. Of the type I interferons, IFN-β inhibits osteoclastogenesis via autoregulatory or exogenous regulatory mechanisms, while IFN-α was recently shown to participate in regulating osteoclast formation. And the only member of type II interferons, IFN-γ, has biphasic effects on osteoclastogenesis. Type III interferons have also been shown to be involved in osteoclast bone resorption, although no direct regulatory mechanism has been demonstrated. In this review, we provide an update account of the current knowledge on these recently revealed novel roles of interferons in the regulation of a variety of signaling pathways in osteoclast differentiation and function. The potential clinical applications are also discussed. Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

  4. Type I interferon pathway in adult and juvenile dermatomyositis

    PubMed Central

    2011-01-01

    Gene expression profiling and protein studies of the type I interferon pathway have revealed important insights into the disease process in adult and juvenile dermatomyositis. The most prominent and consistent feature has been a characteristic whole blood gene signature indicating upregulation of the type I interferon pathway. Upregulation of the type I interferon protein signature has added additional markers of disease activity and insight into the pathogenesis of the disease. PMID:22192711

  5. Hepatitis C Virus Infection: Looking for Interferon Free Regimens

    PubMed Central

    González-Moreno, J.; Payeras-Cifre, A.

    2013-01-01

    Recent developments of new drugs' combinations are changing the treatment paradigm in hepatitis C virus infection. Due to the side effect profile of pegylated interferons, interferon-sparing regimens have become the main target in chronic hepatitis C treatment research. Recent proofs of concept studies have suggested that cure of chronic hepatitis C can be achieved without interferon. The purpose of this paper is to provide an overview of the clinical results recently reported for the treatment of hepatitis C virus infection with interferon-free regimens, focusing on the most promising new compounds and combinations. PMID:23710151

  6. New interferons in the treatment of chronic hepatitis C.

    PubMed

    Ruţă, Simona; Cernescu, Costin

    2011-01-01

    The current standard therapy for chronic HCV infection is a combination of pegylated-interferon (PEG-IFN) and weight-based ribavirin, administered for 24-48 weeks, according to the viral genotype. Although the weekly administration of pegylated interferons provides superior antiviral efficacy over standard interferon alpha, the rate of sustained virological response rarely overpasses 50% in patients infected with HCV genotypes 1 and 4. Consequently, multiple clinical trials with congeners of interferon (consensus interferon, interferon lambda, albinterferon, and controlled-release interferons) are ongoing. Their main advantages consist in maintenance of viral suppression across a longer dosing interval, avoidance of interdose trough and reduced dosing frequencies (twice or even once per month compared to once per week for the actual PEG-IFNs). Along with these superior pharmacokinetic properties, new interferons are expected to have improved side-effect profiles and better tolerability compared with the currently available formulations, providing an option for otherwise difficult to treat, challenging populations. New interferon formulation can be incorporated into future combination with direct acting antivirals, in order to maintain viral suppression over longer periods and minimize the development of viral resistance.

  7. Expansion of amphibian intronless interferons revises the paradigm for interferon evolution and functional diversity

    USDA-ARS?s Scientific Manuscript database

    Interferons (IFNs) are key cytokines identified in vertebrates, and evolutionary dominance of intronless IFN genes in amniotes is a signature event in IFN evolution. For the first time, we show that the emergence and expansion of intronless IFN genes is evident in amphibians, shown by 24-37 intronle...

  8. Interferon action on Mayaro virus replication.

    PubMed

    Rebello, M C; Fonseca, M E; Marinho, J O; Rebello, M A

    1993-08-01

    Treatment of TC7 cells with interferon (IFN) drastically reduced the yield of infectious Mayaro virus under experimental conditions that virus attachment and penetration into the cells were not affected. In IFN-treated cells, synthesis of Mayaro virus proteins was inhibited and cellular protein synthesis was restored. This phenomenon is dependent on IFN concentration and multiplicity of infection. Electron microscopy of these cells revealed normal and anomalous viral particles inside cytoplasmic vacuoles. This suggests that IFN also interferes with Mayaro virus morphogenesis and inhibits the release of virions from cells.

  9. Physiological Proteins in Therapeutics: A Current Review on Interferons.

    PubMed

    Ghosh, Debosree; Ghosh, Debjani; Parida, Pratap

    2016-01-01

    Interferons are produced in vivo and are one of the prime components of natural defense system of animals. They are released by the viral infected cells and provide protection to the neighboring cells against viral infection. The cyto-protective property of the proteins ignited the thought of their pharmaceutical adaptation for therapeutic use against viral diseases in individuals in whom the interferons released naturally are not sufficient to combat the situation. Interferon supplements have been found to complement various antiviral drugs. Considering the efficacy of interferons in regulating angiogenesis and immunomodulation, they can be adapted for therapy of the killer diseases like cancer and AIDS. We have come ahead more than twenty five years after the approval of clinical use of interferon as drugs and are today really in a position to promise a disease free life to our present and next generation. Interferon therapy will be contributing a big share to the upcoming remedies for the new diseases and we are thus armed to fight back the deadly viral threats. Interferons have been modified [pegylated etc.] and have already been adapted to some extent in certain diseases and are in regular use in some. Thus interferons if modified as per need and used in combination with either antiviral drugs, antibiotics, antioxidants may strengthen our defense system effectively to bring about a strong protection against wide range of diseases.

  10. Treatment discontinuation with peg-interferon: what to consider.

    PubMed

    Boccaccio, Vincenzo; Russo, Maria Luisa; Carbone, Marco; Bruno, Savino

    2015-01-01

    Eradication of chronic hepatitis C virus infection improves the outcome of both liver and extrahepatic-related diseases and interferon-based regimens represented, for years, the standard of care to achieve this goal. Several baseline and on-treatment predictors of response, associated with a lower chance to achieve sustained virological response after interferon-based treatment, were developed. In the past few years, the advent of direct acting antivirals has dramatically modified the landscape of antiviral therapy, leading to an evolution from interferon-based to interferon-free therapies. This review will focus on the usefulness of futility stopping rules that allow the discontinuation of therapy in patients with a reduced chance to obtain sustained virological response if treated with interferon-containing regimens.

  11. Specificity, cross-talk and adaptation in Interferon signaling

    NASA Astrophysics Data System (ADS)

    Zilman, Anton

    Innate immune system is the first line of defense of higher organisms against pathogens. It coordinates the behavior of millions of cells of multiple types, achieved through numerous signaling molecules. This talk focuses on the signaling specificity of a major class of signaling molecules - Type I Interferons - which are also used therapeutically in the treatment of a number of diseases, such as Hepatitis C, multiple sclerosis and some cancers. Puzzlingly, different Interferons act through the same cell surface receptor but have different effects on the target cells. They also exhibit a strange pattern of temporal cross-talk resulting in a serious clinical problem - loss of response to Interferon therapy. We combined mathematical modeling with quantitative experiments to develop a quantitative model of specificity and adaptation in the Interferon signaling pathway. The model resolves several outstanding experimental puzzles and directly affects the clinical use of Type I Interferons in treatment of viral hepatitis and other diseases.

  12. Comparative immunochemical analysis of some human leukocytic interferons

    SciTech Connect

    Kostrov, S.V.; Izotova, L.S.; Eremashvili, M.R.; Galaktionov, K.I.; Yurin, V.L.; Korobitsin, L.P.; Pivovarov, A.P.; Pavlov, I.Yu.; Tyagotin, Yu.V.; Fridlyanskaya, I.I.; Margulis, B.A.

    1986-06-20

    It was established by radioimmunological methods based on the use of mono- and polyclonal antibodies against interferon ..cap alpha..A that the latter react quantitatively not only with this protein, but also with interferons ..cap alpha..F and ..cap alpha..N, whereas all the variants of the monoclonal antibodies obtained react only with interferons ..cap alpha..A and ..cap alpha..N. The monoclonal antibodies investigated (5A6, 11E9, 19C10, 258, and 268) are directed against overlapping epitopes of the interferon ..cap alpha..A molecule, which does not bind more than two molecular of antibodies of differing specificity simultaneously. The degree of correlation between the immunochemical and biological activity of interferon ..cap alpha..A upon thermal denaturation and proteolytic degradation as well as the ability of this protein to form oligomeric structures was studied.

  13. Hantavirus interferon regulation and virulence determinants.

    PubMed

    Mackow, Erich R; Dalrymple, Nadine A; Cimica, Velasco; Matthys, Valery; Gorbunova, Elena; Gavrilovskaya, Irina

    2014-07-17

    Hantaviruses predominantly replicate in primary human endothelial cells and cause 2 diseases characterized by altered barrier functions of vascular endothelium. Most hantaviruses restrict the early induction of interferon-β (IFNβ) and interferon stimulated genes (ISGs) within human endothelial cells to permit their successful replication. PHV fails to regulate IFN induction within human endothelial cells which self-limits PHV replication and its potential as a human pathogen. These findings, and the altered regulation of endothelial cell barrier functions by pathogenic hantaviruses, suggest that virulence is determined by the ability of hantaviruses to alter key signaling pathways within human endothelial cells. Our findings indicate that the Gn protein from ANDV, but not PHV, inhibits TBK1 directed ISRE, kB and IFNβ induction through virulence determinants in the Gn cytoplasmic tail (GnT) that inhibit TBK1 directed IRF3 phosphorylation. Further studies indicate that in response to hypoxia induced VEGF, ANDV infection enhances the permeability and adherens junction internalization of microvascular and lymphatic endothelial cells. These hypoxia/VEGF directed responses are rapamycin sensitive and directed by mTOR signaling pathways. These results demonstrate the presence of at least two hantavirus virulence determinants that act on endothelial cell signaling pathways: one that regulates antiviral IFN signaling responses, and a second that enhances normal hypoxia-VEGF-mTOR signaling pathways to facilitate endothelial cell permeability. These findings suggest signaling pathways as potential targets for therapeutic regulation of vascular deficits that contribute to hantavirus diseases and viral protein targets for attenuating pathogenic hantaviruses.

  14. Pharmacology and therapeutic potential of interferons.

    PubMed

    George, Peter M; Badiger, Rekha; Alazawi, William; Foster, Graham R; Mitchell, Jane A

    2012-07-01

    Interferon (IFN) is widely recognised to be an integral part of the innate immune response to viral infection. Since its initial discovery in 1957 by Isaacs and Lindenmann, various IFN sub-types have been identified and there are now three distinct classes recognised-Type I (IFN-α and IFN-β), Type II (IFN-γ) and Type III (IFN-λ), distinguished by their differing receptors. As well as displaying profound antiviral activity in vivo, IFN has anti-proliferative, cytotoxic and anti-tumoural roles. In an attempt to harness their immunomodulatory potential, investigators and clinicians have investigated the use of IFNs for the treatment of human diseases with considerable success. For example, IFN-α preparations are now a critical component in the treatment of chronic Hepatitis C infection and IFN-β therapy is now the first line treatment for relapsing remitting multiple sclerosis. However, IFN therapy is also associated with significant morbidity and in some patients is poorly tolerated. In this review, we explore the scientific basis for IFN therapy and outline its therapeutic scope. We describe the commonly encountered side effects and attempt to explain the less well recognised pulmonary complications including emerging evidence of life threatening and irreversible pulmonary vascular pathology. Finally, we look to the future of interferon drug treatment, examining the potential for emerging therapies.

  15. The interferon-stimulated genes: targets of direct signaling by interferons, double-stranded RNA, and viruses.

    PubMed

    Sen, G C; Sarkar, S N

    2007-01-01

    The interferon system plays a profound role in determining the outcome of viral infection in mammals. Viruses induce the synthesis of interferon, which, in turn, blocks virus replication by inducing the expression of antiviral proteins encoded by interferon-stimulated genes. It is not widely appreciated that without the participation of interferon, many of the same genes can also be induced by a variety of virus-related agents, such as double-stranded RNA and viral proteins. In this chapter, we discuss different signaling pathways, activated by these agents, that lead to the induction of partially overlapping sets of genes, including the interferon-stimulated genes. We also review the biochemical and cellular properties of the protein products of a selected number of these genes including ISG56, ISG54, and ISG15.

  16. Contemporary Use of Interferon Therapy in the Myeloproliferative Neoplasms.

    PubMed

    Foucar, Charles Elliott; Stein, Brady Lee

    2017-09-25

    The purpose of this article is to review the current evidence behind interferon therapy in patients with myeloproliferative neoplasms. Preliminary analysis suggests that interferon may be non-inferior to hydroxyurea in patients with polycythemia vera and essential thrombocytosis. Responses have been observed regardless of JAK2 mutational status, but the presence of non-JAK2 somatic mutations may negatively influence response rates. Pegylated interferon has proven efficacy for patients with myeloproliferative neoplasms. Both newly diagnosed and previously treated patients with polycythemia vera and essential thrombocytosis exhibit high hematologic response rates, and some of these patients achieve molecular responses as well. Interferon therapy leads to lower rates of hematologic response in MF patients, but patients earlier on in their disease course have a better chance of responding. There are ongoing trials comparing pegylated interferon to hydroxyurea in essential thrombocytosis (ET) and polycythemia vera (PV), and early analysis suggests non-inferiority. However, longer follow-up is needed before drawing any conclusions. Future research is needed to better define characteristics of the best responders and to determine whether novel forms of interferon therapy or combination therapy with interferon can enhance efficacy and tolerability.

  17. [Interferon alpha-2b modified with polyethylene glycol].

    PubMed

    Wu, Yingxin; Zhai, Yanqin; Lei, Jiandu; Ma, Guanghui; Su, Zhiguo

    2008-09-01

    In order to obtain a more stable PEGylated interferon alpha-2b, and prolong its half life, interferon alpha-2b (IFN alpha-2b) was modified with monomethoxy polyethylene glycol propionaldehyde (mPEG-ALD) 20000. It was found that the optimized reaction condition for the maximum bioactivity and highest PEGylation degree of the mono PEGylated interferon alpha-2b was as follows: in 20 mmol/L, pH 6.5, citric acid and sodium dihydrogen phosphate buffer, the concentration of IFN alpha-2b was 4 mg/mL, and the molar ratio of PEG/IFN alpha-2b was 8:1, and the reaction time was 20 h at 4 degrees C. Under the optimized reaction condition, the mono PEGylation degree reached to 55%. Ion exchange chromatography was used to separate and purify mono PEGylated interferon alpha-2b from the reaction mixture. The purity of mono PEGylated interferon alpha-2b was higher than 97% characterized by HPLC. The bioactivity of the mono PEGylated interferon alpha-2b was 13.4% of the native IFN alpha-2b, while its half life in SD rat is much longer than the native IFN alpha-2b. The mono PEGylated interferon alpha-2b is also stable in aqueous.

  18. Association of Raynaud's syndrome with interferons. A meta-analysis.

    PubMed

    Mohokum, M; Hartmann, P; Schlattmann, P

    2012-10-01

    Vasospastic disorders of the digital circulation such as the Raynaud's syndrome (RS) are known side-effects of treatment of interferons. The prevalence of RS in patients during treatment with interferons agents is not well-defined. The objective of this paper was to assess the prevalence of RS in patients receiving interferons - a meta-analysis of published data was performed. The PubMed database of the National Library of Medicine and ISI Web of Knowledge was used for studies dealing with RS and patients receiving interferons. The studies provided sufficient data to estimate the prevalence of RS in patients receiving interferons. A forest plot was determined by the revealed prevalences. Statistical analysis was based on methods for a random effects meta-analysis and a finite mixture model for proportions. Publication bias was investigated with the linear regression test (Egger's method). A meta-regression was conducted by the year of publication. Six eligible studies, contributing data on 183 subjects, were included in this meta-analysis. For RS in patients receiving interferons a pooled prevalence of 13.6% and 95% CI (95% CI 0.026, 0.313) was obtained. A mixture model analysis found three latent classes. Statistically, publication bias was not present (p-value 0.335). Despite some heterogeneity there is a possible indication of an association between RS and patients receiving interferons.

  19. Action of Interferon: Kinetics and Differential Effects on Viral Functions

    PubMed Central

    Yamazaki, Shudo; Wagner, Robert R.

    1970-01-01

    A highly purified rabbit interferon was tested for its capacity to inhibit various manifestations of infection of primary rabbit kidney (RK) cells with vesicular stomatitis (VS) virus. A kinetic analysis of the actinomycin-sensitive phase of interferon-induced cellular resistance revealed that RK cells could transcribe virtually all of the hypothetical antiviral messenger ribonucleic acid (mRNA) within 3 hr. Similar exposure to interferon reduced virus yield by 95 to 99% and markedly inhibited cytopathic effect on RK cells infected at a multiplicity of 10 or less. Interferon was less effective in blocking cytopathic effects when RK cells were infected at a multiplicity of 100. However, RK cells pretreated with the same amount of interferon and infected at a multiplicity of 100 failed to incorporate 3H-amino acids into structural or nonstructural proteins of VS virus identified by polyacrylamide gel electrophoresis. Despite this inhibition of viral protein synthesis, interferon did not prevent the switch off by VS virus of cellular protein synthesis. The rapidity with which a high multiplicity of VS virus switched off cellular protein synthesis, even in cells rendered resistant to viral infection by interferon, is further evidence that this reaction is caused by an infecting virion component rather than by a newly synthesized viral product. PMID:5497887

  20. Bioactivity determination of native and variant forms of therapeutic interferons.

    PubMed

    Larocque, Louise; Bliu, Alex; Xu, Ranran; Diress, Abebaw; Wang, Junzhi; Lin, Rongtuan; He, Runtao; Girard, Michel; Li, Xuguang

    2011-01-01

    The traditional antiviral assays for the determination of interferon potency are reported to have considerable variability between and within assays. Although several reporter gene assays based on interferon-inducible promoter activities have been reported, data from comprehensive validation studies are lacking and few studies have been conducted to analyze the variant forms of interferons, which could have undesirable clinical implications. Here, a reporter gene assay employing a HEK293 cell line stably transfected with luciferase gene under the control of interferon-stimulated response element promoter was developed and validated. The assay was found to be more sensitive, with a larger detection range than the antiviral assay. Several cytokines tested did not interfere with the test, suggesting the assay possesses a certain degree of selectivity. Moreover, the robustness of the assay was demonstrated by minimal variations in the results generated by different analysts and cell passage number (up to 52 passages). Finally, the method was employed to analyze several interferon variants (interferon-α 2a) and we found that the aggregated form has completely lost its potency; while a modest loss of bioactivity in oxidized interferon was observed (approx. 23%), the deamidated form essentially retained its activity.

  1. Therapeutic alpha-interferons protein: structure, production, and biosimilar.

    PubMed

    El-Baky, Nawal Abd; Redwan, Elrashdy M

    2015-01-01

    In 2007, the world solemnized the golden jubilee of the discovery of interferon (IFN). Interferon is a small protein messenger called a pluripotent cytokine, produced by several cells of the host in response to various biological as well as synthetic stimuli. There are three major classes of interferons in humans: IFN-alpha, IFN-beta, and IFN-gamma. As a treatment option, interferon-alpha (IFN-α) is the most effective one. IFN-α has proved to be effective as an antiviral therapy and tumor-fighting drug in the past two decades. Meanwhile, great progress has been achieved in establishing IFN-α as the first choice of antiviral therapy for chronic hepatitis C virus (HCV) patients. Recently, novel pegylated IFN-α2 products with extended in vivo half-lives and consensus interferon, an artificially engineered type I interferon, have been developed to substantially improve treatment regimes for HCV patients. Undesirable acute and chronic side effects in addition to immunogenicity of therapeutic IFN products remain constraints to conquer for further improvements in clinical applications of IFN. It is certainly expected that more research will be conducted in the future, not only to face these challenges but also to extend the range of IFN products and their clinical targets. The objective herein is to review the current therapeutic alpha-interferons production, formulation technologies, and prospective future for the original entity and its biogeneric version.

  2. Bioactivity Determination of Native and Variant Forms of Therapeutic Interferons

    PubMed Central

    Larocque, Louise; Bliu, Alex; Xu, Ranran; Diress, Abebaw; Wang, Junzhi; Lin, Rongtuan; He, Runtao; Girard, Michel; Li, Xuguang

    2011-01-01

    The traditional antiviral assays for the determination of interferon potency are reported to have considerable variability between and within assays. Although several reporter gene assays based on interferon-inducible promoter activities have been reported, data from comprehensive validation studies are lacking and few studies have been conducted to analyze the variant forms of interferons, which could have undesirable clinical implications. Here, a reporter gene assay employing a HEK293 cell line stably transfected with luciferase gene under the control of interferon-stimulated response element promoter was developed and validated. The assay was found to be more sensitive, with a larger detection range than the antiviral assay. Several cytokines tested did not interfere with the test, suggesting the assay possesses a certain degree of selectivity. Moreover, the robustness of the assay was demonstrated by minimal variations in the results generated by different analysts and cell passage number (up to 52 passages). Finally, the method was employed to analyze several interferon variants (interferon-α 2a) and we found that the aggregated form has completely lost its potency; while a modest loss of bioactivity in oxidized interferon was observed (approx. 23%), the deamidated form essentially retained its activity. PMID:21403871

  3. Enterovirus 71 Disrupts Interferon Signaling by Reducing the Level of Interferon Receptor 1

    PubMed Central

    Lu, Jing; Yi, Lina; Zhao, Jin; Yu, Jun; Chen, Ying; Lin, Marie C.; Kung, Hsiang-Fu

    2012-01-01

    The recent outbreak of enterovirus 71 (EV71) infected millions of children and caused over 1,000 deaths. To date, neither an effective vaccine nor antiviral treatment is available for EV71 infection. Interferons (IFNs) have been successfully applied to treat patients with hepatitis B and C viral infections for decades but have failed to treat EV71 infections. Here, we provide the evidence that EV71 antagonizes type I IFN signaling by reducing the level of interferon receptor 1 (IFNAR1). We show that the host cells could sense EV71 infection and stimulate IFN-β production. However, the induction of downstream IFN-stimulated genes is inhibited by EV71. Also, only a slight interferon response and antiviral effects could be detected in cells treated with recombinant type I IFNs after EV71 infection. Further studies reveal that EV71 blocks the IFN-mediated phosphorylation of STAT1, STAT2, Jak1, and Tyk2 by reducing IFNAR1. Finally, we identified the 2A protease encoded by EV71 as an antagonist of IFNs and show that the protease activity is required for reducing IFNAR1 levels. Taken together, our study for the first time uncovers a mechanism used by EV71 to antagonize type I IFN signaling and provides new targets for future antiviral strategies. PMID:22258259

  4. Phleboviruses and the Type I Interferon Response

    PubMed Central

    Wuerth, Jennifer Deborah; Weber, Friedemann

    2016-01-01

    The genus Phlebovirus of the family Bunyaviridae contains a number of emerging virus species which pose a threat to both human and animal health. Most prominent members include Rift Valley fever virus (RVFV), sandfly fever Naples virus (SFNV), sandfly fever Sicilian virus (SFSV), Toscana virus (TOSV), Punta Toro virus (PTV), and the two new members severe fever with thrombocytopenia syndrome virus (SFTSV) and Heartland virus (HRTV). The nonstructural protein NSs is well established as the main phleboviral virulence factor in the mammalian host. NSs acts as antagonist of the antiviral type I interferon (IFN) system. Recent progress in the elucidation of the molecular functions of a growing list of NSs proteins highlights the astonishing variety of strategies employed by phleboviruses to evade the IFN system. PMID:27338447

  5. Cerebral malaria: gamma-interferon redux.

    PubMed

    Hunt, Nicholas H; Ball, Helen J; Hansen, Anna M; Khaw, Loke T; Guo, Jintao; Bakmiwewa, Supun; Mitchell, Andrew J; Combes, Valéry; Grau, Georges E R

    2014-01-01

    There are two theories that seek to explain the pathogenesis of cerebral malaria, the mechanical obstruction hypothesis and the immunopathology hypothesis. Evidence consistent with both ideas has accumulated from studies of the human disease and experimental models. Thus, some combination of these concepts seems necessary to explain the very complex pattern of changes seen in cerebral malaria. The interactions between malaria parasites, erythrocytes, the cerebral microvascular endothelium, brain parenchymal cells, platelets and microparticles need to be considered. One factor that seems able to knit together much of this complexity is the cytokine interferon-gamma (IFN-γ). In this review we consider findings from the clinical disease, in vitro models and the murine counterpart of human cerebral malaria in order to evaluate the roles played by IFN-γ in the pathogenesis of this often fatal and debilitating condition.

  6. Cerebral malaria: gamma-interferon redux

    PubMed Central

    Hunt, Nicholas H.; Ball, Helen J.; Hansen, Anna M.; Khaw, Loke T.; Guo, Jintao; Bakmiwewa, Supun; Mitchell, Andrew J.; Combes, Valéry; Grau, Georges E. R.

    2014-01-01

    There are two theories that seek to explain the pathogenesis of cerebral malaria, the mechanical obstruction hypothesis and the immunopathology hypothesis. Evidence consistent with both ideas has accumulated from studies of the human disease and experimental models. Thus, some combination of these concepts seems necessary to explain the very complex pattern of changes seen in cerebral malaria. The interactions between malaria parasites, erythrocytes, the cerebral microvascular endothelium, brain parenchymal cells, platelets and microparticles need to be considered. One factor that seems able to knit together much of this complexity is the cytokine interferon-gamma (IFN-γ). In this review we consider findings from the clinical disease, in vitro models and the murine counterpart of human cerebral malaria in order to evaluate the roles played by IFN-γ in the pathogenesis of this often fatal and debilitating condition. PMID:25177551

  7. Effects of Interferons and Viruses on Metabolism

    PubMed Central

    Fritsch, Stephanie Deborah; Weichhart, Thomas

    2016-01-01

    Interferons (IFNs) are potent pleiotropic cytokines that broadly alter cellular functions in response to viral and other infections. These alterations include changes in protein synthesis, proliferation, membrane composition, and the nutritional microenvironment. Recent evidence suggests that antiviral responses are supported by an IFN-induced rewiring of the cellular metabolism. In this review, we discuss the roles of type I and type II IFNs in regulating the cellular metabolism and biosynthetic reactions. Furthermore, we give an overview of how viruses themselves affect these metabolic activities to promote their replication. In addition, we focus on the lipid as well as amino acid metabolisms, through which IFNs exert potent antiviral and immunomodulatory activities. Conversely, the expression of IFNs is controlled by the nutrient sensor mammalian target of rapamycin or by direct reprograming of lipid metabolic pathways. These findings establish a mutual relationship between IFN production and metabolic core processes. PMID:28066439

  8. Ontogeny of the interferon system in chickens.

    PubMed

    Karpala, Adam J; Bagnaud-Baule, Audrey; Goossens, Kate E; Lowenthal, John W; Bean, Andrew G D

    2012-06-01

    Newborn vertebrates may be susceptible to infection because the immature status of their immune system results in an inability to make an effective immune response. Consequently, newly hatched chicks appear to be more susceptible to infections than mature chickens. In particular, poultry susceptibility to virus infection may be related to poor expression of innate immune elements involved in antiviral responses. Therefore, in this study we assessed the relative development of the interferon (IFN) system: a protective system against virus infection. We investigated the age-related expression of the elements involved in the IFN response including IFN gene expression, their associated receptors and the pattern recognition receptors (PRR) involved in the regulation of IFNs. We observed that the IFN system is somewhat inadequately expressed in embryos and develops over time, just prior to and after hatching, and therefore chicks may be more susceptible to virus than mature birds because of an immature IFN network.

  9. Gamma interferon: a central mediator in atherosclerosis.

    PubMed

    Leon, M L Alfaro; Zuckerman, S H

    2005-10-01

    Atherosclerosis is a chronic inflammatory disease of the vasculature with lesions developing in the arterial wall, frequently in the coronary and carotid arteries. The interaction between macrophages and lymphocytes within the atherosclerotic lesion microenvironment exemplifies a site where both innate and adaptive immunity contribute towards disease progression. As gamma interferon (IFN-gamma), the classic macrophage activating factor, has been localized to atherosclerotic lesions, this review will focus on its contribution to plaque pathology and will finally consider how current therapies, as exemplified by HMG CoA reductase inhibitors or statins, may impact this process beyond lipid lowering, in part by inhibiting IFN-gamma dependent processes. IFN-gamma sources within the atheroma as well as receptors, signaling pathways and its effects on macrophages as well as on vascular smooth muscle and endothelial cells will be considered. Therapeutic interventions targeting molecular events associated with IFN-gamma signaling offer novel approaches to the treatment of atherosclerosis.

  10. The role of interferons in early pregnancy.

    PubMed

    Micallef, Anna; Grech, Nicole; Farrugia, Francesca; Schembri-Wismayer, Pierre; Calleja-Agius, Jean

    2014-01-01

    The interferons (IFNs) form part of the large family of glycoproteins known as cytokines. They are secreted by host cells as a line of defence against pathogens and certain tumours. IFNs affect cell proliferation and differentiation and also play a very important role in the functioning of the immune system. Miscarriage in both humans has been associated with higher levels of IFN, particularly IFN-γ. However, this cytokine is evidently vital in successful murine pregnancies since it is involved in maintaining the decidual layer in addition to remodelling of the vasculature in the uterus. The effects of IFN on human pregnancies are more difficult to study. Hence, there is still a lot more to be discovered in the hope of reaching a definite conclusion regarding the impact of IFN.

  11. Induction of pulmonary indoleamine 2,3-dioxygenase by interferon.

    PubMed Central

    Yoshida, R; Imanishi, J; Oku, T; Kishida, T; Hayaishi, O

    1981-01-01

    Pulmonary indoleamine 2,3-dioxygenase [indoleamine: oxygen 2,3-oxidoreductase(decyclizing)] has been found to be induced (30- to 100-fold) in the mouse after a single intraperitoneal administration of bacterial endotoxin [Yoshida, R. & Hayaishi, O. (1978) Proc. Natl. Acad. Sci. USA 75, 3998-4000] or during in vivo virus infection [Yoshida, R., Urade, Y., Tokuda M. & Hayaishi, O. (1979) Proc. Natl. Acad. Sci. USA 76, 4084-4086]. In the present study, an in vitro system with mouse lung slices was developed in which bacterial endotoxin (5 micrograms/ml)produced an induction (approximately 10-fold) of indoleamine 2,3-dioxygenase. The endotoxin was substituted by interferon from mouse L cells or mouse brain. The pulmonary enzyme activity increased almost linearly for 48 hr after addition of mouse interferon (10(4) units/ml) to lung slices. Interferon from mouse L cells or mouse brain produced a 10- to 15-fold increase in the enzyme activity, whereas that from human leukocytes was all but ineffective. The effect also was observed using highly purified L-cell interferon, prepared by poly(U) affinity column chromatography. When interferon was treated either by heat, alpha-chymotrypsin, or anti-interferon serum, such increase in the enzyme activity was diminished essentially to the same extent as seen in the antiviral activity. The increase in the enzyme activity was blocked when actinomycin D or cycloheximide was added to the slices before interferon treatment. These results suggest that the enzyme induction was produced by interferon and not by possible contaminants in the interferon preparations. Images PMID:6165986

  12. Subcutaneous recombinant interferon-β-1a (Rebif®): a review of its use in the treatment of relapsing multiple sclerosis.

    PubMed

    Sanford, Mark; Lyseng-Williamson, Katherine A

    2011-10-01

    Subcutaneous recombinant interferon-β-1a (SC IFNβ-1a) [Rebif®] is indicated as monotherapy for the prevention of relapses and progression of physical disability in patients with relapsing multiple sclerosis (MS). This article reviews the efficacy and tolerability of SC IFNβ-1a in this indication, with further discussion of its pharmacological properties and pertinent pharmacoeconomic studies. SC IFNβ-1a efficacy and tolerability were evaluated in randomized, double-blind, multinational trials in patients with relapsing-remitting MS (RRMS). Its efficacy was demonstrated in the 2-year PRISMS trial, as SC IFNβ-1a 22 or 44 μg three times weekly (tiw) significantly reduced relapse rates, with an ≈30% relative risk reduction compared with placebo. SC IFNβ-1a was also associated with significantly delayed progression of disability, and lower disease activity according to MRI, relative to placebo. In the 24-week EVIDENCE trial, a significantly higher proportion of SC IFNβ-1a 44 μg tiw than intramuscular IFNβ-1a (Avonex®) 30 μg once weekly recipients remained relapse free. A serum-free formulation of SC IFNβ-1a 44 μg tiw was more efficacious than placebo in preventing the development of brain lesions in the 16-week IMPROVE trial. In the 96-week REGARD trial, the efficacy of SC IFNβ-1a 44 μg tiw was not significantly different to that of glatiramer acetate for clinical endpoints, although it was associated with reduced development of brain lesions compared with glatiramer acetate, according to some MRI endpoints. In the 36-month CAMMS223 trial, alemtuzumab led to significantly lower relapse rates and risk of developing sustained disability than SC IFNβ-1a 44 μg tiw, and was generally more efficacious according to other clinical and MRI endpoints. Across trials, influenza-like symptoms, injection-site reactions, haematological disturbances and hepatic enzyme abnormalities were the most common treatment-emergent adverse events occurring with SC IFN

  13. Interferon regulatory factor 3 in adaptive immune responses.

    PubMed

    Ysebrant de Lendonck, Laure; Martinet, Valerie; Goriely, Stanislas

    2014-10-01

    Interferon regulatory factor (IRF) 3 plays a key role in innate responses against viruses. Indeed, activation of this transcription factor triggers the expression of type I interferons and downstream interferon-stimulated genes in infected cells. Recent evidences indicate that this pathway also modulates adaptive immune responses. This review focuses on the different mechanisms that are implicated in this process. We discuss the role of IRF3 within antigen-presenting cells and T lymphocytes in the polarization of the cellular immune response and its implication in the pathogenesis of immune disorders.

  14. Signalling pathways mediating type I interferon gene expression.

    PubMed

    Edwards, Michael R; Slater, Louise; Johnston, Sebastian L

    2007-09-01

    Type I interferon-alpha/beta play an essential role in immunity to viruses. While interferon-beta has been used as a model of a complex promoter, many of the signalling pathways leading to interferon-beta gene expression remain controversial. Recent milestones include the discovery of Toll-like receptors and RNA helicases that signal via a novel kinase complex composed of I kappa B kinase-iota/epsilon or TANK binding kinase-1. This review provides a timely summary of this rapidly expanding field, focusing specifically on the various viral RNA binding molecules and their associated signalling pathways.

  15. Overview of the biology of type I interferons

    PubMed Central

    2010-01-01

    Type I interferons are pleiotropic cytokines with antiviral, antitumor and immunoregulatory functions. An aspect of their complex biology is the paradox that, depending on context, type I interferons can be anti-inflammatory and tissue protective or can be proinflammatory and promote autoimmunity. Along these lines, the activation of type I interferon pathways is effective in suppressing disease activity in patients with multiple sclerosis and in animal models of arthritis and colitis, while there is an expectation that blockade of the same pathways will be beneficial in the treatment of patients with systemic lupus erythematosus. PMID:20392288

  16. Interferon-λ polymorphisms and response to pegylated interferon in Iranian hepatitis C patients

    PubMed Central

    Haj-sheykholeslami, Arghavan; Keshvari, Maryam; Sharafi, Heidar; Pouryasin, Ali; Hemmati, Khalil; Mohammadzadehparjikolaei, Fatemeh

    2015-01-01

    AIM: To evaluate the efficacy of pegylated interferon in Iranian chronic hepatitis C patients in relation to interferon-λ (IFNL) polymorphisms. METHODS: This study enrolled patients with chronic hepatitis C referred to the Tehran Blood Transfusion Hepatitis Clinic in 2011. Patients were included in the study if they had no concomitant hepatic illness, were negative for human immunodeficiency virus antibodies, and had no prior history of treatment with any type of pegylated interferon. Patients were treated with 180 μg pegylated interferon alpha-2a (Pegaferon®) weekly and 800-1200 mg ribavirin daily for 24 or 48 wk depending on weight and hepatitis C virus (HCV) genotype. Blood samples were collected from patients to obtain DNA for determination of IFNL rs12979860 and rs8099917 polymorphisms. The virologic response in patients was then evaluated and compared between the different IFNL genotypes. RESULTS: A total of 152 patients with a mean age of 41.9 ± 10.0 years were included in the study, of which 141/152 were men (92.8%). The most frequent HCV genotype was type-1, infecting 93/152 (61.2%) patients. Sustained virologic response (SVR) was achieved in 81.9% of patients with HCV genotype-1 and 91.1% of patients with HCV genotype-3. Treatment success was achieved in 91.2% (52/57) of patients with the IFNL rs12979860 CC genotype and 82.1% (78/95) in those with other genotypes. Similar treatment response rates were also observed in patients with rs8099917 TT (39/45; 86.7%) and non-TT (61/68; 89.7%) genotypes. Univariate analyses identified the following factors which influenced treatment response for inclusion in a multivariate analysis: age, HCV RNA level, stage of liver fibrosis, rs12979860 CC genotype, and aspartate transaminase level. A logistic regression analysis revealed that only the rs12979860 CC genotype was significantly associated with achievement of SVR (OR = 6.2; 95%CI: 1.2-31.9; P = 0.03). CONCLUSION: The rs12979860 CC genotype was associated with

  17. A critical function for type I interferons in cancer immunoediting.

    PubMed

    Dunn, Gavin P; Bruce, Allen T; Sheehan, Kathleen C F; Shankaran, Vijay; Uppaluri, Ravindra; Bui, Jack D; Diamond, Mark S; Koebel, Catherine M; Arthur, Cora; White, J Michael; Schreiber, Robert D

    2005-07-01

    'Cancer immunoediting' is a process wherein the immune system protects hosts against tumor development and facilitates outgrowth of tumors with reduced immunogenicity. Although interferon-gamma (IFN-gamma) is known to be involved in this process, the involvement of type I interferons (IFN-alpha/beta) has not been elucidated. We now show that, like IFN-gamma, endogenously produced IFN-alpha/beta was required for the prevention of the growth of primary carcinogen-induced and transplantable tumors. Although tumor cells are important IFN-gamma targets, they are not functionally relevant sites of the actions of the type I interferons. Instead, host hematopoietic cells are critical IFN-alpha/beta targets during development of protective antitumor responses. Therefore, type I interferons are important components of the cancer immunoediting process and function in a way that does not completely overlap the functions of IFN-gamma.

  18. Electrophoretically pure mouse interferon exerts multiple biologic effects.

    PubMed Central

    Gresser, I; De Maeyer-Guignard, J; Tovey, M G; De Maeyer, E

    1979-01-01

    Electrophoretically pure mouse interferon was examined for a number of biologic effects previously ascribed to crude or partially purified interferon preparations. These effects include: inhibition of the growth of a transplantable tumor in mice; inhibition of cell multiplication of mouse tumor cells in vitro; enhancement of the expression of histocompatibility antigens on mouse tumor cells in vitro; inhibition of antibody formation in vitro; inhibition of sensitization to sheep erythrocytes and the expression of delayed type hypersensitivity in mice; enhancement of natural killer cell activity in vivo and in vitro; enhancement of cell sensitivity to the toxicity of poly(I)-poly(C); and enhanced production ("priming") of interferon production in vitro. Our results establish that the molecules responsible for the antiviral action of interferon are also responsible for these varied biologic effects. PMID:291948

  19. Recombinant DNA products: Insulin, interferon and growth hormone

    SciTech Connect

    Bollon, A.P.

    1984-01-01

    This book provides the discussion of products of biotechnology of recombinant DNA. The contents include: Recombinant DNA techniques; isolation, cloning, and expression of genes; from somatostatin to human insulin; yeast; an alternative organism for foreign protein production; background in human interferon; preclinical assessment of biological properties of recombinant DNA derived human interferons; human clinical trials of bacteria-derived human ..cap alpha.. interferon.f large scale production of human alpha interferon from bacteria; direct expression of human growth hormone in escherichia coli with the lipoprotein promoter; biological actions in humans of recombinant DNA synthesized human growth hormone; NIH guidelines for research involving recombinant DNA molecules; appendix; viral vectors and the NHY guidelines; FDA's role in approval and regulation of recombinant DNA drugs; and index.

  20. Beta-interferon inhibits cell infection by Trypanosoma cruzi

    NASA Technical Reports Server (NTRS)

    Kierszenbaum, F.; Sonnenfeld, G.

    1984-01-01

    Beta interferon has been shown to inhibit the capacity of bloodstream forms of the flagellate Trypanosoma cruzi, the causative agent of Chagas' disease, to associate with and infect mouse peritoneal macrophages and rat heart myoblasts. The inhibitory effect was abrogated in the presence of specific antibodies to the interferon. Pretreatment of the parasites with interferon reduced their infectivity for untreated host cells, whereas pretreament of either type of host cell did not affect the interaction. The effect of interferon on the trypanosomes was reversible; the extent of the inhibitory effect was significantly reduced afer 20 min, and was undetectable after 60 min when macrophages were used as host cells. For the myoblasts, 60 min elapsed before the inhibitory effect began to subside and 120 min elapsed before it became insignificant or undetectable.

  1. Consensus interferon and ribavirin in patients with chronic hepatitis C who were nonresponders to pegylated interferon alfa-2b and ribavirin.

    PubMed

    Leevy, Carroll B

    2008-07-01

    Recent studies suggest that consensus interferon and ribavirin is effective in retreating patients with chronic hepatitis C who failed therapy with interferon alfa and ribavirin. The objective of the present study was to assess the efficacy, safety, and tolerability of consensus interferon and ribavirin in patients who did not respond to pegylated interferon alfa-2b and ribavirin. We retrospectively identified 137 consecutive nonresponders to pegylated interferon alfa-2b and ribavirin and initiated patients on daily treatment with consensus interferon 15 mug subcutaneously and weight-based ribavirin for 48 weeks. If patients were HCV RNA negative at 12 weeks, the dose was reduced to 15 mug three times weekly for the remaining 36 weeks. The sustained virologic response rate was 37%. Daily consensus interferon therapy was safe and well tolerated in all patients. No dose reductions were required, and no patient discontinued therapy. Further studies of consensus interferon and ribavirin in nonresponders are warranted.

  2. Chlorite-Oxidized Amylose as an Adjuvant for Interferon Production

    PubMed Central

    Levy, Hilton B.; Duenwald, Jeff; Buckler, Charles E.

    1973-01-01

    Chlorite-oxidized amylose (COAM), when given intraperitoneally to mice and to cats, increased the titer of serum interferon subsequently induced by polyinosinic·polycytidylic acid (In·Cn). Increases ranged from 6- to 100-fold. Maximal effect was observed when COAM was given 3 h prior to In·Cn. COAM given intravenously prior to Newcastle disease virus also significantly increased serum interferon titers. PMID:4713694

  3. Human Cytokinome Analysis for Interferon Response

    PubMed Central

    Al-Yahya, Suhad; Mahmoud, Linah; Al-Zoghaibi, Fahad; Al-Tuhami, Abdullah; Amer, Haithem; Almajhdi, Fahad N.; Polyak, Stephen J.

    2015-01-01

    ABSTRACT Cytokines are a group of small secreted proteins that mediate a diverse range of immune and nonimmune responses to inflammatory and microbial stimuli. Only a few of these cytokines mount an antiviral response, including type I, II, and III interferons (IFNs). During viral infections and under inflammatory conditions, a number of cytokines and chemokines are coproduced with IFN; however, no systematic study exists on the interactions of the cytokine repertoire with the IFN response. Here, we performed the largest cytokine and chemokine screen (the human cytokinome, with >240 members) to investigate their modulation of type I and type II IFN responses in a cell line model. We evaluated the cytokine activities in both IFN-stimulated response element (ISRE) and IFN-γ activation sequence (GAS) reporter systems. Several cytokine clusters that augment either or both ISRE- and GAS-mediated responses to IFNs were derived from the screen. We identified novel modulators of IFN response—betacellulin (BTC), interleukin 11 (IL-11), and IL-17F—that caused time-dependent induction of the IFN response. The ability to induce endogenous IFN-β and IFN-stimulated genes varies among these cytokines and was largely dependent on Stat1, as assessed by Stat1 mutant fibroblasts. Certain cytokines appear to augment the IFN-β response through the NF-κB pathway. The novel IFN-like cytokines augmented the antiviral activity of IFN-α against several RNA viruses, including encephalomyocarditis virus, vesicular stomatitis virus, and influenza virus, in susceptible cell lines. Overall, the study represents a large-scale analysis of cytokines for enhancing the IFN response and identified cytokines capable of enhancing Stat1, IFN-induced gene expression, and antiviral activities. IMPORTANCE Innate immunity to viruses is an early defense system to ward off viruses. One mediator is interferon (IFN), which activates a cascade of biochemical events that aim to control the virus life

  4. Interferon gamma release assays: principles and practice.

    PubMed

    Lalvani, Ajit; Pareek, Manish

    2010-04-01

    The last decade has witnessed significant advances in mycobacterial genomics and cellular research which have resulted in the development of two new blood tests, the enzyme-linked immunospot assay (ELISpot) (TSPOT.TB, Oxford Immunotec, Oxford, UK) and the enzyme-linked immunosorbent assay (ELISA) (QuantiFERON-TB Gold In-Tube, Cellestis, Carnegie, Australia). These tests, which are collectively known as interferon gamma release assays (IGRAs), detect latent tuberculosis infection (LTBI) by measuring interferon (IFN)-gamma release in response to antigens present in Mycobacterium tuberculosis, but not bacille Calmette-Guerin (BCG) vaccine and most nontuberculous mycobacteria. This is done through enumeration of IFN-gamma-secreting T cells (ELISpot) or by measurement of IFN-gamma concentration (ELISA). The evidence base for these tests has expanded rapidly and now demonstrates that IGRAs are more specific than the tuberculin skin test (TST) as they are not confounded by previous BCG vaccination. In addition, with active tuberculosis (TB) as a surrogate for LTBI, it appears that the ELISA has a similar sensitivity to the TST, whereas the ELISpot is more sensitive. Using degree of exposure to TB as a surrogate for LTBI, both assays correlate at least as well with TB exposure as the TST. Recent longitudinal data have now demonstrated the prognostic power of positive IGRA results in recent contacts for the subsequent progression to active TB. Deployment of IGRAs, driven by new guidelines internationally, will impact on clinical practice in several ways. Their high specificity means that BCG-vaccinated individuals with a false-positive TST will not receive unnecessary preventive treatment, whereas improved sensitivity in individuals with weakened cellular immunity at highest risk of progressing to active TB (for example HIV-positive individuals) enables more reliable targeted testing and treatment of these vulnerable groups. The role of IGRAs in active TB is less clear but

  5. Axonal interferon responses and alphaherpesvirus neuroinvasion

    NASA Astrophysics Data System (ADS)

    Song, Ren

    Infection by alphaherpesviruses, including herpes simplex virus (HSV) and pseudorabies virus (PRV), typically begins at a peripheral epithelial surface and continues into the peripheral nervous system (PNS) that innervates this tissue. Inflammatory responses are induced at the infected peripheral site prior to viral invasion of the PNS. PNS neurons are highly polarized cells with long axonal processes that connect to distant targets. When the peripheral tissue is first infected, only the innervating axons are exposed to this inflammatory milieu, which include type I interferon (e.g. IFNbeta) and type II interferon (i.e. IFNgamma). IFNbeta can be produced by all types of cells, while IFNgamma is secreted by some specific types of immune cells. And both types of IFN induce antiviral responses in surrounding cells that express the IFN receptors. The fundamental question is how do PNS neurons respond to the inflammatory milieu experienced only by their axons. Axons must act as potential front-line barriers to prevent PNS infection and damage. Using compartmented cultures that physically separate neuron axons from cell bodies, I found that pretreating isolated axons with IFNbeta or IFNgamma significantly diminished the number of HSV-1 and PRV particles moving from axons to the cell bodies in an IFN receptor-dependent manner. Furthermore, I found the responses in axons are activated differentially by the two types of IFNs. The response to IFNbeta is a rapid, axon-only response, while the response to IFNgamma involves long distance signaling to the PNS cell body. For example, exposing axons to IFNbeta induced STAT1 phosphorylation (p-STAT1) only in axons, while exposure of axons to IFNgamma induced p-STAT1 accumulation in distant cell body nuclei. Blocking transcription in cell bodies eliminated IFNgamma-, but not IFNbeta-mediated antiviral effects. Proteomic analysis of IFNbeta- or IFNgamma-treated axons identified several differentially regulated proteins. Therefore

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

    DTIC Science & Technology

    1988-01-01

    acid solubilized with poly-L-Iysine in carboxy methyl cellulose (pICLC) in treating metastatic disease was investigated by comparing effector cell...polycytidylic acid, poly(l.C)-LC or pICLC, poly(lC) solubilized with poly-L- lysine in carboxymethyl cellulose . Paul L. Black’s present address is Virology...with poly-L-lysine and solubilized with carboxymethyl cellulose [poly(IC)-LC] alleviates this problem [44,45]. Both recombinant murine interferon-gamma

  7. Interferons: Success in anti-viral immunotherapy

    PubMed Central

    Lin, Fan-ching; Young, Howard A.

    2014-01-01

    The interferons (IFNs) are glycoproteins with strong antiviral activities that represent one of the first lines of host defense against invading pathogens. These proteins are classified into three groups, Type I, II and III IFNs, based on the structure of their receptors on the cell surface. Due to their ability to modulate immune responses, they have become attractive therapeutic options to control chronic virus infections. In combination with other drugs, Type I IFNs are considered a “standard of care” in suppressing Hepatitis C (HCV) and Hepatitis B (HBV) infections, while Type III IFN has generated encouraging results as a treatment for HCV infection in phase III clinical trials. However, though effective, using IFNs as a treatment is not without the need for caution. IFNs are such powerful cytokines that affect a wide array of cell types; as a result, patients usually experience unpleasant symptoms, with a percentage of patients suffering system wide effects. Thus, constant monitoring is required for patients treated with IFN in order to reach the treatment goals of suppressing virus infection and maintaining quality of life. PMID:25156421

  8. Avian Interferons and Their Antiviral Effectors

    PubMed Central

    Santhakumar, Diwakar; Rubbenstroth, Dennis; Martinez-Sobrido, Luis; Munir, Muhammad

    2017-01-01

    Interferon (IFN) responses, mediated by a myriad of IFN-stimulated genes (ISGs), are the most profound innate immune responses against viruses. Cumulatively, these IFN effectors establish a multilayered antiviral state to safeguard the host against invading viral pathogens. Considerable genetic and functional characterizations of mammalian IFNs and their effectors have been made, and our understanding on the avian IFNs has started to expand. Similar to mammalian counterparts, three types of IFNs have been genetically characterized in most avian species with available annotated genomes. Intriguingly, chickens are capable of mounting potent innate immune responses upon various stimuli in the absence of essential components of IFN pathways including retinoic acid-inducible gene I, IFN regulatory factor 3 (IRF3), and possibility IRF9. Understanding these unique properties of the chicken IFN system would propose valuable targets for the development of potential therapeutics for a broader range of viruses of both veterinary and zoonotic importance. This review outlines recent developments in the roles of avian IFNs and ISGs against viruses and highlights important areas of research toward our understanding of the antiviral functions of IFN effectors against viral infections in birds. PMID:28197148

  9. The ebolavirus VP24 interferon antagonist

    PubMed Central

    Zhang, Adrianna P.P.; Abelson, Dafna M.; Bornholdt, Zachary A.; Liu, Tong; Woods, Jr, Virgil L.; Saphire, Erica Ollmann

    2012-01-01

    Suppression during the early phases of the immune system often correlates directly with a fatal outcome for the host. The ebolaviruses, some of the most lethal viruses known, appear to cripple initial stages of the host defense network via multiple distinct paths. Two of the eight viral proteins are critical for immunosuppression. One of these proteins is VP35, which binds double-stranded RNA and antagonizes several antiviral signaling pathways.1,2 The other protein is VP24, which binds transporter molecules to prevent STAT1 translocation.3 A more recent discovery is that VP24 also binds STAT1 directly,4 suggesting that VP24 may operate in at least two separate branches of the interferon pathway. New crystal structures of VP24 derived from pathogenic and nonpathogenic ebolaviruses reveal its novel, pyramidal fold, upon which can be mapped sites required for virulence and for STAT1 binding. These structures of VP24, and new information about its direct binding to STAT1, provide avenues by which we may explore its many roles in the viral life cycle, and reasons for differences in pathogenesis among the ebolaviruses. PMID:23076242

  10. The Interferon Stimulated Gene 54 Promotes Apoptosis*

    PubMed Central

    Stawowczyk, Marcin; Van Scoy, Sarah; Kumar, K. Prasanna; Reich, Nancy C.

    2011-01-01

    The ability of interferons (IFNs) to inhibit viral replication and cellular proliferation is well established, but the specific contribution of each IFN-stimulated gene (ISG) to these biological responses remains to be completely understood. In this report we demonstrate that ISG54, also known as IFN-induced protein with tetratricopeptide repeats 2 (IFIT2), is a mediator of apoptosis. Expression of ISG54, independent of IFN stimulation, elicits apoptotic cell death. Cell death and apoptosis were quantified by propidium iodide uptake and annexin-V staining, respectively. The activation of caspase-3, a key mediator of the execution phase of apoptosis, was clearly apparent in cells expressing ISG54. The anti-apoptotic B cell lymphoma-xl (Bcl-xl) protein inhibited the apoptotic effects of ISG54 as did the anti-apoptotic adenoviral E1B-19K protein. In addition, ISG54 was not able to promote cell death in the absence of pro-apoptotic Bcl family members, Bax and Bak. Analyses of binding partners of ISG54 revealed association with two homologous proteins, ISG56/IFIT1 and ISG60/IFIT3. In addition, ISG60 binding negatively regulates the apoptotic effects of ISG54. The results reveal a previously unidentified role of ISG54 in the induction of apoptosis via a mitochondrial pathway and shed new light on the mechanism by which IFN elicits anti-viral and anti-cancer effects. PMID:21190939

  11. Cytokine therapeutics: lessons from interferon alpha.

    PubMed Central

    Gutterman, J U

    1994-01-01

    Cytokines are soluble proteins that allow for communication between cells and the external environment. Interferon (IFN) alpha, the first cytokine to be produced by recombinant DNA technology, has emerged as an important regulator of growth and differentiation, affecting cellular communication and signal transduction pathways as well as immunological control. This review focuses on the biological and clinical activities of the cytokine. Originally discovered as an antiviral substance, the efficacy of IFN-alpha in malignant, viral, immunological, angiogenic, inflammatory, and fibrotic diseases suggests a spectrum of interrelated pathophysiologies. The principles learned from in vivo studies will be discussed, particularly hairy cell leukemia, chronic myelogenous leukemia, certain angiogenic diseases, and hepatitis. After the surprising discovery of activity in a rare B-cell neoplasm, IFN-alpha emerged as a prototypic tumor suppressor protein that represses the clinical tumorigenic phenotype in some malignancies capable of differentiation. Regulatory agencies throughout the world have approved IFN-alpha for treatment of 13 malignant and viral disorders. The principles established with this cytokine serve as a paradigm for future development of natural proteins for human disease. PMID:8108387

  12. Interferon regulatory factor 6 regulates keratinocyte migration

    PubMed Central

    Biggs, Leah C.; Naridze, Rachelle L.; DeMali, Kris A.; Lusche, Daniel F.; Kuhl, Spencer; Soll, David R.; Schutte, Brian C.; Dunnwald, Martine

    2014-01-01

    ABSTRACT Interferon regulatory factor 6 (Irf6) regulates keratinocyte proliferation and differentiation. In this study, we tested the hypothesis that Irf6 regulates cellular migration and adhesion. Irf6-deficient embryos at 10.5 days post-conception failed to close their wound compared with wild-type embryos. In vitro, Irf6-deficient murine embryonic keratinocytes were delayed in closing a scratch wound. Live imaging of the scratch showed deficient directional migration and reduced speed in cells lacking Irf6. To understand the underlying molecular mechanisms, cell–cell and cell–matrix adhesions were investigated. We show that wild-type and Irf6-deficient keratinocytes adhere similarly to all matrices after 60 min. However, Irf6-deficient keratinocytes were consistently larger and more spread, a phenotype that persisted during the scratch-healing process. Interestingly, Irf6-deficient keratinocytes exhibited an increased network of stress fibers and active RhoA compared with that observed in wild-type keratinocytes. Blocking ROCK, a downstream effector of RhoA, rescued the delay in closing scratch wounds. The expression of Arhgap29, a Rho GTPase-activating protein, was reduced in Irf6-deficient keratinocytes. Taken together, these data suggest that Irf6 functions through the RhoA pathway to regulate cellular migration. PMID:24777480

  13. Interferon Alpha Association with Neuromyelitis Optica

    PubMed Central

    Asgari, Nasrin; Voss, Anne; Kyvik, Kirsten Ohm; Thue Lillevang, Soeren

    2013-01-01

    Interferon-alpha (IFN-α) has immunoregulatory functions in autoimmune inflammatory diseases. The goal of this study was to determine occurrence and clinical consequences of IFN-α in neuromyelitis optica (NMO) patients. Thirty-six NMO and 41 multiple sclerosis (MS) patients from a population-based retrospective case series were included. Expanded Disability Status Scale (EDSS) score and MRI findings determined disease activity. Linear regression was used to assess the effects of the level of IFN-α on disability (EDSS). IFN-α was determined by sensitive ELISA assays. IFN-α was detectable in sera from 9/36 NMO patients, significantly more often than in the MS group (2/41) (P = 0.0197). A higher frequency of IFN-α was observed in NMO patients with acute relapse compared to NMO patients in remission (P < 0.001) and compared to the MS patients with relapse (P = 0.010). In NMO patients, the levels of IFN-α were significantly associated with EDSS (P = 0.0062). It may be concluded that IFN-α was detectable in a subgroup of NMO patients. Association of IFN-α levels with clinical disease activity and severity suggests a role for IFN-α in disease perpetuation and may provide a plausible explanation for a negative effect of IFN-1 treatment in NMO patients. PMID:24348680

  14. Immunomodulatory Effects of Interferons in Malignancies

    PubMed Central

    Bekisz, Joseph; Sato, Yuki; Johnson, Chase; Husain, Syed R.; Puri, Raj K.

    2013-01-01

    Investigation of the antitumor and immunomodulatory activities of interferon (IFN) began shortly after the cytokine was discovered in 1957. Early work showed a direct correlation between administration of IFN and inhibition of symptoms associated with virally induced leukemia in mice as well as an increase in their survival time. Subsequent studies with purified IFNs confirmed the direct and indirect stimulation of immune cells, resulting in antitumor activities of IFN. Clinically, IFN-alphas (αs) have been shown to have activity against a variety of tumors. Initially, the U.S. Food and Drug Administration licensed 2 recombinant IFN-αs for the treatment of hairy-cell leukemia and then later for several other cancers. The success rate seen with IFNs and certain tumors has been varied. Unfortunately, some neoplasms show no response to IFN. Monocytes/macrophages play an important role in cancer progression. Monocytes in combination with IFN may be an important therapy for several cancers. This article focuses on the role of IFN and monocytes alone or in combination in affecting malignancies. PMID:23570381

  15. Avian Interferons and Their Antiviral Effectors.

    PubMed

    Santhakumar, Diwakar; Rubbenstroth, Dennis; Martinez-Sobrido, Luis; Munir, Muhammad

    2017-01-01

    Interferon (IFN) responses, mediated by a myriad of IFN-stimulated genes (ISGs), are the most profound innate immune responses against viruses. Cumulatively, these IFN effectors establish a multilayered antiviral state to safeguard the host against invading viral pathogens. Considerable genetic and functional characterizations of mammalian IFNs and their effectors have been made, and our understanding on the avian IFNs has started to expand. Similar to mammalian counterparts, three types of IFNs have been genetically characterized in most avian species with available annotated genomes. Intriguingly, chickens are capable of mounting potent innate immune responses upon various stimuli in the absence of essential components of IFN pathways including retinoic acid-inducible gene I, IFN regulatory factor 3 (IRF3), and possibility IRF9. Understanding these unique properties of the chicken IFN system would propose valuable targets for the development of potential therapeutics for a broader range of viruses of both veterinary and zoonotic importance. This review outlines recent developments in the roles of avian IFNs and ISGs against viruses and highlights important areas of research toward our understanding of the antiviral functions of IFN effectors against viral infections in birds.

  16. Interferons: Success in anti-viral immunotherapy.

    PubMed

    Lin, Fan-ching; Young, Howard A

    2014-08-01

    The interferons (IFNs) are glycoproteins with strong antiviral activities that represent one of the first lines of host defense against invading pathogens. These proteins are classified into three groups, Type I, II and III IFNs, based on the structure of their receptors on the cell surface. Due to their ability to modulate immune responses, they have become attractive therapeutic options to control chronic virus infections. In combination with other drugs, Type I IFNs are considered as "standard of care" in suppressing Hepatitis C (HCV) and Hepatitis B (HBV) infections, while Type III IFN has generated encouraging results as a treatment for HCV infection in phase III clinical trials. However, though effective, using IFNs as a treatment is not without the need for caution. IFNs are such powerful cytokines that affect a wide array of cell types; as a result, patients usually experience unpleasant symptoms, with a percentage of patients suffering system wide effects. Thus, constant monitoring is required for patients treated with IFN in order to reach the treatment goals of suppressing virus infection and maintaining quality of life. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Human leukocyte interferon: structural and biological relatedness to adrenocorticotropic hormone and endorphins.

    PubMed Central

    Blalock, J E; Smith, E M

    1980-01-01

    Anti-alpha-corticotropin [anti-ACTH alpha (1-13)](also alpha-melanotropin) and anti-gamma-endorphin antisera neutralized human leukocyte interferon activity but not fibroblast interferon activity. Human leukocyte interferon was not neutralized by anti-human lutenizing hormone (lutropin) or follicle-stimulating hormone (follitropin) antisra. Conversely, antisera to human leukocyte interferon neutralized ACTH activity. The neturalization of human leukocyte interferon by anti-human leukocyte interferon serum was partially blocked by ACTH. These studies show strong antigenic relatedness among human leukocyte interferon, ACTH, and endorphins, implying that there are underlying structural similarities. Structural relatedness is shown by pepsin cleavage of ACTH activity from human leukocyte interferon. The implication for the natural functions of human leukocyte interferon are discussed. PMID:6160589

  18. Transforming growth factor beta 1, a cytokine with regenerative functions

    PubMed Central

    Sulaiman, Wale; Nguyen, Doan H.

    2016-01-01

    We review the biology and role of transforming growth factor beta 1 (TGF-β1) in peripheral nerve injury and regeneration, as it relates to injuries to large nerve trunks (i.e., sciatic nerve, brachial plexus), which often leads to suboptimal functional recovery. Experimental studies have suggested that the reason for the lack of functional recovery resides in the lack of sufficient mature axons reaching their targets, which is a result of the loss of the growth-supportive environment provided by the Schwann cells in the distal stump of injured nerves. Using an established chronic nerve injury and delayed repair animal model that accurately mimics chronic nerve injuries in humans, we summarize our key findings as well as others to better understand the pathophysiology of poor functional recovery. We demonstrated that 6 month TGF-β1 treatment for chronic nerve injury significantly improved Schwann cell capacity to support axonal regeneration. When combined with forskolin, the effect was additive, as evidenced by a near doubling of regenerated axons proximal to the repair site. We showed that in vivo application of TGF-β1 and forskolin directly onto chronically injured nerves reactivated chronically denervated Schwann cells, induced their proliferation, and upregulated the expression of regeneration-associated proteins. The effect of TGF-β1 and forskolin on old nerve injuries is quite impressive and the treatment regiment appears to mediate a growth-supportive milieu in the injured peripheral nerves. In summary, TGF-β1 and forskolin treatment reactivates chronically denervated Schwann cells and could potentially be used to extend and prolong the regenerative responses to promote axonal regeneration. PMID:27904475

  19. Opposing Roles for Interferon Regulatory Factor-3 (IRF-3) and Type I Interferon Signaling during Plague

    PubMed Central

    Patel, Ami A.; Lee-Lewis, Hanni; Anderson, Deborah M.

    2012-01-01

    Type I interferons (IFN-I) broadly control innate immunity and are typically transcriptionally induced by Interferon Regulatory Factors (IRFs) following stimulation of pattern recognition receptors within the cytosol of host cells. For bacterial infection, IFN-I signaling can result in widely variant responses, in some cases contributing to the pathogenesis of disease while in others contributing to host defense. In this work, we addressed the role of type I IFN during Yersinia pestis infection in a murine model of septicemic plague. Transcription of IFN-β was induced in vitro and in vivo and contributed to pathogenesis. Mice lacking the IFN-I receptor, Ifnar, were less sensitive to disease and harbored more neutrophils in the later stage of infection which correlated with protection from lethality. In contrast, IRF-3, a transcription factor commonly involved in inducing IFN-β following bacterial infection, was not necessary for IFN production but instead contributed to host defense. In vitro, phagocytosis of Y. pestis by macrophages and neutrophils was more effective in the presence of IRF-3 and was not affected by IFN-β signaling. This activity correlated with limited bacterial growth in vivo in the presence of IRF-3. Together the data demonstrate that IRF-3 is able to activate pathways of innate immunity against bacterial infection that extend beyond regulation of IFN-β production. PMID:22911267

  20. Validation of an interferon stimulatory response element reporter gene assay for quantifying type I interferons.

    PubMed

    McCoski, S R; Xie, M; Hall, E B; Mercadante, P M; Spencer, T E; Lonergan, P; Ealy, A D

    2014-04-01

    The goal of this work was to develop a virus-free, cell-based interferon (IFN) bioassay and determine the utility of this assay on biological samples that contained IFN-τ, the trophoblast-secreted maternal recognition of pregnancy factor in ruminants. Madin-Darby bovine kidney cells were transduced with lentiviral particles that contained a firefly luciferase reporter construct driven by an IFN stimulatory response element (ISRE). Stably transduced cells were selected with the use of puromycin resistance. A linear, dose-responsive response was detected with human IFN-α and ovine IFN-τ. Interferon activity was detected in conditioned media from bovine trophoblast cells and uterine flushes collected from sheep and cattle. Activity also was detected in media collected after individual or small group culture of in vitro-produced bovine blastocysts at day 8 to 10 after fertilization. In summary, this IFN stimulatory response element-reporter assay may be used as an alternative to virus-dependent, cytopathic assays. It contains a similar sensitivity to IFNs and can be completed in a shorter time than cytopathic assays and does not require heightened biosafety conditions after cell transduction. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Interferons-beta versus glatiramer acetate for relapsing-remitting multiple sclerosis.

    PubMed

    La Mantia, Loredana; Di Pietrantonj, Carlo; Rovaris, Marco; Rigon, Giulio; Frau, Serena; Berardo, Francesco; Gandini, Anna; Longobardi, Anna; Weinstock-Guttman, Bianca; Vaona, Alberto

    2016-11-24

    Interferons-beta (IFNs-beta) and glatiramer acetate (GA) were the first two disease-modifying therapies (DMTs) approved 20 years ago for the treatment of multiple sclerosis (MS). DMTs' prescription rates as first or switching therapies and their costs have both increased substantially over the past decade. As more DMTs become available, the choice of a specific DMT should reflect the risk/benefit profile, as well as the impact on quality of life. As MS cohorts enrolled in different studies can vary significantly, head-to-head trials are considered the best approach for gaining objective reliable data when two different drugs are compared. The purpose of this systematic review is to summarise available evidence on the comparative effectiveness of IFNs-beta and GA on disease course through the analysis of head-to-head trials.This is an update of the Cochrane review 'Interferons-beta versus glatiramer acetate for relapsing-remitting multiple sclerosis' (first published in the Cochrane Library 2014, Issue 7). To assess whether IFNs-beta and GA differ in terms of safety and efficacy in the treatment of people with relapsing-remitting (RR) MS. We searched the Trials Register of the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group (08 August 2016) and the reference lists of retrieved articles. We contacted authors and pharmaceutical companies. Randomised controlled trials (RCTs) comparing directly IFNs-beta versus GA in study participants affected by RRMS. We used standard methodological procedures as expected by Cochrane. Six trials were included and five trials contributed to this review with data. A total of 2904 participants were randomly assigned to IFNs (1704) and GA (1200). The treatment duration was three years for one study, two years for the other four RCTs while one study was stopped early (after one year). The IFNs analysed in comparison with GA were IFN-beta 1b 250 mcg (two trials, 933 participants), IFN-beta 1a 44 mcg (three trials, 466

  2. Inhibition of Interferons by Ectromelia Virus

    PubMed Central

    Smith, Vincent P.; Alcami, Antonio

    2002-01-01

    Ectromelia virus (EV) is an orthopoxvirus (OPV) that causes mousepox, a severe disease of laboratory mice. Mousepox is a useful model of OPV infection because EV is likely to be a natural mouse pathogen, unlike its close relatives vaccinia virus (VV) and variola virus. Several studies have highlighted the importance of mouse interferons (IFNs) in resistance to and recovery from EV infection, but little is known of the anti-IFN strategies encoded by the virus itself. We have determined that 12 distinct strains and isolates of EV encode soluble, secreted receptors for IFN-γ (vIFN-γR) and IFN-α/β (vIFN-α/βR) that are homologous to those identified in other OPVs. We demonstrate for the first time that the EV vIFN-γR has the unique ability to inhibit the biological activity of mouse IFN-γ. The EV vIFN-α/βR was a potent inhibitor of human and mouse IFN-α and human IFN-β but, surprisingly, was unable to inhibit mouse IFN-β. The replication of all of the EVs included in our study and of cowpox virus was more resistant than VV to the antiviral effects induced in mouse L-929 cells by IFN-α/β and IFN-γ. Sequencing studies showed that this EV resistance is likely to be partly mediated by the double-stranded-RNA-binding protein encoded by an intact EV homolog of the VV E3L gene. The absence of a functional K3L gene, which encodes a viral eIF-2α homolog, in EV suggests that the virus encodes a novel mechanism to counteract the IFN response. These findings will facilitate future studies of the role of viral anti-IFN strategies in mousepox pathogenesis. Their significance in the light of earlier data on the role of IFNs in mousepox is discussed. PMID:11773388

  3. Bilateral Ischemic Optic Neuropathy Developed under Interferon Therapy.

    PubMed

    Selcukbiricik, Fatih; Tural, Deniz; Senel, Tuba Elif; Sarıca, Ahmet; Soyluk, Ozlem; Serdengecti, Suheyla

    2012-01-01

    Introduction. Interferon is a glycoprotein produced by assigned cells of immune system. It has been used in many different diseases. Although flu-like syndrome, myalgia, rash, hypotension, thrombocytopenia and peripheral neuropathy due to interferon use are encountered frequently, ocular side effects are rare, generally mild and transient. Case Report. 47-year-old female patient, presented with a mass lesion in right renal pelvis. Right radical nephrectomy was applied and the histopathological examination was consistent with papillary renal cell carcinoma. Interferon alpha treatment was started subcutaneously at the dose of 5 MIU/3 times in a week. Four weeks after the interferon therapy, suddenly bilateral visual loss developed. We discussed the diagnosis, followup, and treatment of the patient who developed irreversible ischemic optic neuropathy and had no previous known primary systemic disease to cause this condition. Conclusion. We suggest that patients should be screened for risk factors causing optic ischemic neuropathy, before interferon therapy. Although there was no adequate information in the literature for the followup, patients should be monitorized before, 1 month after, and 2 months after the treatment. And if there is no complication, we suggest that they should be followed up at 3-month intervals.

  4. Controlled-release interferon alpha 2b, a new member of the interferon family for the treatment of chronic hepatitis C.

    PubMed

    Jansen, Peter L M; De Bruijne, Joep

    2012-01-01

    Combination therapy with pegylated interferon alpha (Peg-interferon) and ribavirin is currently the cornerstone of antiviral therapy for chronic hepatitis C. Monotherapy with Peg-interferon still is important for the treatment of chronic hepatitis B. With the advent of new therapies, protease inhibitors for chronic hepatitis C and nucleotide inhibitors for chronic hepatitis B, there remains a need for interferon-based therapies. The side effects of Peg-interferon are a main disadvantage and represent a stumbling block for many patients to enter and continue therapy. In this review, the authors will discuss controlled-release interferon alpha 2b (CR2b) (Locteron®, Biolex Therapeutics, Pittsboro, NC, USA), a new slow-release interferon alpha 2b preparation for the treatment of chronic viral hepatitis. Other alternative interferons will also be discussed. CR2b is a slow-release microsphere preparation for the administration of plant-derived recombinant human interferon alpha 2b. Compared with Peg-interferon, treatment with CR2b shows less flu-like reactions and less depression, and is at least as effective as conventional Peg-interferon-based therapy in patients with chronic hepatitis C. CR2b has the added advantage of biweekly instead of once weekly administration. CR2b appears to cause more neutropenia than Peg-interferon alpha 2b. This may be due to higher trough serum levels of CR2b at the end of a dosing interval. The bone marrow effects of CR2b closely resemble those published for the registered Peg-interferon alpha 2a. CR2b appears to have at least comparable efficacy with fewer side effects than current registered Peg-interferons.

  5. Altered pharmacological properties of liposome-associated human interferon-alpha.

    PubMed Central

    Eppstein, D A; Stewart, W E

    1982-01-01

    Human interferon-alpha was associated in different ways with positively (stearylamine) and negatively (phosphatidylserine) charged phosphatidylcholine multilamellar vesicles, depending on the presence or absence of a cholesterol component. Inclusion of cholesterol resulted in interferon that was significantly (P = 0.0001) more deeply internalized within the liposomes, such that detergent disruption was necessary before most of the interferon activity was expressed. Interferon was stably associated with stearylamine-containing liposomes, both with and without a cholesterol component. However, inclusion of cholesterol in the phosphatidylserine-containing liposomes was necessary for stable association of the interferon for more than 2 days at 4 degrees C or for more than 24 h at 37 degrees C. After intramuscular injection into mice, liposome-associated interferon in reverse-phase evaporation vesicles was retained at the local site of injection significantly longer than free interferon. Even 3 days after intramuscular injection, stearylamine-containing liposomes with or without cholesterol resulted in local interferon levels that were comparable to the peak levels obtained 2 to 4 h after free interferon was injected. In contrast, free interferon was not detectable in the local muscles 24 h after injection of 10(4.6) U. Liposomes containing phosphatidylserine and cholesterol resulted in intermediate levels of local interferon retention; without a cholesterol component, phosphatidylserine-containing liposomes resulted in no increased local interferon retention compared with the results when free interferon was injected. PMID:6176726

  6. Adherence to treatment of chronic hepatitis C: from interferon containing regimens to interferon and ribavirin free regimens

    PubMed Central

    Younossi, Zobair M.; Stepanova, Maria; Henry, Linda; Nader, Fatema; Younossi, Youssef; Hunt, Sharon

    2016-01-01

    Abstract Patients’ experience during treatment may affect treatment adherence. Our aim was to assess the impact of patient-reported outcomes (PROs) on adherence to different anti-hepatitis C virus (HCV) regimens. Clinical, demographic, and PRO data (short form-36 [SF-36], chronic liver disease questionnaire-hepatitis C version [CLDQ-HCV], functional assessment of chronic illness therapy-fatigue [FACIT-F], work productivity and activity impairment: specific health problem [WPAI:SHP]) from 13 multinational clinical trials of anti-HCV treatment were available. Treatment adherence was defined as >80% of prescribed doses taken. Included were 4825 HCV patients. Regimens were grouped into: interferon- and ribavirin (RBV)-containing (±sofosbuvir [SOF]), interferon-free RBV-containing (RBV + SOF ± ledipasvir [LDV]), and interferon-free RBV-free (LDV/SOF). The adherence to these regimens were 77.6%, 84.3%, and 96.2%, respectively (P < 0.0001). Nonadherent patients were more likely to be unemployed and to have a greater PRO impairment at baseline (up to −5.3% lower PRO scores, P < 0.0001). During treatment with interferon- or RBV-based regimens, nonadherent patients experienced lower PROs and had larger decrements from their baseline PRO scores. In contrast, there were no significant declines in PRO scores (all P > 0.05) for the small number of patients who were nonadherent to LDV/SOF. In multivariate analysis, being treatment-naive, longer treatment duration, and receiving an interferon- or RBV-containing regimen were associated with a lower likelihood of adherence (all P < 0.003). Better baseline and on-treatment PRO scores were associated with a higher likelihood of adherence to interferon and RBV. The use of interferon and/or RBV, longer duration of treatment, and lower baseline and on-treatment PRO scores were linked to a decreased likelihood of being adherent to interferon + RBV-containing or interferon-free RBV-containing antiviral

  7. Role of interferon in resistance and immunity to protozoa

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, G.; Degee, A. L. W.; Mansfield, J. M.; Newsome, A. L.; Arnold, R. R.

    1985-01-01

    Production of interferon (I) in response to protozoan infection, and the interferon-mediated inhibition of parasite replication were studied in order to determine if these effects may be related to immunologic-mediated resistance of the hosts. Two extracellular parasites-Trypanosoma brucei rhodesiense and Naegleria fowlei were used. Upon infection with the trypanosome, only resistant strains of mice produced I. An early peak of alpha/beta I is followed by appearance of gamma I, which coincided with antibody production and a drop in parasitemia. In case of the amoeba, pretreatment of its suspension with alpha/beta I inhibits its replication in vitro, and appears to protect mice from the infection and the disease. It is proposed that production of interferon, with its regulatory effect on the immune responses, may play a major role in regulating the processes of protozoan-caused diseases.

  8. Rhabdomyolysis and interferon-β: case report and short review.

    PubMed

    Jerman, Alexander; Kovač, Damjan; Večerić-Haler, Željka; Hočevar, Alojzija; Ota, Ajda; Banović, Sanela; Lindič, Jelka

    We present a case of acute rhabdomyolysis in the setting of interferon-β treatment and concomitant pomelo juice ingestion, with concern of possible pharmacological interaction, which has not yet been described in the literature. A young Caucasian female with multiple sclerosis on chronic therapy with interferon-β presented with acute rhabdomyolysis after mild exercise and concomitant ingestion of pomelo extract. After stopping the suspected drugs, the signs of rhabdomyolysis diminished, the subsequent course was favorable. The most probable cause of rhabdomyolysis in our patient could have been the combination of interferon effect, which down-regulates P450 expression, with inhibition of the P450 activity by furanocoumarin derivatives from pomelo juice. Therefore, patients treated with drugs that have a possible interaction with inhibitors of cytochrome P450 should be warned against pomelo ingestion.
.

  9. The role of type I interferons in TLR responses.

    PubMed

    Noppert, Susie J; Fitzgerald, Katherine A; Hertzog, Paul J

    2007-01-01

    Recent advances in unravelling the complexities of the signalling pathways that constitute innate immunity have highlighted type I interferon as a key component in the response to infection. Here we focus on the emerging field of pattern-recognition receptor signalling, specifically Toll-like receptors and retinoic acid inducible gene-like helicases, from the perspective of this 50-year-old cytokine. The type I interferon gene family encompasses more than 20 subtypes, whose nature and properties have been extensively studied during its relatively long history. In this review we update and integrate available data on the mechanics of activation of the interferon genes and the role of this cytokine family in the innate immune response.

  10. The effect of lead on immune and viral interferon production.

    PubMed Central

    Blakley, B R; Archer, D L; Osborne, L

    1982-01-01

    Female BDF1 mice were exposed to lead acetate in the drinking water at concentrations ranging form 0 to 1000 micrograms/mL lead for three weeks. The mice tolerated these levels of lead exposure without exhibiting signs of clinical toxicity. Weight gains were not affected by lead exposure. The production of viral interferon induced by the oral administration of tilorone was not altered by lead exposure. The T-lymphocyte mitogens concanavalin A, phytohemagglutinin and staphylococcal enterotoxin A induced immune interferon to varying degrees, with concanavalin A and staphylococcal enterotoxin A exhibiting the most potent induction capabilities. The production of immune interferon induced by T-lymphocyte mitogens was not suppressed by lead exposure. PMID:6176302

  11. Antiviral activities of hybrids of two major human leukocyte interferons.

    PubMed Central

    Weck, P K; Apperson, S; Stebbing, N; Gray, P W; Leung, D; Shepard, H M; Goeddel, D V

    1981-01-01

    Four hybrid human leukocyte interferon (LeIF or IFN-alpha) genes have been constructed by in vitro recombination of LeIF-A (IFN-alpha 2) and LeIF-D (IFN-alpha 1) genes at common restriction endonuclease sites located within their coding regions. These hybrid genes have been expressed in E. coli under trp promoter control. The interferons produced [LeIF-AD (BglII), -AD (PvuII), -DA (BglII), -DA (PvuII)] have antiviral properties distinct from the parental molecules LeIF-A and -D, varying considerably in their abilities to inhibit plaque formation by different viruses in a range of mammalian cells. All six of the cloned LeIFs exhibit the heat stability, pH 2 stability and antigenic specificity of natural leukocyte interferons. PMID:6171779

  12. Role of interferon in resistance and immunity to protozoa

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, G.; Degee, A. L. W.; Mansfield, J. M.; Newsome, A. L.; Arnold, R. R.

    1985-01-01

    Production of interferon (I) in response to protozoan infection, and the interferon-mediated inhibition of parasite replication were studied in order to determine if these effects may be related to immunologic-mediated resistance of the hosts. Two extracellular parasites-Trypanosoma brucei rhodesiense and Naegleria fowlei were used. Upon infection with the trypanosome, only resistant strains of mice produced I. An early peak of alpha/beta I is followed by appearance of gamma I, which coincided with antibody production and a drop in parasitemia. In case of the amoeba, pretreatment of its suspension with alpha/beta I inhibits its replication in vitro, and appears to protect mice from the infection and the disease. It is proposed that production of interferon, with its regulatory effect on the immune responses, may play a major role in regulating the processes of protozoan-caused diseases.

  13. Interferons and inflammasomes: Cooperation and counterregulation in disease.

    PubMed

    Labzin, Larisa I; Lauterbach, Mario A R; Latz, Eicke

    2016-07-01

    Interferons and the IL-1 family of cytokines have important roles in host defense against invading viruses and bacteria. Inflammasomes, multimeric cytosolic sensors of infection, are required for IL-1β and IL-18 processing and release. Interferons, IL-1β, and IL-18 are also implicated in autoimmune disease and chronic inflammation. Although independent but complementary pathways induce these cytokine subsets during infection, in some circumstances the cross-talk between these key inflammatory mediators is a particular requirement for effective host defense. In this review we will summarize recent discoveries concerning the potentiation of inflammasome responses by type I interferons, particularly in patients with gram-negative bacterial infections, and reflect on the molecular mechanisms of IFN-β's immunosuppressive effects through modulation of inflammasome and IL-1β signaling in patients with tuberculosis and multiple sclerosis. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  14. 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.

  15. The type I interferons: Basic concepts and clinical relevance in immune-mediated inflammatory diseases.

    PubMed

    López de Padilla, Consuelo M; Niewold, Timothy B

    2016-01-15

    There is increasing scientific and clinical interest in elucidating the biology of type I Interferons, which began approximately 60 years ago with the concept of "viral interference", a property that reduces the ability of a virus to infect cells. Although our understanding of the multiple cellular and molecular functions of interferons has advanced significantly, much remains to be learned and type I Interferons remain an active and fascinating area of inquiry. In this review, we cover some general aspects of type I interferon genes, with emphasis on interferon-alpha, and various aspects of molecular mechanisms triggered by type I interferons and toll-like receptor signaling by the Janus activated kinase/signal transducer activation of transcription (JAK-STAT) pathway and interferon regulatory factor pathway. We will also describe the role of type I interferons in autoimmune and inflammatory diseases, and its potential use as therapeutic agent. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Expansion of amphibian intronless interferons revises the paradigm for interferon evolution and functional diversity.

    PubMed

    Sang, Yongming; Liu, Qinfang; Lee, Jinhwa; Ma, Wenjun; McVey, D Scott; Blecha, Frank

    2016-06-30

    Interferons (IFNs) are key cytokines identified in vertebrates and evolutionary dominance of intronless IFN genes in amniotes is a signature event in IFN evolution. For the first time, we show that the emergence and expansion of intronless IFN genes is evident in amphibians, shown by 24-37 intronless IFN genes in each frog species. Amphibian IFNs represent a molecular complex more complicated than those in other vertebrate species, which revises the established model of IFN evolution to facilitate re-inspection of IFN molecular and functional diversity. We identified these intronless amphibian IFNs and their intron-containing progenitors, and functionally characterized constitutive and inductive expression and antimicrobial roles in infections caused by zoonotic pathogens, such as influenza viruses and Listeria monocytogenes. Amphibians, therefore, may serve as overlooked vectors/hosts for zoonotic pathogens, and the amphibian IFN system provides a model to study IFN evolution in molecular and functional diversity in coping with dramatic environmental changes during terrestrial adaption.

  17. Expansion of amphibian intronless interferons revises the paradigm for interferon evolution and functional diversity

    PubMed Central

    Sang, Yongming; Liu, Qinfang; Lee, Jinhwa; Ma, Wenjun; Blecha, Frank

    2016-01-01

    Interferons (IFNs) are key cytokines identified in vertebrates and evolutionary dominance of intronless IFN genes in amniotes is a signature event in IFN evolution. For the first time, we show that the emergence and expansion of intronless IFN genes is evident in amphibians, shown by 24–37 intronless IFN genes in each frog species. Amphibian IFNs represent a molecular complex more complicated than those in other vertebrate species, which revises the established model of IFN evolution to facilitate re-inspection of IFN molecular and functional diversity. We identified these intronless amphibian IFNs and their intron-containing progenitors, and functionally characterized constitutive and inductive expression and antimicrobial roles in infections caused by zoonotic pathogens, such as influenza viruses and Listeria monocytogenes. Amphibians, therefore, may serve as overlooked vectors/hosts for zoonotic pathogens, and the amphibian IFN system provides a model to study IFN evolution in molecular and functional diversity in coping with dramatic environmental changes during terrestrial adaption. PMID:27356970

  18. Interferon Lambda: Modulating Immunity in Infectious Diseases

    PubMed Central

    Syedbasha, Mohammedyaseen; Egli, Adrian

    2017-01-01

    Interferon lambdas (IFN-λs; IFNL1-4) modulate immunity in the context of infections and autoimmune diseases, through a network of induced genes. IFN-λs act by binding to the heterodimeric IFN-λ receptor (IFNLR), activating a STAT phosphorylation-dependent signaling cascade. Thereby hundreds of IFN-stimulated genes are induced, which modulate various immune functions via complex forward and feedback loops. When compared to the well-characterized IFN-α signaling cascade, three important differences have been discovered. First, the IFNLR is not ubiquitously expressed: in particular, immune cells show significant variation in the expression levels of and susceptibilities to IFN-λs. Second, the binding affinities of individual IFN-λs to the IFNLR varies greatly and are generally lower compared to the binding affinities of IFN-α to its receptor. Finally, genetic variation in the form of a series of single-nucleotide polymorphisms (SNPs) linked to genes involved in the IFN-λ signaling cascade has been described and associated with the clinical course and treatment outcomes of hepatitis B and C virus infection. The clinical impact of IFN-λ signaling and the SNP variations may, however, reach far beyond viral hepatitis. Recent publications show important roles for IFN-λs in a broad range of viral infections such as human T-cell leukemia type-1 virus, rotaviruses, and influenza virus. IFN-λ also potentially modulates the course of bacterial colonization and infections as shown for Staphylococcus aureus and Mycobacterium tuberculosis. Although the immunological processes involved in controlling viral and bacterial infections are distinct, IFN-λs may interfere at various levels: as an innate immune cytokine with direct antiviral effects; or as a modulator of IFN-α-induced signaling via the suppressor of cytokine signaling 1 and the ubiquitin-specific peptidase 18 inhibitory feedback loops. In addition, the modulation of adaptive immune functions via macrophage and

  19. Functional Characterization of Canine Interferon-Lambda

    PubMed Central

    Fan, Wenhui; Xu, Lei; Ren, Liqian; Qu, Hongren; Li, Jing; Liang, Jingjing; Liu, Wenjun

    2014-01-01

    In this study, we provide the first comprehensive annotation of canine interferon-λ (CaIFN-λ, type III IFN). Phylogenetic analysis based on genomic sequences indicated that CaIFN-λ is located in the same branch with Swine IFN-λ1 (SwIFN-λ), Bat IFN-λ1 (BaIFN-λ), and human IFN-λ1 (HuIFN-λ1). CaIFN-λ was cloned, expressed in Escherichia coli, and purified to further investigate the biological activity in vitro. The recombinant CaIFN-λ (rCaIFN-λ) displayed potent antiviral activity on both homologous and heterologous animal cells in terms of inhibiting the replication of the New Jersey serotype of vesicular stomatitis virus (VSV), canine parvovirus, and influenza virus A/WSN/33 (H1N1), respectively. In addition, we also found that rCaIFN-λ exhibits a significant antiproliferative response against A72 canine tumor cells and MDCK cells in a dose-dependent manner. Furthermore, CaIFN-λ activated the JAK-STAT signaling pathway. To evaluate the expression of CaIFN-λ induced by virus and the expression of IFN-stimulated genes (ISGs) induced by rCaIFN-λ in the MDCK cells, we measured the relative mRNA level of CaIFN-λ and ISGs (ISG15, Mx1, and 2′5′-OAS) by quantitative real-time PCR and found that the mRNA level of CaIFN-λ and the ISGs significantly increased after treating the MDCK cells with viruses and rCaIFN-λ protein, respectively. Finally, to evaluate the binding activity of rCaIFN-λ to its receptor, we expressed the extracellular domain of the canine IFN-λ receptor 1 (CaIFN-λR1-EC) and determined the binding activity via ELISA. Our results demonstrated that rCaIFN-λ bound tightly to recombinant CaIFN-λR1-EC (rCaIFN-λR1-EC). PMID:24950142

  20. Recurrent Pericarditis, an Unexpected Effect of Adjuvant Interferon Chemotherapy for Malignant Melanoma

    PubMed Central

    Marmoush, Fady; Shafi, Muhammad Ismail; Shah, Ashish

    2016-01-01

    Drug-induced pericarditis is a well-described cardiac pathology that can result from a variety of medications; however, interferon-mediated pericarditis is extremely rare. We present a case of a young female with recurrent pericarditis due to interferon therapy. The role of interferon in adjuvant chemotherapy is well known and yields good effect, but this case highlights the very uncommon phenomena of interferon induced pericarditis and the significant distress it can cause. PMID:27418981

  1. HIV-1 Vpu Does Not Degrade Interferon Regulatory Factor 3

    PubMed Central

    Hotter, Dominik

    2013-01-01

    It has been reported that HIV-1 Vpu mediates the degradation of interferon regulatory factor 3 (IRF-3) to avoid innate immune sensing. Here, we show that Vpu does not deplete IRF-3 from transfected cell lines or HIV-1-infected primary cells. Furthermore, the Vpu-dependent suppression of beta interferon expression described in previous studies could be ascribed to inhibition of NF-κB activation. Thus, Vpu suppresses innate immune activation through inhibition of NF-κB rather than degradation of IRF-3. PMID:23552418

  2. Biological effects of the interferons and other cytokines.

    PubMed

    Friedman, R M; Grimley, P; Baron, S

    1996-01-01

    There were seven workshops that primarily concerned the biological effects of the interferons and the other cytokines. These were: Workshop 6, The refractory state in the response to interferons (IFNs) and antibodies in treated patients; Workshop 7, IFNs, multiple sclerosis, and the nervous system; Workshop 9, Viral inhibition of the response to IFNs and other cytokines; Workshop 10, Cell growth inhibition by IFNs and other cytokines; Workshop 12, Cytokines and cell death; Workshop 13, Interactions between cytokines; and, Workshop 14, Cytokine gene therapy. Summaries of each of these sessions follow.

  3. Effect of acyclovir and interferon on human hematopoietic progenitor cells.

    PubMed Central

    Parker, L M; Lipton, J M; Binder, N; Crawford, E L; Kudisch, M; Levin, M J

    1982-01-01

    Continuous in vitro exposure of human bone marrow cells to acyclovir (approximately 200 microM) or human leukocyte interferon (approximately 250 U/ml) caused 50% inhibition of granulocyte colony-forming cell differentiation. Colonies expressed in the presence of either agent were reduced both in size and number. Erythroid progenitors were more resistant than granulocyte progenitors to the antiproliferative effects of acyclovir. Progenitor cells of patients recovering from cytotoxic chemotherapy were no more sensitive to the effects of acyclovir or interferon than were cells obtained from patients before chemotherapy. PMID:6177284

  4. Protozoan parasites and type I interferons: a cold case reopened.

    PubMed

    Beiting, Daniel P

    2014-10-01

    Protozoan parasites, such as Plasmodium, Toxoplasma, Cryptosporidium, trypanosomes, and Leishmania, are a major cause of disease in both humans and other animals, highlighting the need to understand the full spectrum of strategies used by the host immune system to sense and respond to parasite infection. Although type II interferon (IFN-γ) has long been recognized as an essential antiparasite immune effector, much less is known about the role of type I interferons (IFN-α and -β) in host defense, particularly in vivo. Recent studies are reviewed which collectively highlight that type I IFN can be induced in response to parasite infection and influence the outcome of infection.

  5. Local synthesis of interferon-alpha in lupus nephritis is associated with type I interferons signature and LMP7 induction in renal tubular epithelial cells.

    PubMed

    Castellano, Giuseppe; Cafiero, Cesira; Divella, Chiara; Sallustio, Fabio; Gigante, Margherita; Pontrelli, Paola; De Palma, Giuseppe; Rossini, Michele; Grandaliano, Giuseppe; Gesualdo, Loreto

    2015-03-22

    Type I interferons are pivotal in the activation of autoimmune response in systemic lupus erythematous. However, the pathogenic role of interferon-alpha in patients affected by lupus nephritis remains uncertain. The aim of our study was to investigate the presence of a specific interferon signature in lupus nephritis and the effects of interferon-alpha at renal level. We performed immunohistochemical analysis for MXA-protein and in situ hybridization to detect interferon-alpha signature and production in human lupus nephritis. Through microarray studies, we analyzed the gene expression profile of renal tubular epithelial cells, stimulated with interferon-alpha. We validated microarray results through real-time polymerase chain reaction, flow cytometry on renal tubular epithelial cells, and through immunohistochemical analysis and confocal microscopy on renal biopsies. Type I interferons signature was characterized by MXA-specific staining in renal tubular epithelial cells; in addition, in situ hybridization showed that renal tubular epithelial cells were the major producers of interferon-alpha, indicating a potential autocrine effect. Whole-genome expression profile showed interferon-alpha induced up-regulation of genes involved in innate immunity, protein ubiquitination and switching to immunoproteasome. In accordance with the in vitro data, class IV lupus nephritis showed up-regulation of the immunoproteasome subunit LMP7 in tubular epithelial cells associated with type I interferon signature. Our data indicate that type I interferons might have a pathogenic role in lupus nephritis characterized by an autocrine effect of interferon-alpha on renal tubular epithelial cells. Therefore we hypothesize that inhibition of type I interferons might represent a therapeutic target to prevent tubulo-interstitial damage in patients with lupus nephritis.

  6. [The role of the interferon system in pathogenesis of endothelial dysfunction in patients with metabolic syndrome].

    PubMed

    Voloshyna, O O; Rybalko, S L

    2008-01-01

    We have studied the serum interferon activity and its relation to the endothelial dysfunction. Atherosclerosis development in patients with metabolic syndrome is followed by significant increase in interferon activity. Close relation presents between activity of the serum interferon and indexes of structural and functional changes of arterial vessels compromised with atherosclerosis process.

  7. [The antiproliferative effects associated with vincristine and human interferons in experimental in vitro systems].

    PubMed

    Danielescu, G; Maniu, H; Jucu, V; Cajal, N

    1989-01-01

    Cytotoxic potential of suboptimal doses of vincristine associated with human interferon was studied in two cell lines of tumoral origin, as compared to the action of or gamma type interferon preparations. Results show that the vincristine cytotoxic effect may be synergistically augmented in both culture types by simultaneous interferon administration.

  8. Interferons and their receptors in birds: a comparison of gene structure, phylogenetic analysis, and cross modulation.

    PubMed

    Zhou, Hao; Chen, Shun; Wang, Mingshu; Cheng, Anchun

    2014-11-14

    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.

  9. Interferon Gamma as a Biomarker of Exposure to Enteric Viruses

    EPA Science Inventory

    Interferon gamma (IFN-γ) was selected as a biomarker for viral exposure. Twelve-week-old BALB/c mice were intraperitoneally injected with Coxsackievirus B3 or B4 diluted in phosphate-buffered saline (PBS). Control mice were injected with PBS only. Four months after viral infectio...

  10. Interferon Gamma as a Biomarker of Exposure to Enteric Viruses

    EPA Science Inventory

    Interferon gamma (IFN-γ) was selected as a biomarker for viral exposure. Twelve-week-old BALB/c mice were intraperitoneally injected with Coxsackievirus B3 or B4 diluted in phosphate-buffered saline (PBS). Control mice were injected with PBS only. Four months after viral infectio...

  11. Adenovirus infection reverses the antiviral state induced by human interferon.

    PubMed

    Feduchi, E; Carrasco, L

    1987-04-06

    HeLa cells treated with human lymphoblastoid interferon do not synthesize poliovirus proteins. The antiviral state against poliovirus is reversed if cells are previously infected with adenovirus type 5. A late gene product seems to be involved in this reversion, since no effect is observed at early stages of infection or in the presence of aphidicolin.

  12. Functional interferon system is required for clearance of lassa virus.

    PubMed

    Yun, Nadezhda E; Poussard, Allison L; Seregin, Alexey V; Walker, Aida G; Smith, Jennifer K; Aronson, Judith F; Smith, Jeanon N; Soong, Lynn; Paessler, Slobodan

    2012-03-01

    Lassa virus (LASV) is the causative agent of Lassa hemorrhagic fever (LF) in humans, a deadly disease endemic to West Africa that results in 5,000 to 10,000 deaths annually. Here we present results demonstrating that functional type I and type II interferon (IFN) signaling is required for efficient control of LASV dissemination and clearance.

  13. Complexation hydrogels for intestinal delivery of interferon beta and calcitonin.

    PubMed

    Kamei, Noriyasu; Morishita, Mariko; Chiba, Hitomi; Kavimandan, Nikhil J; Peppas, Nicholas A; Takayama, Kozo

    2009-03-04

    Recent studies have suggested that complexation hydrogels poly(methacrylic acid-g-ethylene glycol) (henceforth designated as P(MAA-g-EG)) exhibit high insulin incorporation efficiency, rapid insulin release in the intestine based on their pH-dependent complexation properties, enzyme-inhibiting effects and mucoadhesive characteristics. Therefore, they are promising carriers for insulin delivery via an oral route. As we designed these hydrogels as carriers suitable for oral administration of various peptide/protein drugs, in this study we aimed at investigating the applicability of P(MAA-g-EG) hydrogels to improving the intestinal absorption of various peptide/protein drugs. High loading efficiency into hydrogels was observed for insulin, calcitonin, and interferon beta. In addition, polymer microparticles loaded with calcitonin and interferon beta exhibited complexation/decomplexation and pH-sensitive release behavior. The molecular weight and chemical structure appeared to affect the efficiency of loading and release depending on the peptides and proteins. Furthermore, a drastic reduction of plasma calcium concentration accompanied by calcium absorption and a dose-dependent enhancement of plasma interferon beta concentration were observed after the administration of particles loaded with calcitonin or interferon beta into closed rat ileal segments. These findings indicate that P(MAA-g-EG) hydrogels are promising carriers for administration of various peptides and proteins via an oral route.

  14. Interferon induced IFIT family genes in host antiviral defense

    USDA-ARS?s Scientific Manuscript database

    Secretion of interferons (IFNs) from virus-infected cells is a hallmark of host antiviral immunity and in fact, IFNs exert their antiviral activities through the induction of antiviral proteins. The IFN-induced protein with tetratricopeptide repeats (IFITs) family is among hundreds of IF stimulated ...

  15. Interferons limit inflammatory responses by induction of tristetraprolin

    PubMed Central

    Sauer, Ines; Schaljo, Barbara; Vogl, Claus; Gattermeier, Irene; Kolbe, Thomas; Müller, Mathias; Blackshear, Perry J.; Kovarik, Pavel

    2014-01-01

    Interferons (IFNs) are cytokines with pronounced proinflammatory properties. Here we provide evidence that IFNs play a key role also in decline of inflammation by inducing expression of tristetraprolin (TTP). TTP is an RNA-binding protein that destabilizes several AU-rich element-containing mRNAs including TNFα. By promoting mRNA decay TTP significantly contributes to cytokine homeostasis. Now we report that IFNs strongly stimulate expression of TTP if a co-stimulatory stress signal is provided. IFN-induced expression of TTP depends on the IFN-activated transcription factor STAT1, and the co-stimulatory stress signal requires p38 MAPK. Within the TTP promoter we have identified a functional gamma interferon-activated sequence that recruits STAT1. Consistently, STAT1 is required for full expression of TTP in response to LPS that stimulates both p38 MAPK and, indirectly, interferon signaling. We demonstrate that in macrophages IFN-induced TTP protein limits LPS-stimulated expression of several proinflammatory genes such as TNFα, IL-6, Ccl2 and Ccl3. Thus, our findings establish a link between interferon responses and TTP-mediated mRNA decay during inflammation, and propose a novel immunomodulatory role of IFNs. PMID:16514065

  16. Endogenous interferon-β-inducible gene expression and interferon-β-treatment are associated with reduced T cell responses to myelin basic protein in multiple sclerosis.

    PubMed

    Börnsen, Lars; Romme Christensen, Jeppe; Ratzer, Rikke; Hedegaard, Chris; Søndergaard, Helle B; Krakauer, Martin; Hesse, Dan; Nielsen, Claus H; Sorensen, Per S; Sellebjerg, Finn

    2015-01-01

    Autoreactive CD4+ T-cells are considered to play a major role in the pathogenesis of multiple sclerosis. In experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, exogenous and endogenous type I interferons restrict disease severity. Recombinant interferon-β is used for treatment of multiple sclerosis, and some untreated multiple sclerosis patients have increased expression levels of type I interferon-inducible genes in immune cells. The role of endogenous type I interferons in multiple sclerosis is controversial: some studies found an association of high expression levels of interferon-β-inducible genes with an increased expression of interleukin-10 and a milder disease course in untreated multiple sclerosis patients, whereas other studies reported an association with a poor response to treatment with interferon-β. In the present study, we found that untreated multiple sclerosis patients with an increased expression of interferon-β-inducible genes in peripheral blood mononuclear cells and interferon-β-treated multiple sclerosis patients had decreased CD4+ T-cell reactivity to the autoantigen myelin basic protein ex vivo. Interferon-β-treated multiple sclerosis patients had increased IL10 and IL27 gene expression levels in monocytes in vivo. In vitro, neutralization of interleukin-10 and monocyte depletion increased CD4+ T-cell reactivity to myelin basic protein while interleukin-10, in the presence or absence of monocytes, inhibited CD4+ T-cell reactivity to myelin basic protein. Our findings suggest that spontaneous expression of interferon-β-inducible genes in peripheral blood mononuclear cells from untreated multiple sclerosis patients and treatment with interferon-β are associated with reduced myelin basic protein-induced T-cell responses. Reduced myelin basic protein-induced CD4+ T-cell autoreactivity in interferon-β-treated multiple sclerosis patients may be mediated by monocyte-derived interleukin-10.

  17. The antiviral effect of human interferon alpha is dependent on phosphoinositide-derived messengers.

    PubMed

    Cernescu, C; Constantinescu, S N; Baltă, F; Popescu, L M

    1988-01-01

    Neomycin the putative blocker of membrane polyphosphoinositide hydrolysis, inhibited the antiviral activity of human interferon alpha, when tested on human quiescent fibroblasts challenged with vesicular stomatitis virus. The anti-interferon effect of neomycin could be correlated in terms of dose dependence for both neomycin (0.05-1 mM) and interferon (100-5,000 IU/ml). The results suggest that the antiviral activity of interferon alpha depends on diacylglycerol formation. Indeed, the synthetic diacylglycerol (50 microM) was as effective as 100 IU/ml interferon in inducing the antiviral state.

  18. Neuromyelitis optica-like pathology is dependent on type I interferon response.

    PubMed

    Khorooshi, Reza; Wlodarczyk, Agnieszka; Asgari, Nasrin; Owens, Trevor

    2013-09-01

    Neuromyelitis optica is an antibody-mediated autoimmune inflammatory disease of the central nervous system. Reports have suggested that interferon beta which is beneficial for multiple sclerosis, exacerbates neuromyelitis optica. Our aim was to determine whether type I interferon plays a role in the formation of neuromyelitis optica lesions. Immunoglobulin G from a neuromyelitis optica patient was injected intracerebrally with human complement to type I interferon receptor deficient and wildtype mice. Loss of aquaporin-4 and glial fibrillary acidic protein was reduced in type I interferon receptor deficient mice brain. Our findings suggest that type I interferon signaling contributes to neuromyelitis optica pathogenesis. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Effect of flight in mission SL-3 on interferon-gamma production by rats

    NASA Technical Reports Server (NTRS)

    Gould, C. L.; Williams, J. A.; Mandel, A. D.; Sonnenfeld, G.

    1985-01-01

    Rats flown in Space Shuttle mission SL-3 were sacrificed after flight and spleens were removed. Cultures of spleen cells were challenged with the mitogen concanavalin-A to attempt to induce interferon-gamma. Most control, ground-based rats had spleen cells that produced moderate titers of interferon-gamma. Spleen cells from flown rats did not produce interferon-gamma in most cases, and one flown rat produced minimally detectable amounts of interferon. These data suggest that interferon-gamma production was inhibited in rats flown in mission SL-3 immediately upon return to earth.

  20. CD40-mediated NFκB activation in B cells is increased in multiple sclerosis and modulated by therapeutics1

    PubMed Central

    Chen, Ding; Ireland, Sara J.; Remington, Gina; Alvarez, Enrique; Racke, Michael K.; Greenberg, Benjamin; Frohman, Elliot M.; Monson, Nancy L.

    2017-01-01

    CD40 interacts with CD40 ligand and plays an essential role in immune regulation and homeostasis. Recent research findings, however, support a pathogenic role of CD40 in a number of autoimmune diseases. We previously showed that memory B cells from relapsing-remitting multiple sclerosis (RRMS) patients exhibited enhanced proliferation with CD40 stimulation compared to healthy donors. In this study, we used a multi-parameter phosflow approach to analyze the phosphorylation status of NFκB and three major MAP kinases (P38, ERK and JNK), the essential components of signaling pathways downstream of CD40 engagement in B cells from MS patients. We found that memory and naïve B cells from RRMS and secondary progressive MS (SPMS) patients exhibited a significantly elevated level of phosphorylated NFκB (p-P65) following CD40 stimulation compared to healthy donor controls. Combination therapy with interferon beta-1a (Avonex) and mycophenolate mofetil (Cellcept) modulated the hyper-phosphorylation of P65 in B cells of RRMS patients at levels similar to healthy donor controls. Lower disease activity after the combination therapy correlated with the reduced phosphorylation of P65 following CD40 stimulation in treated patients. In addition, glatiramer acetate (GA) treatment also significantly reduced CD40-mediated P65 phosphorylation in RRMS patients, suggesting that reducing CD40-mediated p-P65 induction may be a general mechanism by which some current therapies modulate MS disease. PMID:27798157

  1. 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

  2. Inhibition by interferon of biochemical transformation induced by cloned herpesvirus thymidine kinase genes.

    PubMed

    Otsuka, H; Qavi, H; Kit, S

    1982-10-01

    To learn whether interferon could prevent the biochemical transformations induced by cloned herpesvirus thymidine kinase (TK) genes, LM(TK-) mouse fibroblast cultures were pretreated for 24 h with 2.4-40 international units (I.U.)/ml mouse alpha + beta interferon, and subsequently transformed to the TK+ phenotype with recombinant plasmids containing the herpes simplex virus type 1 (HSV-1) TK gene (pAGO and pMH110) and the marmoset herpesvirus (MarHV) TK gene (pMAR035). Mouse alpha + beta interferon inhibited transformation and the inhibition was interferon dose-dependent. Transformation was also inhibited when LM(TK-) cells were pretreated for 2-5 h with 40 I.U./ml interferon. Maximal inhibitions of TK+ colony formation were observed following a 9-20 h pretreatment period with interferon. In contrast, 40 I.U./ml interferon treatment for 20 h did not reduce the rate or extent of LM(TK-) cell growth. Experiments in which cultures were first treated with plasmid pAGO and only afterwards treated with interferon also showed that, as the interferon concentration used, interferon did not inhibit the outgrowth of transformated colonies. Enzyme assays showed that pretreatment with interferon inhibited the induction of TK activity in cells that had been transfected with pAGO DNA.

  3. Psoriasis exacerbated by interferon-alpha in a patient with chronic myeloid leukemia.

    PubMed

    Ladoyanni, E; Nambi, R

    2005-01-01

    Interferon-alpha can exacerbate existing psoriasis and induce de novo psoriasis and psoriatic arthritits. The exact underlying mechanism is not very well understood. It is not a contraindication to treat patients with pre-existing psoriasis with interferon-alpha. In these patients interferon-alpha should be used with care and only if the potential benefits justify the potential risk. Control of psoriasis prior to initiation of interferon-alpha and simultaneous antipsoriatic therapy while on interferon-alpha are essential. We would like to report a 61-year-old male patient with stable psoriasis for over 20 years, who experienced exacerbation of his psoriasis after receiving interferon-alpha for chronic myeloid leukemia. The association between the interferon-alpha therapy and the exacerbation of his psoriasis was only recognized on rechallenge at the stage he was referred to our department.

  4. Expression of Interferon Effector Gene SART1 Correlates with Interferon Treatment Response against Hepatitis B Infection

    PubMed Central

    Li, Yong; Zhu, Chuanlong; Wang, Faxi; Zhu, Tiantian; Liu, Shufeng

    2016-01-01

    Interferon-α (IFN-α) has limited response rate in the treatment of chronic hepatitis B (CHB). The underlying mechanism of differential responsiveness to IFN remains elusive. It has been recently reported that SART1 mediates antiviral effects of IFN-α in the hepatitis C virus (HCV) cell culture model. In this study, we investigated the role of SART1 in antiviral activity of IFN-α against hepatitis B virus (HBV) using blood and liver biopsy samples from chronic hepatitis B patients treated with pegylated IFN-α and HepG2 cells transfected with cloned HBV DNA. We observed that the basal SART1 expression in liver and PBMCs before IFN treatment was significantly higher in responders than in nonresponders. Furthermore, baseline SART1 expression level positively correlated with the degree of HBV DNA and HBeAg decline after IFN treatment. Mechanistically, silencing SART1 abrogated the antiviral activity of IFN-α, reduced the expression of IFN-stimulated genes (ISGs) Mx, OAS, and PKR, and attenuated JAK-STAT signaling in HepG2 cells, suggesting that SART1 regulates IFN-mediated antiviral activity through JAK-STAT signaling and ISG expression. Our study elucidates the important role of SART1 in IFN-mediated anti-HBV response and provides new insights into understanding variation of IFN treatment response in CHB patients. PMID:28077916

  5. Borna disease virus nucleoprotein inhibits type I interferon induction through the interferon regulatory factor 7 pathway

    SciTech Connect

    Song, Wuqi; Kao, Wenping; Zhai, Aixia; Qian, Jun; Li, Yujun; Zhang, Qingmeng; Zhao, Hong; Hu, Yunlong; Li, Hui; Zhang, Fengmin

    2013-09-06

    Highlights: •IRF7 nuclear localisation was inhibited by BDV persistently infected. •BDV N protein resistant to IFN induction both in BDV infected OL cell and N protein plasmid transfected OL cell. •BDV N protein is related to the inhibition of IRF7 nuclear localisation. -- Abstract: The expression of type I interferon (IFN) is one of the most potent innate defences against viral infection in higher vertebrates. Borna disease virus (BDV) establishes persistent, noncytolytic infections in animals and in cultured cells. Early studies have shown that the BDV phosphoprotein can inhibit the activation of type I IFN through the TBK1–IRF3 pathway. The function of the BDV nucleoprotein in the inhibition of IFN activity is not yet clear. In this study, we demonstrated IRF7 activation and increased IFN-α/β expression in a BDV-persistently infected human oligodendroglia cell line following RNA interference-mediated BDV nucleoprotein silencing. Furthermore, we showed that BDV nucleoprotein prevented the nuclear localisation of IRF7 and inhibited endogenous IFN induction by poly(I:C), coxsackie virus B3 and IFN-β. Our findings provide evidence for a previously undescribed mechanism by which the BDV nucleoprotein inhibits type I IFN expression by interfering with the IRF7 pathway.

  6. Anti-inflammatory action of type I interferons deduced from mice expressing interferon beta.

    PubMed

    Boscá, L; Bodelón, O G; Hortelano, S; Casellas, A; Bosch, F

    2000-05-01

    Type I interferons (IFN) are widely used for the therapeutic treatment of viral infections, tumor growth and various chronic diseases such as multiple sclerosis. Antagonism between type I IFNs and IFN-gamma has been described in cells of the immune system, in particular in the activation of macrophages. To study the systemic effects of type I IFNs we used transgenic mice carrying a human IFN-beta (hIFN-beta) gene under the control of the rat insulin I promoter. These animals expressed high levels of hIFN-beta in beta-pancreatic cells, and the ability of the macrophages to respond to pro-inflammatory stimuli was analyzed. Transgenic mice exhibited an increased extravasation of cells to the peritoneal cavity after eliciting with thioglycollate broth. The expression of the inducible form of nitric oxide synthase and cyclooxygenase-2, two enzymes involved in inflammation, was impaired in transgenic animals challenged with lipopolysaccharide and IFN-gamma. Analysis of the mechanisms leading to this attenuated inflammatory response showed a decrease in the serum levels of TNF-alpha and an inhibition of the activation of the transcription factor NF-KB in various tissues. These results indicate that systemic administration of IFN-beta might influence the response to pro-inflammatory stimuli, in particular through the antagonism of IFN-gamma signaling.

  7. Localization of Type I Interferon Receptor Limits Interferon-Induced TLR3 in Epithelial Cells

    PubMed Central

    Ciencewicki, Jonathan M.; Brighton, Luisa E.

    2009-01-01

    Previous studies have shown that influenza infections increase Toll-like receptor 3 (TLR3) expression and that type I interferons (IFNs) may play a role in this response. This study aimed to expand on the role of type I IFNs in the influenza-induced upregulation of TLR3 and determine whether and how the localization of the IFN-α/β receptor (IFNAR) in respiratory epithelial cells could modify IFN-induced responses. Using differentiated primary human airway epithelial cells this study demonstrates that soluble mediators secreted in response to influenza infection upregulate TLR3 expression in naive cells. This response was associated with an upregulation of type I IFNs and stimulation with type I, but not type II, IFNs enhanced TLR3 expression. Interestingly, although influenza infection results in IFN-β release both toward the apical and basolateral sides of the epithelium, TLR3 expression is only enhanced in cells stimulated with IFN-β from the basolateral side. Immunohistochemical analysis demonstrates that IFNAR expression is limited to the basolateral side of differentiated human airway epithelial cells. However, non- or poorly differentiated epithelial cells express IFNAR more toward the apical side. These data demonstrate that restricted expression of the IFNAR in the differentiated airway epithelium presents a potential mechanism of regulating type I IFN-induced TLR3 expression. PMID:19231996

  8. Regulation of Epstein-Barr virus infection by recombinant interferons. Selected sensitivity to interferon-gamma.

    PubMed

    Lotz, M; Tsoukas, C D; Fong, S; Carson, D A; Vaughan, J H

    1985-05-01

    Interferons (IFN) are antiviral proteins that may be important in mediating cellular defenses against Epstein-Barr virus (EBV) infection. However, the means by which IFN-alpha, -beta and -gamma modify EBV infectivity are not clear. We have evaluated the effects of purified recombinant preparations of all three classes of IFN on EBV-induced B lymphocyte proliferation and Ig secretion. When added early after EBV infection, all three recombinant IFN reduced B cell outgrowth and Ig secretion. IFN-gamma exerted a 7-10-fold more potent antiviral effect than IFN-alpha or -beta. All three types of IFN act directly on B cells. Monocytes and natural killer cells are not necessary for the anti-EBV activity. Of the three recombinant IFN, only IFN-gamma reduced EBV-induced proliferation and Ig secretion when added 3-4 days after virus infection; IFN-alpha/beta were only effective up to 24 h. B lymphoblastoid lines already transformed by EBV are insensitive to the anti-proliferative actions of all three types of IFN. On the basis of these findings, we propose three phases of regulation during EBV infection. In the early phase, EBV-infected cells can be regulated by all IFN. Subsequently, there is an intermediate period where only IFN-gamma is capable of directly affecting EBV-induced B cell responses. In the third phase, B lymphocytes become insensitive to direct actions of all IFN and are now subject to regulation only by cytotoxic cells.

  9. microRNA control of interferons and interferon induced anti-viral activity.

    PubMed

    Sedger, Lisa M

    2013-12-01

    Interferons (IFNs) are cytokines that are spontaneously produced in response to virus infection. They act by binding to IFN-receptors (IFN-R), which trigger JAK/STAT cell signalling and the subsequent induction of hundreds of IFN-inducible genes, including both protein-coding and microRNA genes. IFN-induced genes then act synergistically to prevent virus replication and create an anti-viral state. miRNA are therefore integral to the innate response to virus infection and are important components of IFN-mediated biology. On the other hand viruses also encode miRNAs that in some cases interfere directly with the IFN response to infection. This review summarizes the important roles of miRNAs in virus infection acting both as IFN-stimulated anti-viral molecules and as critical regulators of IFNs and IFN-stimulated genes. It also highlights how recent knowledge in RNA editing influence miRNA control of virus infection. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Consensus Interferon Plus Ribavirin for Hepatitis C Genotype 3 Patients Previously Treated With Pegylated Interferon Plus Ribavirin

    PubMed Central

    Abbas, Zaigham; Tayyab, Ghiasun Nabi; Qureshi, Mustafa; Memon, Mohammad Sadik; Subhan, Amna; Shakir, Tanzila; Jafri, Wasim; Hamid, Saeed

    2013-01-01

    Background Not enough data are available about the effectiveness of consensus interferon (CIFN) among HCV genotype 3 patients who failed to respond to pegylated interferon and ribavirin. Objectives We aimed to assess the efficacy and safety of CIFN and ribavirin in non-responders and relapsers to pegylated interferon with ribavirin therapy. Patients and Methods This open-label investigator-initiated study included 44 patients who received CIFN 15 µg /day plus ribavirin 800-1200 mg daily. In patients with an early virological response (EVR), the dose of CIFN was reduced to 15 µg thrice a week for further 36 weeks. Patients with delayed virological response continued to receive daily CIFN plus ribavirin to complete 48 weeks. The patients were considered “non-responders” if there were less than 2 log reduction in HCV RNA at 12 weeks and detectable HCV RNA at 24 weeks. Results Twenty-four patients (55%) were non-responders and 20 patients were relapsers to the previous treatment with pegylated interferon plus ribavirin (mean age 43.6 ± 9.4 years, males 25 (57%)). Nine patients were clinically cirrhotic (Child A). End of treatment virological response was achieved in 19 (43.1%) patients and sustained virological response (SVR) occurred in 12 (27.3%). Out of these 12 patients, eight were non-responders and four were relapsers to the previous treatment. Advanced fibrosis or clinical cirrhosis was associated with low SVR. Adverse events were fever, myalgia, anorexia, depression, and weight loss. Two patients received granulocyte colony stimulating factor for transient neutropenia. Seven patients were given erythropoietin to improve hemoglobin, and six were treated for mild depression. Two patients developed portosystemic encephalopathy. Conclusions More than one-quarter of treatment-experienced patients with HCV genotype 3 achieved SVR after re-treatment with consensus interferon plus ribavirin. PMID:24358041

  11. Crystal structure of Zebrafish interferons I and II reveals conservation of type I interferon structure in vertebrates.

    PubMed

    Hamming, Ole Jensen; Lutfalla, Georges; Levraud, Jean-Pierre; Hartmann, Rune

    2011-08-01

    Interferons (IFNs) play a major role in orchestrating the innate immune response toward viruses in vertebrates, and their defining characteristic is their ability to induce an antiviral state in responsive cells. Interferons have been reported in a multitude of species, from bony fish to mammals. However, our current knowledge about the molecular function of fish IFNs as well as their evolutionary relationship to tetrapod IFNs is limited. Here we establish the three-dimensional (3D) structure of zebrafish IFNϕ1 and IFNϕ2 by crystallography. These high-resolution structures offer the first structural insight into fish cytokines. Tetrapods possess two types of IFNs that play an immediate antiviral role: type I IFNs (e.g., alpha interferon [IFN-α] and beta interferon [IFN-β]) and type III IFNs (lambda interferon [IFN-λ]), and each type is characterized by its specific receptor usage. Similarly, two groups of antiviral IFNs with distinct receptors exist in fish, including zebrafish. IFNϕ1 and IFNϕ2 represent group I and group II IFNs, respectively. Nevertheless, both structures reported here reveal a characteristic type I IFN architecture with a straight F helix, as opposed to the remaining class II cytokines, including IFN-λ, where helix F contains a characteristic bend. Phylogenetic trees derived from structure-guided multiple alignments confirmed that both groups of fish IFNs are evolutionarily closer to type I than to type III tetrapod IFNs. Thus, these fish IFNs belong to the type I IFN family. Our results also imply that a dual antiviral IFN system has arisen twice during vertebrate evolution.

  12. Role of interferon in the pathogenesis of virus diseases in mice as demonstrated by the use of anti-interferon serum. I. Rapid evolution of encephalomyocarditis virus infection

    PubMed Central

    1976-01-01

    The role of interferon in the pathogenesis of encephalomyocarditis (EMC) virus infection was determined by treating mice with potent, partially purified sheep anti-mouse interferon globulin. In control mice, EMC virus was present in low titers in various visceral organs but attained high titers in the brain towards the 4th to 5th day, at which time mice died with signs of central nervous system disease. In mice treated with anti-mouse interferon globulin, virus was present in high titer in visceral organs 24--36 h after viral inoculation and virtually all mice were dead by 45 h. This rapid evolution of EMC virus infection was not observed in mice treated with the globulin fraction prepared from a normal sheep, from a sheep exhibiting a low anti-mouse interferon-neutralizing titer, nor from a sheep having a high titer of antibody to human leukocyte interferon. The experimental results indicated that anti-interferon globulin neutralized the interferon liberated by virus-infected cells, thus permitting extensive virus multiplication in several visceral organs. We conclude that interferon is an important early component of host resistance to this virus infection. PMID:186554

  13. Effect of interferon on the induction of human monocyte secretion of interleukin-1 activity.

    PubMed Central

    Newton, R C

    1985-01-01

    This study investigates the effect of interferons on the induction of human monocyte secretion of interleukin-1 (IL-1) activity by lipopolysaccharides (LPS). Monocytes do not spontaneously produce IL-1 and the addition of interferons to the culture does not lead to detectable secretion. Addition of LPS alone induces the release of measurable amounts of IL-1 activity. The addition of low doses (1-10 units/ml) of alpha, beta, or gamma interferon to the LPS-stimulated cultures further increases this secretion by 50%. The addition of 1000 units/ml of alpha or beta interferon leads to inhibition of IL-1 release. By contrast, gamma interferon is a dose dependent enhancer of IL-1 release. The effect of gamma interferon is on the production of IL-1 and is not an enhancement of IL-1 activity in the biological assay. Results demonstrate that addition of gamma interferon to monocytes increases the rate of secretion of IL-1 by these cells. Gamma interferon also appears to abrogate the loss in the ability of monocytes to produce IL-1 activity after overnight culture. This last result parallels the maintainence of the expression of the HLA-DR surface marker on monocytes by gamma interferon. These results may help define a mechanism involving IL-1 generation which could have bearing on the in vivo pyrogenic effects of purified gamma interferon. PMID:2416675

  14. Interferon inhibits the conversion of 3T3-L1 mouse fibroblasts into adipocytes.

    PubMed Central

    Keay, S; Grossberg, S E

    1980-01-01

    Confluent Swiss mouse 3T3-L1 fibroblasts slowly differentiate functionally and morphologically into adipocytes, a conversion hastened by insulin. The cells are sensitive (although less than L929 cells) to the antiviral action of mouse fibroblast interferons but not to interferons from heterologous species (human and chicken). Cultures stimulated with insulin in the presence of partially purified or electrophoretically pure mouse interferons have a much lower percentage of cells accumulating lipid than do insulin-treated control cultures. Interferon-treated cell cultures also contain much less triglyceride, cholesterol, and cholesterol esters than do replicate control cultures stimulated by insulin to differentiate. Increased de novo lipid biosynthesis that occurs during differentiation is inhibited, as determined by incorporation of [14C]acetate into lipids extractable by the Folch method. This incorporation is a sensitive bioassay of the antidifferentiation effect of interferon; less than 1 antiviral unit is inhibitory. Variously inactivated or mock interferon preparations as well as interferons from several heterologous species fail to inhibit 3T3-L1 adipocyte conversion. Interferon is inhibitory even when applied as long as 3 days after insulin stimulation. The effect of interferon does not appear to depend upon its competition with insulin for cell surface receptors. Because interferon can alter the program of events involved in conversion of 3T3-L1 fibroblasts into adipose cells, it may be able to affect the regulation of eukaryotic cell differentiation. Images PMID:6159626

  15. Phase II Radiation Therapy Oncology Group trial of conventional radiation therapy followed by treatment with recombinant interferon-{beta} for supratentorial glioblastoma: Results of RTOG 9710

    SciTech Connect

    Colman, Howard . E-mail: hcolman@mdanderson.org; Berkey, Brian A.; Maor, Moshe H.; Groves, Morris D.; Schultz, Christopher J.; Vermeulen, Sandra; Mehta, Minesh P.; Yung, W.K. Alfred

    2006-11-01

    Purpose: The aim of this study was to determine whether recombinant human interferon {beta}-1a (rhIFN-{beta}), when given after radiation therapy, improves survival in glioblastoma. Methods and Materials: After surgery, 109 patients with newly diagnosed supratentorial glioblastoma were enrolled and treated with radiation therapy (60 Gy). A total of 55 patients remained stable after radiation and were treated with rhIFN-{beta} (6 MU/day i.m., 3 times/week). Outcomes were compared with Radiation Therapy Oncology Group glioma historical database. Results: RhIFN-{beta} was well tolerated, with 1 Grade 4 toxicity and 8 other patients experiencing Grade 3 toxicity. Median survival time (MST) of the 55 rhIFN-{beta}-treated patients was 13.4 months. MST for the 34 rhIFN-{beta}-treated in RPA Classes III and IV was 16.9 vs. 12.4 months for historical controls (hazard ratio [HR] = 1.27, 95% confidence interval [CI] = 0.89-1.81). There was also a trend toward improved survival across all RPA Classes comparing the 55 rhIFN-{beta} treated patients and 1,658 historical controls (HR = 1.24, 95% CI = 0.94-1.63). The high rate of early failures (54/109) after radiation and before initiation of rhIFN-{beta} was likely caused by stricter interpretation of early radiographic changes in the current study. Matched-pair and intent-to-treat analyses performed to try to address this bias showed no difference in survival between study patients and controls. Conclusion: RhIFN-{beta} given after conventional radiation therapy was well tolerated, with a trend toward survival benefit in patients who remained stable after radiation therapy. These data suggest that rhIFN-{beta} warrants further evaluation in additional studies, possibly in combination with current temozolomide-based regimens.

  16. Regulation of interferon receptor expression in human blood lymphocytes in vitro and during interferon therapy

    SciTech Connect

    Lau, A.S.; Hannigan, G.E.; Freedman, M.H.; Williams, B.R.

    1986-05-01

    Interferons (IFN) elicit antiviral and antineoplastic activities by binding to specific receptors on the cell surface. The binding characteristics of IFN to human lymphocytes were studied using IFN alpha 2 labeled with /sup 125/I to high specific activity. The specific binding curves generated were analyzed by the LIGAND program of Munson and Rodbard to determine receptor numbers. The number of receptors in peripheral blood lymphocytes (PBL) and tonsillar B-lymphocytes (TBL) from normal individuals were 505 +/- 293 (n = 10) and 393 +/- 147 (n = 3) respectively. When these cells were preincubated in vitro with unlabeled IFN alpha 2, the receptor number decreased to 82 +/- 45 and 61 +/- 16 respectively. Receptor binding activities recovered gradually over a period of 72 h when the cells were incubated in IFN-free medium. This recovery of receptors could be blocked by the addition of actinomycin D to the incubation medium. A similar decrease in receptor expression was observed in vivo in PBL from patients being treated daily with 5 X 10(6) units/m2 per d of IFN alpha 2 by subcutaneous injection, for acute lymphoblastic leukemia or papilloma virus infections. Receptor numbers in PBL in vivo were further reduced concurrent with the progression of IFN therapy. Thus, the reduction in IFN receptor expression observed in vitro can be demonstrated in vivo. These studies indicate that monitoring IFN receptor expression in vivo can provide information regarding the availability of IFN receptors at the cell surface for the mediation of IFN actions during the course of IFN therapy.

  17. Alpha interferon and not gamma interferon inhibits salmonid alphavirus subtype 3 replication in vitro.

    PubMed

    Xu, Cheng; Guo, Tz-Chun; Mutoloki, Stephen; Haugland, Øyvind; Marjara, Inderjit S; Evensen, Øystein

    2010-09-01

    Salmonid alphavirus (SAV) is an emerging virus in salmonid aquaculture, with SAV-3 being the only subtype found in Norway. Until now, there has been little focus on the alpha interferon (IFN-alpha)-induced antiviral responses during virus infection in vivo or in vitro in fish. The possible involvement of IFN-gamma in the response to SAV-3 is also not known. In this study, the two IFNs were cloned and expressed as recombinant proteins (recombinant IFN-alpha [rIFN-alpha] and rIFN-gamma) and used for in vitro studies. SAV-3 infection in a permissive salmon cell line (TO cells) results in IFN-alpha and IFN-stimulated gene (ISG) mRNA upregulation. Preinfection treatment (4 to 24 h prior to infection) with salmon rIFN-alpha induces an antiviral state that inhibits the replication of SAV-3 and protects the cells against virus-induced cytopathic effects (CPE). The antiviral state coincides with a strong expression of Mx and ISG15 mRNA and Mx protein expression. When rIFN-alpha is administered at the time of infection and up to 24 h postinfection, virus replication is not inhibited, and cells are not protected against virus-induced CPE. By 40 h postinfection, the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) is phosphorylated concomitant with the expression of the E2 protein as assessed by Western blotting. Postinfection treatment with rIFN-alpha results in a moderate reduction in E2 expression levels in accordance with a moderate downregulation of cellular protein synthesis, an approximately 65% reduction by 60 h postinfection. rIFN-gamma has only a minor inhibitory effect on SAV-3 replication in vitro. SAV-3 is sensitive to the preinfection antiviral state induced by rIFN-alpha, while postinfection antiviral responses or postinfection treatment with rIFN-alpha is not able to limit viral replication.

  18. 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

    SciTech Connect

    Preble, O.T.; Rothko, K.; Klippel, J.H.; Friedman, R.M.; Johnston, M.I.

    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.

  19. The schlafen family of proteins and their regulation by interferons.

    PubMed

    Mavrommatis, Evangelos; Fish, Eleanor N; Platanias, Leonidas C

    2013-04-01

    The Schlafen (SLFN) family of proteins includes several mouse and human members. There is emerging evidence that members of this family of proteins are involved in important functions, such as the control of cell proliferation, induction of immune responses, and the regulation of viral replication. These proteins span across all species with great diversity, with 10 murine and 5 human isoforms. Recent work has established that mouse and human SLFN proteins are regulated by interferons (IFNs). Several Slfn genes were shown to be induced as classical interferon-stimulated genes, and emerging evidence suggests that these proteins play important roles in the growth inhibitory and antineoplastic effects of IFNs. In the current review, the known properties of mouse and human SLFNs are reviewed, and the implications of their emerging functions are discussed.

  20. The Schlafen Family of Proteins and Their Regulation by Interferons

    PubMed Central

    Mavrommatis, Evangelos; Fish, Eleanor N.

    2013-01-01

    The Schlafen (SLFN) family of proteins includes several mouse and human members. There is emerging evidence that members of this family of proteins are involved in important functions, such as the control of cell proliferation, induction of immune responses, and the regulation of viral replication. These proteins span across all species with great diversity, with 10 murine and 5 human isoforms. Recent work has established that mouse and human SLFN proteins are regulated by interferons (IFNs). Several Slfn genes were shown to be induced as classical interferon-stimulated genes, and emerging evidence suggests that these proteins play important roles in the growth inhibitory and antineoplastic effects of IFNs. In the current review, the known properties of mouse and human SLFNs are reviewed, and the implications of their emerging functions are discussed. PMID:23570387

  1. Simian varicella virus inhibits the interferon gamma signalling pathway.

    PubMed

    Ouwendijk, Werner J D; van Veen, Suzanne; Mahalingam, Ravi; Verjans, Georges M G M

    2017-09-13

    The alphaherpesvirus simian varicella virus (SVV) causes varicella and zoster in nonhuman primates. Herpesviruses evolved elaborate mechanisms to escape host immunity, but the immune evasion strategies employed by SVV remain ill-defined. We analysed whether SVV impairs the cellular response to key antiviral cytokine interferon-γ (IFNγ). SVV infection inhibited the expression of IFNγ-induced genes like C-X-C motif chemokine 10 and interferon regulatory factor 1. Phosphorylation and nuclear translocation of the signal transducer and activator of transcription 1 (STAT1) was blocked in SVV-infected cells, which did not involve cellular and viral phosphatases. SVV infection did not downregulate IFNγ receptor α and β chain expression on the cell surface. Instead, STAT1, Janus tyrosine kinases 1 (JAK1) and JAK2 protein levels were significantly decreased in SVV-infected cells. Collectively, these results demonstrate that SVV targets three proteins in the IFNγ signal transduction pathway to escape the antiviral effects of IFNγ.

  2. Interferon-Stimulated Genes: A Complex Web of Host Defenses

    PubMed Central

    Schneider, William M.; Chevillotte, Meike Dittmann; Rice, Charles M.

    2015-01-01

    Interferon-stimulated gene (ISG) products take on a number of diverse roles. Collectively, they are highly effective at resisting and controlling pathogens. In this review, we begin by introducing interferon (IFN) and the JAK-STAT signaling pathway to highlight features that impact ISG production. Next, we describe ways in which ISGs both enhance innate pathogen-sensing capabilities and negatively regulate signaling through the JAK-STAT pathway. Several ISGs that directly inhibit virus infection are described with an emphasis on those that impact early and late stages of the virus life cycle. Finally, we describe ongoing efforts to identify and characterize antiviral ISGs, and we provide a forward-looking perspective on the ISG landscape. PMID:24555472

  3. Systems biology unravels interferon responses to respiratory virus infections.

    PubMed

    Kroeker, Andrea L; Coombs, Kevin M

    2014-02-26

    Interferon production is an important defence against viral replication and its activation is an attractive therapeutic target. However, it has long been known that viruses perpetually evolve a multitude of strategies to evade these host immune responses. In recent years there has been an explosion of information on virus-induced alterations of the host immune response that have resulted from data-rich omics technologies. Unravelling how these systems interact and determining the overall outcome of the host response to viral infection will play an important role in future treatment and vaccine development. In this review we focus primarily on the interferon pathway and its regulation as well as mechanisms by which respiratory RNA viruses interfere with its signalling capacity.

  4. Successful Treatment of Provisional Cutaneous Mastocytosis with Interferon Alpha

    PubMed Central

    Rosario, Andrea; Bhat, Ramesh M

    2016-01-01

    Mastocytosis is a disorder characterized by the clonal proliferation of mast cells and their accumulation in skin, bone marrow, liver, and spleen. Cutaneous mastocytosis presents in children in over 90% of the cases and any cutaneous manifestation in an adult is the earliest sign of the systemic disease. A 45-year-old patient presented with itchy dark lesions over the body since childhood and Darier's sign was positive. Skin biopsy showed features of mastocytosis and immunohistochemistry was positive for CD34. Since the patient was refractory to treatment with antihistamines and psoralen-ultraviolet A therapy, injections of interferon alpha were given – 3 million IU twice weekly subcutaneously as they have been proven to improve constitutional symptoms. Very few reports of successful treatment of cutaneous mastocytosis using interferon alpha have been published. PMID:27293273

  5. Interferon-mediated Tumor Resistance to Oncolytic Virotherapy.

    PubMed

    Ebrahimi, Safieh; Ghorbani, Elnaz; Khazaei, Majid; Avan, Amir; Ryzhikov, Mikhail; Azadmanesh, Keyhan; Hassanian, Seyed Mahdi

    2017-01-30

    Interferons (INFs) elicit antiviral responses in tumor cells upon binding to cell surface receptors. Oncolytic virotherapy (OV) is an effective antitumor therapeutic approach which in combination with standard radiotherapy or chemotherapy regimens potentiates treatment responses in cancer patients. However, oncolytic viruses are susceptible to the IFN-induced antiviral state in the tumor microenvironment. A number of studies have therefore investigated the effects of combined therapy of IFN signaling pharmacological inhibitors with oncolytic viruses, which result in improved virus replication and oncolysis. This review summarizes the current knowledge of the mechanisms of interferon-mediated tumor resistance to oncolytic virotherapy and provides new insights regarding the effectiveness of combinatorial treatment strategies to attenuate INF-induced OV resistance for greater clinical significance in the treatment of cancer patients. This article is protected by copyright. All rights reserved.

  6. Weapons of STAT destruction. Interferon evasion by paramyxovirus V protein.

    PubMed

    Horvath, Curt M

    2004-12-01

    The signal transducer and activator of transcription (STAT) family of proteins function to activate gene transcription downstream of myriad cytokine and growth factor signals. The prototype STAT proteins, STAT1 and STAT2, are required for innate and adaptive antimicrobial immune responses that result from interferon signal transduction. While many viruses have evolved the ability to avoid these antiviral cytokines, the Paramyxoviruses are distinct in their abilities to interfere directly with STAT proteins. Individual paramyxovirus species differ greatly in their precise mechanism of STAT signaling evasion, but a virus-encoded protein called V plays a central role in this process. The theme of V-dependent interferon evasion and its variations provide significant insights into virus-host interactions and viral immune evasion that can help define targets for antiviral drug design. Exposure of the viral weapons of STAT destruction may also be instructive for application to STAT-directed therapeutics for diseases characterized by STAT hyperactivity.

  7. IL-28 and IL-29: newcomers to the interferon family.

    PubMed

    Uzé, Gilles; Monneron, Danièle

    2007-01-01

    IL-28 and IL-29 were recently described as members of a new cytokine family that shares with type I interferon (IFN) the same Jak/Stat signalling pathway driving expression of a common set of genes. Accordingly, they have been named IFN lambda. IFNs lambda exhibit several common features with type I IFNs: antiviral activity, antiproliferative activity and in vivo antitumour activity. Importantly, however, IFNs lambda bind to a distinct membrane receptor, composed of IFNLR1 and IL10R2. This specific receptor usage suggests that this cytokine family does not merely replicate the type I IFN system and justifies its designation as type III IFN by the nomenclature committee of the International Society of Interferon and Cytokine Research.

  8. Interferon induces natural killer cell blastogenesis in vivo

    NASA Technical Reports Server (NTRS)

    Biron, C. A.; Sonnenfeld, G.; Welsh, R. M.

    1984-01-01

    Interferon (IFN), types beta and gamma, and IFN inducers polyinosinic-polycytidylic acid and lymphocytic choriomeningitis virus, all stimulated the generation of blast-natural killer (NK) cells in mouse spleens, Blast-NK cells were characterized on the basis of size, 3H-thymidine uptake, and NK cell markers These data indicate that in addition to augmenting NK cell-mediated lysis, IFN may regulate NK cell proliferation in vivo.

  9. Treatment of Hepatitis C Infections with Interferon: A Historical Perspective

    DTIC Science & Technology

    2010-01-01

    hepatic cirrhosis and hepatocellular transformation [24]. The resistance of HCV to IFN resides in a nonstructural viral protein NS3/4A, a serine protease...and inactivated influenza virus system [1]. The inactivated virus induced a protein that had a broad spectrum of antiviral activity, which...leukemia viruses [9] prompted addi- tional studies employing interferon as therapy for human chronic hepatitis B virus ( HBV ) infections. These had very

  10. Sensitivity of Selected Arenaviruses to a Human Interferon.

    DTIC Science & Technology

    1979-02-25

    AUSTRAC ? (Coat~oue do reviers t-d ner..eemy and Idenify by block number) -sessment of arenavirus sensitivities to an interferon (IF) of human cell...plays a determinant role in the outcome of infection with these viruses. However, at the same time, these results do not ruLe out the possibility that... role in the eventual outcome of the cellular infectious process. In arenavirus-cell interactions, where IF synthesis is induced either upon primary

  11. Interferon induces natural killer cell blastogenesis in vivo

    NASA Technical Reports Server (NTRS)

    Biron, C. A.; Sonnenfeld, G.; Welsh, R. M.

    1984-01-01

    Interferon (IFN), types beta and gamma, and IFN inducers polyinosinic-polycytidylic acid and lymphocytic choriomeningitis virus, all stimulated the generation of blast-natural killer (NK) cells in mouse spleens, Blast-NK cells were characterized on the basis of size, 3H-thymidine uptake, and NK cell markers These data indicate that in addition to augmenting NK cell-mediated lysis, IFN may regulate NK cell proliferation in vivo.

  12. Immunomodulatory intervention with interferon-γ in Escherichia coli pyelonephritis.

    PubMed

    Katsaris, Matthew P; Adamis, Theodoros; Pistiki, Aikaterini; Carrer, Dionyssia-Pinelopi; Galani, Irene; Sabracos, Labros; Droggiti, Dionyssia-Irini; Georgitsi, Marianna; Damoraki, Georgia; Giamarellos-Bourboulis, Evangelos J; Chrisofos, Michael

    2014-08-01

    We investigated the efficacy of recombinant human interferon-γ in experimental pyelonephritis due to Escherichia coli. Pyelonephritis was induced by intrapelvic inoculation of bacteria after ureteral ligation in 38 rabbits assigned to 1 of 3 groups, including group 1-16 controls, group 2-14 rabbits treated with intravenous recombinant human interferon-γ and group 3-8 rabbits treated with intravenous recombinant human interferon-γ plus amikacin. Bacterial counts, cytokines and malondialdehyde were measured in blood. Peripheral blood mononuclear cells were isolated to measure TNFα transcripts, cytokine stimulation and apoptosis. Survival was recorded, and the tissue bacterial load and myeloperoxidase activity were measured after sacrifice. The mortality rate in groups 1, 2 and 3 was 66.7%, 25% and 12.5%, respectively. The circulating bacterial count and tissue bacterial load were less in group 2 than in group 1. Circulating malondialdehyde negatively correlated with the bacterial load of the spleen. Although the number of TNFα transcripts in circulating peripheral blood mononuclear cells did not differ, peripheral blood mononuclear cells isolated from group 2 at 48 hours produced much greater concentrations of tumor necrosis factor-α after stimulation with Pam3Cys. In parallel, the apoptosis rate of circulating monocytes was increased in group 2 at 48 hours. Lung myeloperoxidase activity at 24 hours, serving as indirect evidence of neutrophil infiltration, was decreased in group 2. Recombinant human interferon-γ administration prolonged survival in rabbits with experimental E. coli urosepsis. Its action was probably related to increased bacterial phagocytosis after modulation of oxidant status and reversal of monocyte immunoparalysis. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  13. Interferon γ-inducible protein (IFI) 16 transcriptionally regulates type i interferons and other interferon-stimulated genes and controls the interferon response to both DNA and RNA viruses.

    PubMed

    Thompson, Mikayla R; Sharma, Shruti; Atianand, Maninjay; Jensen, Søren B; Carpenter, Susan; Knipe, David M; Fitzgerald, Katherine A; Kurt-Jones, Evelyn A

    2014-08-22

    The interferon γ-inducible protein 16 (IFI16) has recently been linked to the detection of nuclear and cytosolic DNA during infection with herpes simplex virus-1 and HIV. IFI16 binds dsDNA via HIN200 domains and activates stimulator of interferon genes (STING), leading to TANK (TRAF family member-associated NF-κB activator)-binding kinase-1 (TBK1)-dependent phosphorylation of interferon regulatory factor (IRF) 3 and transcription of type I interferons (IFNs) and related genes. To better understand the role of IFI16 in coordinating type I IFN gene regulation, we generated cell lines with stable knockdown of IFI16 and examined responses to DNA and RNA viruses as well as cyclic dinucleotides. As expected, stable knockdown of IFI16 led to a severely attenuated type I IFN response to DNA ligands and viruses. In contrast, expression of the NF-κB-regulated cytokines IL-6 and IL-1β was unaffected in IFI16 knockdown cells, suggesting that the role of IFI16 in sensing these triggers was unique to the type I IFN pathway. Surprisingly, we also found that knockdown of IFI16 led to a severe attenuation of IFN-α and the IFN-stimulated gene retinoic acid-inducible gene I (RIG-I) in response to cyclic GMP-AMP, a second messenger produced by cyclic GMP-AMP synthase (cGAS) as well as RNA ligands and viruses. Analysis of IFI16 knockdown cells revealed compromised occupancy of RNA polymerase II on the IFN-α promoter in these cells, suggesting that transcription of IFN-stimulated genes is dependent on IFI16. These results indicate a broader role for IFI16 in the regulation of the type I IFN response to RNA and DNA viruses in antiviral immunity. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. [Future prospects for hepatitis C treatment: without interferon and ribavirin?].

    PubMed

    Lens, Sabela; Alfaro, Ignacio

    2014-05-01

    The hepatitis C virus is an important health problem worldwide. Currently, the standard treatment of genotype 1 chronic hepatitis C is the combination of pegylated interferon, ribavirin and a first-generation protease inhibitor: telaprevir or boceprevir. This triple therapy has improved the efficacy of treatment but has also increased regimen complexity, costs, and the number of adverse effects (mainly hematological and cutaneous). Unfortunately, viral response rates are still suboptimal in patients with cirrhosis, particularly those with a prior null response. Moreover, studies carried out in clinical practice have shown that the presence of advanced fibrosis confers a high risk of developing severe adverse effects during treatment (infection, decompensation and even death). It is therefore essential to select candidates for triple therapy according to their risk of complications and possibilities for cure. In this scenario, interferon (and ribavirin)-free combinations are very safe and well tolerated first-line treatments. This review describes the current treatment of hepatitis C as well as the latest results of studies combining distinct direct antiviral agents without interferon. It is hoped that these drugs will be available shortly, although their cost may be high. Consequently, it is essential to identify those patients who could derive the greatest benefit from these treatments. Copyright © 2014 Elsevier España, S.L. and AEEH y AEG. All rights reserved.

  15. Two Modes of the Axonal Interferon Response Limit Alphaherpesvirus Neuroinvasion

    PubMed Central

    Song, Ren; Koyuncu, Orkide O.; Greco, Todd M.; Diner, Benjamin A.; Cristea, Ileana M.

    2016-01-01

    ABSTRACT Infection by alphaherpesviruses, including herpes simplex virus (HSV) and pseudorabies virus (PRV), typically begins at epithelial surfaces and continues into the peripheral nervous system (PNS). Inflammatory responses are induced at the infected peripheral site prior to invasion of the PNS. When the peripheral tissue is first infected, only the innervating axons are exposed to this inflammatory milieu, which includes the interferons (IFNs). The fundamental question is how do PNS cell bodies respond to these distant, potentially damaging events experienced by axons. Using compartmented cultures that physically separate neuron axons from cell bodies, we found that pretreating isolated axons with beta interferon (IFN-β) or gamma interferon (IFN-γ) significantly diminished the number of herpes simplex virus 1 (HSV-1) and PRV particles moving in axons toward the cell bodies in a receptor-dependent manner. Exposing axons to IFN-β induced STAT1 phosphorylation (p-STAT1) only in axons, while exposure of axons to IFN-γ induced p-STAT1 accumulation in distant cell body nuclei. Blocking transcription in cell bodies eliminated antiviral effects induced by IFN-γ, but not those induced by IFN-β. Proteomic analysis of IFN-β- or IFN-γ-treated axons identified several differentially regulated proteins. Therefore, unlike treatment with IFN-γ, IFN-β induces a noncanonical, local antiviral response in axons. The activation of a local IFN response in axons represents a new paradigm for cytokine control of neuroinvasion. PMID:26838720

  16. [Gamma interferon: basics aspects, clinic significance and terapeutic uses].

    PubMed

    Mata-Espinosa, Dulce A; Hernández-Pando, Rogelio

    2008-01-01

    Interferons are a family of pleiotropic cytokines, their name was assigned because of their anti-replicative viral activity. IFNgamma or immune type II interferon does not share receptors with the type I interferon, its structure is different and its gene is located in different chromosome, although its biologic effects are similar. Along of several years of research, it has been found that IFNgamma enhances the transcription of genes involved in immunomodulation, antiviral responses and antitumoral activities. Regarding to the immune system, IFNgamma increases the cytotoxic and phagocytic activity of macrophages and upregulates the expression of major histocompatibility complex (MHC) class I and class II molecules in dendritics cells and other antigen presenting cells. IFNgamma also promotes the development and differentiation of naive CD4+ T lymphocytes to Th1 helper subset. Indeed, this cytokine has a key role in the control of bacterial, micotic, viral and parasitic infections. Depending of the micro-environment, IFNgamma has a dual role as pro or anti inflammatory cytokine. Novel therapeutic strategies are currently being developed with the aim to enhance the immune response or replace IFNgamma gene abnormal expression with beneficial results in humans, being recombinant IFNgamma safe and well tolerated.

  17. Exposure to cold impairs interferon-induced antiviral defense.

    PubMed

    Boonarkart, Chompunuch; Suptawiwat, Ornpreya; Sakorn, Kittima; Puthavathana, Pilaipan; Auewarakul, Prasert

    2017-08-01

    It is commonly believed that exposure to low temperature increases susceptibility to viral infection in the human respiratory tract, but a molecular mechanism supporting this belief has yet to be discovered. In this study, we investigated the effect of low temperature on viral infection and innate defense in cell lines from the human respiratory tract and found that interferon-induced antiviral responses were impaired at low temperatures. Cells maintained at 25°C and 33°C expressed lower levels of myxovirus resistance protein 1 (MxA) and 2'5'-oligoadenylate synthetase 1 (OAS1) mRNAs when compared to cells maintained at 37°C after infection by seasonal influenza viruses. Exogenous β-interferon treatment reduced the viral replication at 37°C, but not at 25°C. Our results suggest that the impairment of interferon-induced antiviral responses by low temperature is one of several mechanisms that could explain an increase in host susceptibility to respiratory viruses after exposure to cold temperature.

  18. Mice devoid of interferon regulatory factor 1 (IRF-1) show normal expression of type I interferon genes.

    PubMed Central

    Reis, L F; Ruffner, H; Stark, G; Aguet, M; Weissmann, C

    1994-01-01

    The transcription factor interferon regulatory factor 1 (IRF-1) binds tightly to the interferon (IFN)-beta promoter and has been implicated in the induction of type I IFNs. We generated mice devoid of functional IRF-1 by targeted gene disruption. As reported by others, IRF-1-deficient mice showed a discrete phenotype: the CD4/CD8 ratio was increased and IFN-gamma-induced levels of macrophage iNO synthase mRNA were strongly diminished. However, type I IFN induction in vivo by virus or double-stranded RNA was unimpaired, as evidenced by serum IFN titers and IFN mRNA levels in spleen, liver and lung. There was also no impairment in the response of type I IFN-inducible genes. Therefore, IRF-1 is not essential for these processes in vivo. Images PMID:7957048

  19. Interferon-λ and interleukin-22 cooperate for the induction of interferon-stimulated genes and control of rotavirus infection

    PubMed Central

    Yang, Ines; Schwierzeck, Vera; Nguyen, Nam; Guendel, Fabian; Gronke, Konrad; Ryffel, Bernhard; Hoelscher, Christoph; Dumoutier, Laure; Renauld, Jean-Christophe; Suerbaum, Sebastian; Staeheli, Peter; Diefenbach, Andreas

    2015-01-01

    The epithelium is the major entry point for many viruses but the processes protecting barrier surfaces against viral infections are incompletely understood. We identify interleukin (IL)-22 produced by group 3 innate lymphoid cells (ILC3s) as an amplifier of interferon (IFN)-λ signaling, a synergism required to curtail replication of rotavirus, the leading cause of childhood gastroenteritis. Cooperation between IL-22 and IFN-λ receptors, both of which are preferentially expressed by intestinal epithelial cells, was required for optimal STAT1 transcription factor activation and expression of interferon-stimulated genes. This data suggests that epithelial cells are protected against virus replication by co-opting two evolutionarily related cytokine networks. These data may inform the design of novel immunotherapies of virus infections that are sensitive to IFNs. PMID:26006013

  20. Production of human beta interferon in insect cells infected with a Baculovirus expression vector

    SciTech Connect

    Smith, G.E.; Summers, M.D.; Fraser, M.J.

    1983-12-01

    Autographa californica nuclear polyhedrosis virus (AcNPV) was used as an expression vector for human beta interferon. By using specially constructed plasmids, the protein-coding sequences for interferon were linked to the AcNPV promoter for the gene encoding for polyhedrin, the major occlusion protein. The interferon gene was inserted at various locations relative to the AcNPV polyhedrin transcriptional and translational signals, and the interferon-polyhedrin hybrid genes were transferred to infectious AcNPV expression vectors. Biologically active interferon was produced, and greater than 95% was secreted from infected insect cells. A maximum of ca. 5 x 10/sup 6/ U of interferon activity was produced by 10/sup 6/ infected cells. These results demonstrate that AcNPV should be suitable for use as a eucaryotic expression vector for the production of products from cloned genes.

  1. [Role of cycloferon and interferon-alphain apoptosis regulation in neuroendocrinal system on aging].

    PubMed

    Bazhanova, E D

    2012-01-01

    A detailed analysis of the literature data gives contradictory information about the role of interferon-alpha in the regulation of apoptosis, while there are almost no data on the participation of cycloferon in this process. Results of original experiments in recent years showed that exogenous interferon-alpha is not apoptosis protector in hypothalamic neurons on aging. The treatment with interferon-alpha activates dystrophic processes in neurosecretory cells of aged mice. However, endogenous interferon induced by cycloferon leads to a decrease in the apoptosis of hypothalamic neurons in both young and old animals. Antiapoptotic activity of interferon-alpha and cycloferon has been found in aged animals under stress condition. Thus, the role of immunomodulators in apoptosis regulation in hypothalamic neurons depends on the age and the type of immunomodulators. This fact opens new prospects for the clinical use of interferon-alpha and cycloferon.

  2. Enhanced antitumor reactivity of tumor-sensitized T cells by interferon alfa

    SciTech Connect

    Vander Woude, D.L.; Wagner, P.D.; Shu, S.; Chang, A.E. )

    1991-03-01

    Tumor-draining lymph node cells from mice bearing the methylcholanthrene-induced MCA 106 tumors can be sensitized in vitro to acquire antitumor reactivity. We examined the effect of interferon alfa on the function of cells that underwent in vitro sensitization in adoptive immunotherapy. Interferon alfa increased the antitumor reactivity of in vitro sensitized cells in the treatment of MCA 106 pulmonary metastases. This effect was evident in irradiated mice, indicating that a host response to the interferon alfa was not required. Interferon alfa treatment increased class I major histocompatibility complex antigen expression on tumor cells and increased their susceptibility to lysis by in vitro sensitized cells. These results suggest that interferon alfa enhancement of adoptive immunotherapy was mediated by its effect on tumor cells. Interferon alfa may be a useful adjunct to the adoptive immunotherapy of human cancer.

  3. Delayed Liver Function Impairment Secondary to Interferon β-1a Use in Multiple Sclerosis

    PubMed Central

    Liao, Ming-Feng; Yen, Su-Chen; Chun-Yen, Lin; Rong-Kuo, Lyu

    2013-01-01

    Interferon β-1a is a widely used immunomodulation treatment for multiple sclerosis. Liver function impairment is a common side effect and usually develops in the first 6 months after interferon use. Here, we describe 2 multiple sclerosis patients who developed delayed liver function impairment 5 years after receiving interferon β-1a treatment. Their liver function recovered after discontinuing interferon use, and further detailed hepatological evaluations excluded other etiologies of liver function impairment. Our case reports illustrate that liver function impairment induced by interferon β-1a can be delayed for 5 years after starting treatment and, probably, this is an idiosyncratic reaction. Regular liver function monitoring in multiple sclerosis patients who receive interferon β is necessary even after the first 6 months of treatment, especially in those patients with concomitant use of other liver-toxic medications. PMID:23904853

  4. Interferon treatment of mice: enhanced expression of histocompatibility antigens on lymphoid cells.

    PubMed Central

    Lindahl, P; Gresser, I; Leary, P; Tovey, M

    1976-01-01

    Treatment of young and mature mice with potent mouse interferon preparations results in a marked enhancement of the expression of histocompatibility antigens on the surface of thymocytes and splenic lymphocytes as measured by an enhanced absorption of alloantiserum. We postulate that such modifications of the cell surface may reflect an effect of interferon on lymphocyte maturation and may be relevant to the effect of interferon on lymphocyte function. PMID:1063409

  5. [Psychiatric and cognitive problems associated to hepatitis C and its treatment with interferon].

    PubMed

    Caneo R, Constanza; González T, Matías; Repetto L, Paula B; Soza R, Alejandro

    2010-11-01

    This article is a literature search about the psychopathology related to hepatitis C and its treatment with interferon. An overview of the methodology of the available studies is presented. New theories for a better understanding and diagnosis of the psychiatric alteration associated to hepatitis C or interferon treatment are proposed, to improve future research. We discuss neurobiological aspects, clinical manifestations, psychosocial features and pharmacotherapy of the psychiatric manifestations of hepatitis C and its treatment with interferon.

  6. Interferon-Related Depression: A Primer on Mechanisms, Treatment, and Prevention of a Common Clinical Problem

    PubMed Central

    Pinto, Ekta Franscina; Andrade, Chittaranjan

    2016-01-01

    Abstract: Background Depression is among the commonest of psychiatric disorders, and inflammatory mechanisms have been suggested to play a role in its pathophysiology. Interferons are a superfamily of proinflammatory cytokines that play a role in host defence mechanisms. Interferons are used in the treatment of a variety of autoimmune (e.g. multiple sclerosis), viral (e.g. chronic hepatitis B and C), and malignant (e.g. malignant melanoma, hairy cell leukemia) disorders; depression, however, is a notable and clinically troublesome adverse effect. Objective This article seeks to present a simple explanation and update for the reader about what interferons are, how interferons are classified, the clinical conditions in which interferons are used, the occurrence of depression as a clinical adverse effect of interferon therapy, possible mechanisms that explain interferon-related depression, the treatment of interferon-related depression, and the prevention of interferon-related depression. Methods A qualitative literature review is presented. Results and Conclusions Irrespective of the indication for IFN therapy, IFNs are associated with a 30-70% risk of treatment-emergent depression. This risk could be due to the IFN, or to an interaction between the IFN and the indication for which it was prescribed. Various neurohormonal, neurochemical, neurohistological, and other mechanisms have been put forth to explain IFN-related depression. Prophylactic treatment with antidepressants reduces the risk of IFN-related depression; antidepressants also effectively treat the condition. Recent alternatives to IFNs have shown to decrease the risk of treatment-emergent depression. PMID:26733280

  7. [Sarcoïdose in patient with chronic hepatitis C treated with pegylated interferon].

    PubMed

    Moudden, M K; Ziadi, T; Al Bouzidi, A; Ouarssani, A; Hadri, L; El Baaj, M

    2014-12-01

    Induced sarcoïdosis during therapy with interferon for chronic viral hepatitis C involves mainly by isolated cutaneous lesions or with lung lesions. Systemic forms are very rare. We report an observation. A 50-year-old patient developed a systemic sarcoïdosis two months after the end of treatment for hepatitis C with pegylated interferon and ribavirin with lung, joint and hepatic manifestations. After starting corticosteroid therapy, the evolution was favourable. Induced sarcoïdosis by interferon therapy is rare, treatment necessitates stopping interferon, and sometimes corticosteroid therapy. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  8. Consensus Interferon for Recurrent Hepatitis C Infection in Nonresponders to Peginterferon and Ribavirin After Liver Transplant.

    PubMed

    Nordstrom, Eric M; Biggins, Scott W; Gralla, Jane; Rosen, Hugo R; Everson, Gregory T; Burton, James R

    2015-12-01

    Hepatitis C virus infection universally recurs in liver transplant recipients. Peginterferon/ribavirin achieves a sustained virologic response rate of 30% in recipients infected with hepatitis C virus genotype 1. Consensus-interferon plus ribavirin yields sustained virologic response rates to 30% in patients failing to achieve sustained virologic response with peginterferon/ribavirin pretransplant, but it has not been studied posttransplant. We sought to evaluate the efficacy and tolerability of consensus-interferon and ribavirin in treating posttransplant hepatitis C virus. Clinical, laboratory, and virologic data were collected retrospectively from all patients who received at least 1 dose of consensus-interferon after transplant between January 2008 and December 2011. A standardized treatment protocol was used. The primary aim was sustained virologic response defined by undetectable hepatitis C virus RNA at 24 weeks after completing therapy. Twenty-three patients were treated with consensus-interferon/ribavirin; 15 with prior nonresponse (87%) or breakthrough (6.7%) during peginterferon/ribavirin, and 8 as initial therapy. The intention-to-treat sustained virologic response with consensus-interferon was 30%. Anemia, leukopenia, and growth factor requirement were similar between peginterferon and consensus-interferon cohorts. Consensus-interferon may rescue liver recipients who are nonresponders to peginterferon-based therapy. The efficacy of interferon-based treatment regimens may benefit from substitution of consensus-interferon for peginterferon.

  9. Interferon-Related Depression: A Primer on Mechanisms, Treatment, and Prevention of a Common Clinical Problem.

    PubMed

    Pinto, Ekta Franscina; Andrade, Chittaranjan

    2016-01-01

    Depression is among the commonest of psychiatric disorders, and inflammatory mechanisms have been suggested to play a role in its pathophysiology. Interferons are a superfamily of proinflammatory cytokines that play a role in host defence mechanisms. Interferons are used in the treatment of a variety of autoimmune (e.g. multiple sclerosis), viral (e.g. chronic hepatitis B and C), and malignant (e.g. malignant melanoma, hairy cell leukemia) disorders; depression, however, is a notable and clinically troublesome adverse effect. This article seeks to present a simple explanation and update for the reader about what interferons are, how interferons are classified, the clinical conditions in which interferons are used, the occurrence of depression as a clinical adverse effect of interferon therapy, possible mechanisms that explain interferon-related depression, the treatment of interferon-related depression, and the prevention of interferon-related depression. A qualitative literature review is presented. Irrespective of the indication for IFN therapy, IFNs are associated with a 30- 70% risk of treatment-emergent depression. This risk could be due to the IFN, or to an interaction between the IFN and the indication for which it was prescribed. Various neurohormonal, neurochemical, neurohistological, and other mechanisms have been put forth to explain IFN-related depression. Prophylactic treatment with antidepressants reduces the risk of IFN-related depression; antidepressants also effectively treat the condition. Recent alternatives to IFNs have shown to decrease the risk of treatment-emergent depression.

  10. The Use of Interferons in the Treatment of Cutaneous T-Cell Lymphoma.

    PubMed

    Spaccarelli, Natalie; Rook, Alain H

    2015-10-01

    Interferons are polypeptides that naturally occur in the human body as a part of the innate immune response. By harnessing these immunomodulatory functions, synthetic interferons have shown efficacy in combating various diseases including cutaneous T-cell lymphoma. This article closely examines the qualities of interferon alfa and interferon gamma and the evidence behind their use in the 2 most common types of cutaneous T-cell lymphomas, namely, mycosis fungoides and Sézary syndrome. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Divergent effects of type-I interferons on regulatory T cells.

    PubMed

    Piconese, Silvia; Pacella, Ilenia; Timperi, Eleonora; Barnaba, Vincenzo

    2015-04-01

    Regulatory T cells (Treg) exert a dominant role in the protection of unwanted immune responses and in the resolution of inflammation. To ensure the proper mounting of protective immune responses, Treg should be finely modulated by microenvironmental signals, mostly conveyed by cytokines. Type-I interferons are pleiotropic cytokines, best known for their anti-viral activities but also playing relevant immunostimulatory as well as immunomodulatory functions. The impact of type-I interferons on Treg homeostasis and functions is quite controversial, as some studies indicate that interferons sustain Treg stability and suppression, while other reports describe a null or even negative role for interferons in Treg activities. Interferons may also establish alternative routes of suppression, through the induction of other suppressive populations, such as Tr1 and the recently discovered FoxA1+ Treg. Discrepant results about Treg behavior in vivo emerge also from data collected in patients with multiple sclerosis, chronic hepatitis C or cancer undergoing interferon therapy. Concurrent events, such as Treg-extrinsic interferon activities, desensitization to chronic interferon exposure, and changes in microenvironmental signals during the evolution of diseases, may contribute to depict such a complex scenario, in which short-term and long-term effects of interferon exposure may give rise to apparently opposite conclusions. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. The effects of interferon-alpha/beta in a model of rat heart transplantation

    NASA Technical Reports Server (NTRS)

    Slater, A. D.; Klein, J. B.; Sonnenfeld, G.; Ogden, L. L. 2nd; Gray, L. A. Jr

    1992-01-01

    Interferons have multiple immunologic effects. One such effect is the activation of expression of cell surface antigens. Interferon alpha/beta enhance expression of class I but not class II histocompatibility antigens. Contradictory information has been published regarding the effect of interferon-alpha/beta administration in patients with kidney transplantation. In a model of rat heart transplantation we demonstrated that administration of interferon-alpha/beta accelerated rejection in a dose-dependent fashion in the absence of maintenance cyclosporine. Animals treated with maintenance cyclosporine had evidence of increased rejection at 20 days that was resolved completely at 45 days with cyclosporine alone.

  13. Synergistic Induction of Interferon α through TLR-3 and TLR-9 Agonists Identifies CD21 as Interferon α Receptor for the B Cell Response

    PubMed Central

    Kim, Dhohyung; Niewiesk, Stefan

    2013-01-01

    Maternal antibodies inhibit seroconversion and the generation of measles virus (MeV)-specific antibodies (both neutralizing and non-neutralizing antibodies) after vaccination whereas T cell responses are usually unaffected. The lack of seroconversion leaves individuals susceptible to vaccine-preventable infections. Inhibition of antibody secretion is due to the inhibition of B cells through a cross-link of the B cell receptor with the inhibitory FcγIIB receptor (CD32) by maternal antibody/vaccine complexes. Here, we demonstrate that a combination of TLR-3 and TLR-9 agonists induces synergistically higher levels of type I interferon in vitro and in vivo than either agonist alone. The synergistic action of TLR-3 and TLR-9 agonists is based on a feedback loop through the interferon receptor. Finally, we have identified CD21 as a potential receptor for interferon α on B cells which contributes to interferon α-mediated activation of B cells in the presence of maternal antibodies. The combination leads to complete restoration of B cell and antibody responses after immunization in the presence of inhibitory MeV-specific IgG. The strong stimulatory action of type I interferon is due to the fact that type I interferon uses not only the interferon receptor but also CD21 as a functional receptor for B cell activation. PMID:23516365

  14. Interferons beta have vasoconstrictive and procoagulant effects: a woman who developed livedo reticularis and Raynaud phenomenon in association with interferon beta treatment for multiple sclerosis.

    PubMed

    Rot, Uroš; Ledinek, Alenka Horvat

    2013-12-01

    A 31-year-old woman with MS developed livedo reticularis and secondary Raynaud phenomenon 2.5 years after introduction of interferon beta-1b. The symptoms disappeared after withdrawal of the drug. Livedo reticularis and Raynaud phenomenon as well as pulmonary arterial hypertension, venous sinus thrombosis, pulmonary embolism and renal thrombotic microangiopathy have all been described in association with interferon beta therapy. These complications strongly suggest that type I interferons have vasoconstrictive and procoagulant effects with potentially serious systemic complications. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. Component(s) of Sendai virus that can induce interferon in mouse spleen cells.

    PubMed Central

    Ito, Y; Hosaka, Y

    1983-01-01

    To identify the active component of Sendai virus that induces interferon in mouse spleen cells, infectious and noninfectious viruses, envelope particles derived from them, and isolated hemagglutinin-neuraminidase (HN) glycoproteins were examined for interferon induction. The interaction between membranous structures containing Sendai virus HN glycoprotein and the receptors on the cell surface was shown to be sufficient for interferon induction in mouse spleen cells, suggesting that the actual inducer of interferon in mouse spleen cells is the HN glycoprotein of Sendai virus. When mouse spleen cells were stimulated in vitro with Sendai virus grown in eggs or LLC-MK2 cells or with membranous structures containing glycoproteins obtained from these viruses, interferon could be detected in the culture fluid. Furthermore, isolated HN glycoprotein per se could induce interferon in the cells. A linear correlation was found between the titer of interferon induced and the hemagglutinating activity of the membranous structure containing the HN glycoprotein. It was concluded from these findings that HN glycoprotein was the active component of Sendai virus responsible for interferon induction in mouse spleen cells and that viral RNA and F glycoprotein were not required. The results also showed that the interaction between HN glycoprotein and receptors on the cell surface triggered production of type I interferon (IFN-alpha and IFN-beta). Although when Sendai virus was incubated at 56 degrees C for 5 min it lost its hemolytic and hemagglutinating activities, it induced a considerable amount of interferon in the culture fluid of mouse spleen cells. The interferon-inducing ability of heat-inactivated virus could be absorbed with mouse spleen cells but not with sheep erythrocytes or mouse erythrocytes, indicating that the inactivated virus retained ability to bind to mouse lymphoid cells. PMID:6301988

  16. Interferoids: In vitro and in vivo conversion of native interferons to lower molecular weight forms

    PubMed Central

    Stewart, William E.; Chudzio, Tadeusz; Lin, Leo S.; Wiranowska-Stewart, Marzenna

    1978-01-01

    Mouse interferons appear as two distinct molecular forms, one migrating at 38,000 daltons in sodium dodecyl sulfate/polyacrylamide gels and one migrating at 22,000 daltons; these interferons comprise about 80% and 20% of total activities, respectively. When such interferon preparations are briefly exposed to acidic periodate buffer, the larger interferon species is apparently converted to the smaller form since the activity at 38,000 daltons is completely eliminated while the activity at 22,000 daltons increases significantly; upon further oxidative cleavage, antiviral activity becomes detectable migrating at 15,000 daltons. Because no native mouse interferon has been reported as such small molecules, this antiviral activity is designated mouse “interferoid” to distinguish it from the native, naturally occurring interferon forms. Prolonged acidperiodate treatment fails to quantitatively convert the 22,000-dalton interferon to the 15,000-dalton interferoid since both are inactivated. When L cells are induced to make interferon in the presence of glycosylation inhibitors, either D-glucosamine or 2-deoxy-D-glucose, they produce approximately normal levels of antiviral activity. However, when such preparations are analyzed by sodium dodecyl sulfate/polyacrylamide gel electrophoresis, little activity (<10%) migrates as either the 38,000-dalton or 22,000-dalton native interferons. The interferons and interferoid are antigenically and hydrophobically indistinguishable. These data suggest that induced mouse cells normally synthesize the interferoid as a precursor polypeptide that is either partially or extensively modified by carbohydrate additions to produce, respectively, the 22,000- and 38,000-dalton mouse interferons. Because interferoid is apparently fully biologically active without these moieties, chemical synthesis of such unmodified polypeptides or active fragments from them appears feasible. PMID:217001

  17. Acetaminophen Modulates the Transcriptional Response to Recombinant Interferon

    PubMed Central

    Farnsworth, Aaron; Flaman, Anathea S.; Prasad, Shiv S.; Gravel, Caroline; Williams, Andrew; Yauk, Carole L.; Li, Xuguang

    2010-01-01

    Background Recombinant interferon treatment can result in several common side effects including fever and injection-site pain. Patients are often advised to use acetaminophen or other over-the-counter pain medications as needed. Little is known regarding the transcriptional changes induced by such co-administration. Methodology/Principal Findings We tested whether the administration of acetaminophen causes a change in the response normally induced by interferon-β treatment. CD-1 mice were administered acetaminophen (APAP), interferon-β (IFN-β) or a combination of IFN-β+APAP and liver and serum samples were collected for analysis. Differential gene expression was determined using an Agilent 22 k whole mouse genome microarray. Data were analyzed by several methods including Gene Ontology term clustering and Gene Set Enrichment Analysis. We observed a significant change in the transcription profile of hepatic cells when APAP was co-administered with IFN-β. These transcriptional changes included a marked up-regulation of genes involved in signal transduction and cell differentiation and down-regulation of genes involved in cellular metabolism, trafficking and the IκBK/NF-κB cascade. Additionally, we observed a large decrease in the expression of several IFN-induced genes including Ifit-3, Isg-15, Oasl1, Zbp1 and predicted gene EG634650 at both early and late time points. Conclusions/Significance A significant change in the transcriptional response was observed following co-administration of IFN-β+APAP relative to IFN-β treatment alone. These results suggest that administration of acetaminophen has the potential to modify the efficacy of IFN-β treatment. PMID:20544007

  18. Interferon-γ links ultraviolet radiation to melanomagenesis in mice.

    PubMed

    Zaidi, M Raza; Davis, Sean; Noonan, Frances P; Graff-Cherry, Cari; Hawley, Teresa S; Walker, Robert L; Feigenbaum, Lionel; Fuchs, Elaine; Lyakh, Lyudmila; Young, Howard A; Hornyak, Thomas J; Arnheiter, Heinz; Trinchieri, Giorgio; Meltzer, Paul S; De Fabo, Edward C; Merlino, Glenn

    2011-01-27

    Cutaneous malignant melanoma is a highly aggressive and frequently chemoresistant cancer, the incidence of which continues to rise. Epidemiological studies show that the major aetiological melanoma risk factor is ultraviolet (UV) solar radiation, with the highest risk associated with intermittent burning doses, especially during childhood. We have experimentally validated these epidemiological findings using the hepatocyte growth factor/scatter factor transgenic mouse model, which develops lesions in stages highly reminiscent of human melanoma with respect to biological, genetic and aetiological criteria, but only when irradiated as neonatal pups with UVB, not UVA. However, the mechanisms underlying UVB-initiated, neonatal-specific melanomagenesis remain largely unknown. Here we introduce a mouse model permitting fluorescence-aided melanocyte imaging and isolation following in vivo UV irradiation. We use expression profiling to show that activated neonatal skin melanocytes isolated following a melanomagenic UVB dose bear a distinct, persistent interferon response signature, including genes associated with immunoevasion. UVB-induced melanocyte activation, characterized by aberrant growth and migration, was abolished by antibody-mediated systemic blockade of interferon-γ (IFN-γ), but not type-I interferons. IFN-γ was produced by macrophages recruited to neonatal skin by UVB-induced ligands to the chemokine receptor Ccr2. Admixed recruited skin macrophages enhanced transplanted melanoma growth by inhibiting apoptosis; notably, IFN-γ blockade abolished macrophage-enhanced melanoma growth and survival. IFN-γ-producing macrophages were also identified in 70% of human melanomas examined. Our data reveal an unanticipated role for IFN-γ in promoting melanocytic cell survival/immunoevasion, identifying a novel candidate therapeutic target for a subset of melanoma patients.

  19. Effect of space flight on interferon production - mechanistic studies

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald

    1991-01-01

    Ground-based models were studied for the effects of space flight on immune responses. Most time was spent on the model for the antiorthostatic, hypokinetic, hypodynamic suspension model for rats. Results indicate that suspension is useful for modeling the effects of spaceflight on functional immune responses, such as interferon and interleukin production. It does not appear to be useful for modeling shifts in leukocyte sub-populations. Calcium and 1,25-dihydroxyvitamin D sub 3 appear to play a pivitol role in regulating shifts in immune responses due to suspension. The macrophage appears to be an important target cell for the effects of suspension on immune responses.

  20. Treatment of chronic recurrent multifocal osteomyelitis with interferon gamma.

    PubMed

    Gallagher, K T; Roberts, R L; MacFarlane, J A; Stiehm, E R

    1997-09-01

    Chronic recurrent multifocal osteomyelitis is characterized by recurrent episodes of painful swollen lesions of the bone and overlying skin with radiographic changes and an elevated sedimentation rate. It resembles infectious osteomyelitis but with negative findings on bacterial culture and no response to antibiotics. We treated a 13-year-old girl with interferon gamma for 3 months. She had 11 episodes of chronic recurrent multifocal osteomyelitis in 2 1/2 years before therapy and has had none in the 15 months since therapy, an outcome suggesting a favorable therapeutic response.

  1. TLRs and interferons: a central paradigm in autoimmunity.

    PubMed

    Kono, Dwight H; Baccala, Roberto; Theofilopoulos, Argyrios N

    2013-12-01

    Investigations into the pathogenesis of lupus have largely focused on abnormalities in components of the adaptive immune system. Despite important advances, however, the question about the origin of the pathogenic process, the primary disease trigger, and the dominance of autoantibodies against nuclear components, remained unanswered. Discoveries in the last decade have provided some resolution to these questions by elucidating the central role of nucleic acid-sensing TLRs and the attendant inflammatory response, particularly the production of type I interferons. These priming events are responsible for initiating the adaptive responses that ultimately mediate the pathogenic process.

  2. Interferon: signal molecules involved in its antiviral effect.

    PubMed

    Constantinescu, S N; Cernescu, C; Baltă, F; Popescu, L M

    1989-01-01

    A major problem concerning interferon (IFN)-cell interaction is the second messenger system that transduces the IFN signal. We discuss the evidences existing in literature and our arguments which suggest that the antiviral effect of IFNs alpha and beta are mediated by a membrane mechanism including a phospholipase C dependent hydrolysis of phosphoinositides. The resulting two second messengers: diacylglycerol and inositol triphosphate and subsequent, separate but interacting, signal pathways: activation of protein kinase C and ionic events are tested in respect with the antiviral effect of IFN.

  3. Chronic inflammatory demyelinating polyneuropathy after treatment with interferon-alpha.

    PubMed

    Hirotani, Makoto; Nakano, Hitoshi; Ura, Shigehisa; Yoshida, Kazuto; Niino, Masaaki; Yabe, Ichiro; Sasaki, Hidenao

    2009-01-01

    Interferon-alpha (IFN-alpha), though widely used for the treatment of chronic viral hepatitis, may be associated with the occurrence of autoimmune disorders. In this case report, a patient with chronic hepatitis C virus infection had chronic inflammatory demyelinating polyneuropathy (CIDP) after the initiation of IFN-alpha therapy. The neurological symptoms of this patient continued to progress even though the treatment with IFN-alpha had been withdrawn; the symptoms improved dramatically following treatment with intravenous immunoglobulin. This case may therefore provide an important clue to understand the immune mechanism of CIDP and IFN-alpha.

  4. Comparative genomic analysis of eutherian interferon-γ-inducible GTPases.

    PubMed

    Premzl, Marko

    2012-11-01

    The interferon-γ-inducible GTPases, IFGGs, are intracellular proteins involved in immune response against pathogens. A comprehensive comparative genomic review and analysis of eutherian IFGGs was carried out using public genomic sequences. The 64 eutherian IFGG genes were examined in detail and annotated. The eutherian IFGG promoter types were first catalogued followed by a phylogenetic analysis of eutherian IFGGs, which described five major IFGG clusters. The patterns of differential gene expansions and protein regions that may regulate IFGG catalytic features suggested a new classification of eutherian IFGGs. This mini-review has also provided new tests of reliability of public genomic sequences as well as tests of protein molecular evolution.

  5. Treatment of hypereosinophilic syndromes with prednisone, hydroxyurea, and interferon.

    PubMed

    Butterfield, Joseph H

    2007-08-01

    The hypereosinophilic syndromes continue to challenge our clinical acumen and skills. Prednisone, hydroxyurea, and interferon alpha 2b are three of the oldest agents that allow control of eosinophilia and its devastating clinical consequences. They still work. As our experience with them has grown, it has become evident that use of these agents in combination will control eosinophilia in most patients. Moreover, with time, the doses can frequently be reduced. Even with the advent of newer agents for treatment of hypereosinophilic syndromes, these three medications still afford an excellent, cost-effective avenue for disease management.

  6. [Solubilization Specificities Interferon beta-1b from Inclusion Bodies].

    PubMed

    Zhuravko, A S; Kononova, N V; Bobruskin, A I

    2015-01-01

    A new solubilization method of recombinant interferon beta-1b (IFNβ-1b) from the inclusion bodies was developed. This method allows to extract the target protein selectively in the solutions of different alcohols, such as ethanol, propanol and isopropanol. It was shown that the more effective IFNβ-1b solubilization was achieved in the 55% propanol solution. This method allowed to extract the target protein from inclusion bodies around 85-90%, and significantly reduced Escherichia coli content in the solubilizate, in comparison with standard methods.

  7. [The treatment of chronic myeloleukemia with recombinant alfa-2 interferon].

    PubMed

    Strozha, I; Petukhov, V; Bondare, D; Feldmane, G; Duks, A; Teilane, I; Medne, I; Mauritsas, M; Grinberga, L

    1993-01-01

    A trial has been conducted of recombinant alpha 2-interferon (reaferon) used in 32 patients with Ph'[correction of Rh']-positive chronic myeloid leukemia (CML). A chronic stage was in 3, transient in 3 and blast in 1 patients. 25 CML patients were newly diagnosed. The treatment lasted from 2 months to 3 years. Clinicohematological remission was confirmed conventionally and by the degree of Ph'-positive clone reduction. An attempt is made to clarify the mechanism underlying the resistance to reaferon basing on the immunological data (detection of antireaferon neutralizing antibodies). The authors propose a combined treatment (myelosan plus reaferon) of CML which has obvious advantages over myelosan monotherapy.

  8. Computer simulations of human interferon gamma mutated forms

    NASA Astrophysics Data System (ADS)

    Lilkova, E.; Litov, L.; Petkov, P.; Petkov, P.; Markov, S.; Ilieva, N.

    2010-01-01

    In the general framework of the computer-aided drug design, the method of molecular-dynamics simulations is applied for investigation of the human interferon-gamma (hIFN-γ) binding to its two known ligands (its extracellular receptor and the heparin-derived oligosaccharides). A study of 100 mutated hIFN-γ forms is presented, the mutations encompassing residues 86-88. The structural changes are investigated by comparing the lengths of the α-helices, in which these residues are included, in the native hIFN-γ molecule and in the mutated forms. The most intriguing cases are examined in detail.

  9. Interferons as Inducers of Apoptosis in Malignant Cells

    PubMed Central

    Kotredes, Kevin P.

    2013-01-01

    Discovered as antiviral cytokines, interferons (IFNs) are now also recognized for their capacity to inhibit the growth of malignant cells via activation of programmed cell death, better known as apoptosis. In this review, we will cover recent advances made in this field, as it pertains to the various proposed mechanisms of IFN-induced apoptosis and the characterization of IFN-responsive genes not previously known to have apoptotic function. Also mentioned here is a description of the activation and crosstalk of survival signaling pathways as a mode of IFN resistance that remains a persistent clinical adversary to overcome and the future of IFNs as antitumor agents. PMID:23570382

  10. Impaired production of alpha and gamma interferon in asymptomatic homosexual males.

    PubMed

    Bergström, T; Biberfeldt, G; Böttiger, B; Håkansson, C; Hellstrand, K; Hermodsson, S; Norkrans, G; Strannegård, O; Thorén, K

    1986-10-01

    In vitro production of alpha interferon and gamma interferon was examined in cell cultures from 90 asymptomatic homosexual males and 19 healthy heterosexual male controls. The production of alpha and gamma interferon was significantly suppressed in homosexuals as compared to that in heterosexual controls (p less than 0.005 and p less than 0.001, respectively). Forty-one of the homosexuals produced less gamma interferon than any of the heterosexual controls. Antibodies against the human immune system virus (HIV) were found in eight homosexuals, who produced significantly less alpha and gamma interferon than did the HIV-seronegative homosexuals (p less than 0.02). Neither carriage of Entamoeba histolytica or Giardia lamblia nor serological evidence of infection with cytomegalovirus, Epstein-Barr virus or hepatitis B virus was associated with a significantly lower production of interferon than that found in homosexual males seronegative for these infections. No correlation was found between number of partners or practice of passive anal intercourse and production of interferons in homosexual men. It is concluded that the significantly lower production of both alpha and gamma interferon in asymptomatic homosexual males may play an important role in susceptibility to viruses, including HIV.

  11. Interferon-. alpha. selectively activates the. beta. isoform of protein kinase C through phosphatidylcholine hydrolysis

    SciTech Connect

    Pfeffer, L.M.; Saltiel, A.R. ); Strulovici, B. )

    1990-09-01

    The early events that occur after interferon binds to discrete cell surface receptors remain largely unknown. Human leukocyte interferon (interferon-{alpha}) rapidly increases the binding of ({sup 3}H)phorbol dibutyrate to intact HeLa cells a measure of protein kinase C activation, and induces the selective translocation of the {beta} isoform of protein kinase C from the cytosol to the particulate fraction of HeLa cells. The subcellular distribution of the {alpha} and {epsilon} isoforms is unaffected by interferon-{alpha} treatment. Activation of protein kinase C by phorbol esters mimics the inhibitory action of interferon-{alpha} on HeLa cell proliferation and down-regulation of protein kinase C blocks the induction of antiviral activity by interferon-{alpha} in HeLa cells. Increased phosphatidylcholine hydrolysis and phosphorylcholine production is accompanied by diacylglycerol production in response to interferon. However, inositol phospholipid turnover and free intracellular calcium concentration are unaffected. These results suggest that the transient increase in diacylglycerol, resulting from phosphatidylcholine hydrolysis, may selectively activate the {beta} isoform of protein kinase C. Moreover, the activation of protein kinase C is a necessary element in interferon action on cells.

  12. Inhibitory effect of interferon-gamma on adenovirus replication and late transcription.

    PubMed

    Mistchenko, A S; Diez, R A; Falcoff, R

    1989-06-15

    We have previously shown that human interferon-gamma inhibited adenovirus multiplication in vitro in a dose-dependent fashion. This action was previous to capsid proteins synthesis and did not involve virus adsorption nor penetration. In this report we have analysed viral mRNA levels at early (7 hr post infection (p.i.)) or late (20 hr p.i.) times, as well as DNA replication in Wish cells pretreated with interferon-gamma and infected with adenovirus 5. Controls included untreated cells as well as cells treated with interferon-alpha, to which adenovirus are reported to be resistant. Transcription of adenovirus regions E1, E4, L1 and L2 has been analysed by Northern blot. Adenovirus DNA replication was determined by DNA-DNA hybridization with total adenovirus 2 DNA. We have also searched for adenovirus E1A proteins by immunoblot with a specific monoclonal antibody. Although pretreatment of cells with either interferon-alpha or interferon-gamma resulted in reduced amounts of E1 and E4 mRNA in the early phase of infection (7 hr p.i.), the near complete inhibition of viral DNA and late transcription was only achieved by interferon-gamma. Immunoblot has shown the absence of the 48-kD E1A protein in cells pretreated with interferon-gamma. The lack of this regulatory adenovirus protein may be involved in the inhibitory mechanism of interferon-gamma on adenovirus.

  13. Bell's palsy during interferon therapy for chronic hepatitis C infection in patients with haemorrhagic disorders.

    PubMed

    Ogundipe, O; Smith, M

    2000-03-01

    Two adult patients with life-long severe haemorrhagic disorders commenced on interferon-alpha2b therapy for chronic hepatitis C infection. Both developed Bell's palsy several weeks after commencing therapy, They were started on steroids and, in addition, the first patient discontinued interferon-alpha2b therapy while the second patient elected to continue with therapy. In both cases facial paralysis improved over the ensuing weeks. Bell's palsy is often idiopathic but has been reported. in association with herpesviruses. It is not a recognised complication of chronic hepatitis B or C infection, or interferon-alpha2b therapy. However, the interferons are associated with numerous adverse reactions including various neuropsychiatric manifestations and neurological syndromes. There are several reports of nerve palsies, including optic tract neuropathy, occurring during interferon therapy, and immune-based mechanisms are thought to play a role in the aetiopathogenesis. No reports of Bell's palsy in association with interferon therapy were identified in our literature search, although one possible case has been reported to the Committee of Safety in Medicine. Although Bell's palsy in our patients may have occurred by chance, a neuropathic effect of interferon-alpha2b on the facial nerve cannot be excluded and we urge physicians using interferons to be aware of this potential side-effect.

  14. Targeted Therapies: Bevacizumab and interferon-alpha in metastatic renal-cell carcinoma.

    PubMed

    Bukowski, Ronald M

    2009-05-01

    Rini and colleagues provide additional data on bevacizumab and interferon-alpha in clear-cell carcinoma of the kidney; a comparison of these results with the findings from contemporary trials suggests that bevacizumab and interferon-alpha is another clinically useful treatment option for patients with metastatic renal-cell carcinoma.

  15. Successful topical treatment of focal epithelial hyperplasia (Heck's disease) with interferon-beta.

    PubMed

    Steinhoff, M; Metze, D; Stockfleth, E; Luger, T A

    2001-05-01

    We report the successful topical treatment of focal epithelial hyperplasia (Heck's disease) with interferon-beta (Fiblaferon gel). Topical treatment with interferon-beta appears to be an effective, simple, non-invasive, cheap and low-risk alternative to other invasive or surgical therapeutic modalities.

  16. The genes of interferons and interferon-related factors: localization and relationships with chromosome aberrations in cancer.

    PubMed

    Haus, O

    2000-01-01

    The paper presents a review of data on the localization of interferons (IFNs) and IFN system genes and their relationship with human diseases, mainly cancer. Genes of interferon system proteins are located at the sites of breakpoints of the structural chromosome aberrations in cancer. Thus, any of them are rearranged or translocated in various tumor types. As the activity of these genes plays a role in cancer development, their rearrangements may be one of the crucial points in the pathogenesis of some cancer types. Besides, they also take part in organism immunity against viral infections. Transfection experiments with IFN system genes have proved the influence of these genes on cancer behavior and may serve as a basis for clinical gene therapy. IFN-alpha and IFN-beta genes are located at 9p21-22, the site of frequent homozygotic deletions in cancer. Their loss sensitizes cells to the growth inhibitory actions of exogenous IFNs. The IFN-gamma gene, a representative of class II genes, is located at 12q24.1. Transfection of class II IFNs genes to cancer cell lines causes cell proliferation arrest and augments the expression of HLA antigens, which may be clinically useful in stimulating the immune destruction of tumor cells. The interferon regulatory factor 1 (IRF-1) gene is located at 5q31, the site of common deletions in myelodysplastic syndromes (MDS) and secondary leukemias. The loss of heterozygosity of this gene was found in MDS, which proves that IRF-1 may be a tumor suppressor. A transfection of its gene causes neoplastic transformation arrest. The double-stranded RNA-activated protein kinase (PKR) gene is located at 2p21-22, a region which is frequently rearranged in leukemia. Transfection of a wild type PKR gene reverses neoplastic transformation caused by transfection of a mutated PKR gene, proving that PKR acts as a dominant negative cancer suppressor.

  17. The bacterial pathogen Listeria monocytogenes and the interferon family: type I, type II and type III interferons

    PubMed Central

    Dussurget, Olivier; Bierne, Hélène; Cossart, Pascale

    2014-01-01

    Interferons (IFNs) are secreted proteins of the cytokine family that regulate innate and adaptive immune responses to infection. Although the importance of IFNs in the antiviral response has long been appreciated, their role in bacterial infections is more complex and is currently a major focus of investigation. This review summarizes our current knowledge of the role of these cytokines in host defense against the bacterial pathogen Listeria monocytogenes and highlights recent discoveries on the molecular mechanisms evolved by this intracellular bacterium to subvert IFN responses. PMID:24809023

  18. The bacterial pathogen Listeria monocytogenes and the interferon family: type I, type II and type III interferons.

    PubMed

    Dussurget, Olivier; Bierne, Hélène; Cossart, Pascale

    2014-01-01

    Interferons (IFNs) are secreted proteins of the cytokine family that regulate innate and adaptive immune responses to infection. Although the importance of IFNs in the antiviral response has long been appreciated, their role in bacterial infections is more complex and is currently a major focus of investigation. This review summarizes our current knowledge of the role of these cytokines in host defense against the bacterial pathogen Listeria monocytogenes and highlights recent discoveries on the molecular mechanisms evolved by this intracellular bacterium to subvert IFN responses.

  19. [Gamma interferon induced in human leukocytes by phytohemagglutinin: its production and biological characteristics].

    PubMed

    Danielescu, G; Maniu, H; Georgescu, T; Cajal, N

    1988-01-01

    Human gamma type interferon (IFN) preparations were obtained through phytohemagglutinin stimulation of leukocytes from the peripheral blood. Biological value of these preparations varied between 160 u and 800 u/ml, depending on leukocyte incubation medium, culture system and inductor conservation. The rising of the antiviral activity through association between gamma (3 u) and alpha (27 u) interferons was revealed by the virus quantity reduction (in this case the vesicular stomatitis virus was used) during a 24-hour multiplication cycle. The protection ensured by the mixture of the two types of interferon was about ten times higher than the additive effect of the two preparations. Study of the antiproliferative activity of a gamma interferon preparation was conducted on two human cell lines of tumoral origin (T-10 from a glioblastoma, and HEp-2) and revealed the difficulties to quantify precisely this property of the crude gamma interferon preparations.

  20. Role for herpes simplex virus 1 ICP27 in the inhibition of type I interferon signaling

    SciTech Connect

    Johnson, Karen E.; Song, Byeongwoon; Knipe, David M.

    2008-05-10

    Host cells respond to viral infection by many mechanisms, including the production of type I interferons which act in a paracrine and autocrine manner to induce the expression of antiviral interferon-stimulated genes (ISGs). Viruses have evolved means to inhibit interferon signaling to avoid induction of the innate immune response. Herpes simplex virus 1 (HSV-1) has several mechanisms to inhibit type I interferon production, the activities of ISGs, and the interferon signaling pathway itself. We report that the inhibition of the Jak/STAT pathway by HSV-1 requires viral gene expression and that viral immediate-early protein ICP27 plays a role in downregulating STAT-1 phosphorylation and in preventing the accumulation of STAT-1 in the nucleus. We also show that expression of ICP27 by transfection causes an inhibition of IFN-induced STAT-1 nuclear accumulation. Therefore, ICP27 is necessary and sufficient for at least some of the effects of HSV infection on STAT-1.

  1. [Mechanisms underlying interferon-mediated host innate immunity during influenza A virus infection].

    PubMed

    Chen, Chao; Chi, Xiaojuan; Bai, Qingling; Chen, Jilong

    2015-12-01

    Influenza A virus can create acute respiratory infection in humans and animals throughout the world, and it is still one of the major causes of morbidity and mortality in humans worldwide. Numerous studies have shown that influenza A virus infection induces rapidly host innate immune response. Influenza A virus triggers the activation of signaling pathways that are dependent on host pattern recognition receptors (PRRs) including toll like receptors (TLRs) and RIG-I like receptors (RLRs). Using a variety of regulatory mechanisms, these signaling pathways activate downstream transcript factors that control expression of various interferons and cytokines, such as type I and type III interferons. Thus, these interferons stimulate the transcript of relevant interferon-stimulated genes (ISGs) and expression of the antiviral proteins, which are critical components of host innate immunity. In this review, we will highlight the mechanisms by which influenza A virus infection induces the interferon-mediated host innate immunity.

  2. Effect of antiorthostatic suspension on interferon-alpha/beta production by the mouse (41939)

    NASA Technical Reports Server (NTRS)

    Rose, Andrea; Steffen, Joseph M.; Musacchia, X. J.; Sonnenfeld, Gerald; Mandel, Adrian D.

    1984-01-01

    Mice were suspended in a model that simulates the weightlessness that occurs during prolonged space flight. After one and two weeks of suspension in an antiorthostatic (head-down tilt) position, the mice were challenged with polyriboinosinic-polyribocytidylic acid to induce interferon-alpha/beta. Interferon production was severely reduced in mice that had been suspended. When mice were allowed to recover in cages for a week following removal from suspension, they recovered their full interferon-production capacity. Mice suspended in an orthostatic (horizontal) position did not have their interferon production capabilities affected, which indicates that stress per se was not a major component in the effects of antiorthostatic suspension on interferon induction.

  3. How cells respond to interferons revisited: From early history to current complexity

    PubMed Central

    Stark, George R.

    2007-01-01

    A brief account of how I became involved in interferon research is followed by recollections of key experiments that led to the discovery of the roles of the JAKs and STATs in interferon-dependent signaling. I then outline the complex responses of cells to interferons, including the roles of kinases other than JAKs and transcription factors other than STATs, differential responses to interferons α and β, modulation of response by prior exposure to other cytokines (“priming”), cytokine-dependent induction of high level expression of STATs 1 and 3 and the activation of a new set of genes by these unphosphorylated STATs, and diverse patterns of STAT activation in different cell types in response to a single interferon. PMID:17683974

  4. Microalbuminuria and pegylated interferon in hepatitis-C patients.

    PubMed

    Elshahawi, Yasser; Sany, Dawlat; Abd Elmohsen, Walid Anwar; Tantawi, Tarek

    2015-11-01

    To determine the relation between hepatitis C virus (HCV) genotype 4 and microalbuminuria in relation to hepatic histology and viremia in the absence of cryoglobulinemia and to examine the effect of treatment on microalbuminuria, we studied 400 HCV genotype-4-infected patients who were tested for microalbuminuria, albumin creatinine ratio (ACR), urea, creatinine and estimated glomerular filtration rate (eGFR). The parameters were measured again in the HCV patients after six months of treatment with pegylated interferon and ribavirin. Microalbuminuria was detected in 56 (14%) HCV-positive patients. There was a highly significant reduction in the microalbuminuria levels among the HCV-positive individuals after six months of therapy (P <0.001). Microalbuminuria was significantly associated with older age [Odds Ratio (OR): 1.1, 95% confidence interval (CI): 1.0-1.2, P = 0.01], elevated creatinine (OR: 0.09, 95% CI: 0.01- 0.7, P = 0.02), high modified Histological Activity Index score (OR: 1.5, 95% CI: 1.1-1.5, P = 0.004) and increased viral load (OR: 2.8, 95% CI: 1.1-6.6, P = 0.01). Sustained virological response (SRV) was achieved in 272 (86%) patients. The individuals with SVR had lower microalbuminuria post-treatment (P = 0.56). We conclude that HCV infection can be associated with microalbuminuria, which can be reduced by the use of a combination therapy of pegylated interferon-ribavirin.

  5. Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer

    PubMed Central

    Trott, Josephine F.; Kim, Jeffrey; Aboud, Omran Abu; Wettersten, Hiromi; Stewart, Benjamin; Berryhill, Grace; Uzal, Francisco; Hovey, Russell C.; Chen, Ching-Hsien; Anderson, Katie; Graef, Ashley; Sarver, Aaron L; Modiano, Jaime F.; Weiss, Robert H.

    2016-01-01

    Renal cell carcinoma (RCC) is increasing in incidence, and a complete cure remains elusive. While immune-checkpoint antibodies are promising, interferon-based immunotherapy has been disappointing. Tryptophan metabolism, which produces immunosuppressive metabolites, is enhanced in RCC. Here we show indolamine-2,3-dioxygenase-1 (IDO1) expression, a kynurenine pathway enzyme, is increased not only in tumor cells but also in the microenvironment of human RCC compared to normal kidney tissues. Neither kynurenine metabolites nor IDO inhibitors affected the survival or proliferation of human RCC or murine renal cell adenocarcinoma (RENCA) cells in vitro. However, interferon-gamma (IFNγ) induced high levels of IDO1 in both RCC and RENCA cells, concomitant with enhanced kynurenine levels in conditioned media. Induction of IDO1 by IFNα was weaker than by IFNγ. Neither the IDO1 inhibitor methyl-thiohydantoin-DL-tryptophan (MTH-trp) nor IFNα alone inhibited RENCA tumor growth, however the combination of MTH-trp and IFNα reduced tumor growth compared to IFNα. Thus, the failure of IFNα therapy for human RCC is likely due to its inability to overcome the immunosuppressive environment created by increased IDO1. Based on our data, and given that IDO inhibitors are already in clinical trials for other malignancies, IFNα therapy with an IDO inhibitor should be revisited for RCC. PMID:27572319

  6. Type I interferon signaling protects mice from lethal henipavirus infection.

    PubMed

    Dhondt, Kévin P; Mathieu, Cyrille; Chalons, Marie; Reynaud, Joséphine M; Vallve, Audrey; Raoul, Hervé; Horvat, Branka

    2013-01-01

    Hendra virus (HeV) and Nipah virus (NiV) are closely related, recently emerged paramyxoviruses that form Henipavirus genus and are capable of causing considerable morbidity and mortality in a number of mammalian species, including humans. However, in contrast to many other species and despite expression of functional virus entry receptors, mice are resistant to henipavirus infection. We report here the susceptibility of mice deleted for the type I interferon receptor (IFNAR-KO) to both HeV and NiV. Intraperitoneally infected mice developed fatal encephalitis, with pathology and immunohistochemical features similar to what was found in humans. Viral RNA was found in the majority of analyzed organs, and sublethally infected animals developed virus-specific neutralizing antibodies. Altogether, these results reveal IFNAR-KO mice as a new small animal model to study HeV and NiV pathogenesis, prophylaxis, and treatment and suggest the critical role of type I interferon signaling in the control of henipavirus infection.

  7. Environmental triggers of thyroiditis: hepatitis C and interferon-α.

    PubMed

    Menconi, F; Hasham, A; Tomer, Y

    2011-01-01

    Autoimmune thyroid diseases (AITD) are postulated to develop as a result of a complex interplay between several genetic and environmental influences. The pathogenesis of AITD is still not clearly defined. However, among the implicated triggers (e.g. iodine, infections, medications), more recent data confirmed strong associations of AITD with the hepatitis C virus (HCV) infection and interferon-α (IFNα) therapy. Moreover, it is likely that HCV and IFN act in synergism to trigger AITD in patients. Indeed, approximately 40% of HCV patients develop either clinical or subclinical disease while receiving IFNα. Interferon induced thyroiditis (IIT) can manifest as non-autoimmune thyroiditis (presenting as destructive thyroiditis, or non-autoimmune hypothyroidism), or autoimmune thyroiditis [presenting with clinical features of Graves' disease (GD) or Hashimoto's thyroiditis (HT)]. Although not yet clearly understood, it is thought that IFNα can induce thyroiditis via both immune stimulatory and direct toxic effects on the thyroid. In view of the high frequency of IIT, routine screening and surveillance of HCV patients receiving IFNα is recommended to avoid the complications, such as cardiac arrhythmias, associated with thyrotoxicosis. In summary, IIT is a common clinical problem that can be readily diagnosed with routine thyroid function screening of HCV patients receiving IFN. The treatment of IIT consists of the standard therapy for differing clinical manifestations of IIT such as GD, HT, or destructive thyroiditis. However, anti-thyroid medications are not recommended in this setting since they can potentially be hepatotoxic.

  8. INTERFERONS AND THEIR STIMULATED GENES IN THE TUMOR MICROENVIRONMENT

    PubMed Central

    Cheon, HyeonJoo; Borden, Ernest C.; Stark, George R.

    2014-01-01

    Constitutive expression of interferons (IFNs) and activation of their signaling pathways have pivotal roles in host responses to malignant cells in the tumor microenvironment. IFNs are induced from the innate immune system and in tumors through stimulation of Toll-like receptors (TLRs) and through other signaling pathways in response to specific cytokines. Although in the oncologic context IFNs have been thought of more as exogenous pharmaceuticals, the autocrine and paracrine actions of endogenous IFNs probably have even more critical effects on neoplastic disease outcomes. Through high-affinity cell surface receptors, IFNs modulate transcriptional signaling, leading to regulation of over 2000 genes with varying patterns of temporal expression. Induction of the gene products by both unphosphorylated and phosphorylated STAT1 after ligand binding, results in alterations in tumor cell survival, inhibition of angiogenesis, and augmentation of actions of T, natural killer (NK), and dendritic cells. The interferon-stimulated gene (ISG) signature can be a favorable biomarker of immune response but, in a seemingly paradoxical finding, a specific subset of the full ISG signature indicates an unfavorable response to DNA damaging interventions such as radiation. IFNs in the tumor microenvironment thus can alter the emergence, progression, and regression of malignancies. PMID:24787290

  9. The HIN-200 family: More than interferon-inducible genes?

    SciTech Connect

    Ludlow, Louise E.A.; Johnstone, Ricky W.; Clarke, Christopher J.P. . E-mail: chris.clarke@petermac.org

    2005-08-01

    The HIN-200 family was initially grouped together based on their hemopoietic expression, interferon-inducibility, nuclear localization, and characteristic 200 amino-acid domains. In this review, we performed a comprehensive search of genome databases and determined the location of previously characterized and predicted genes within the human, mouse, and rat HIN-200 loci. Several novel proteins were predicted in the mouse and rat. We also discuss recent advances in our understanding of this family of proteins and highlight the most important findings. In addition to a role in interferon biology, there is now good evidence supporting a role for these proteins as regulators of cell proliferation and differentiation. The activity of HIN-200 proteins is not restricted to the hemopoietic system as they are expressed and can function in a variety of other cells and tissues. The importance of HIN-200 proteins in disease now is beginning to be understood as they appear to be involved in autoimmunity and may act as tumor suppressor proteins.

  10. Interferon-stimulated gene 15 and the protein ISGylation system.

    PubMed

    Zhang, Dongxian; Zhang, Dong-Er

    2011-01-01

    Interferon-stimulated gene 15 (ISG15) is one of the most upregulated genes upon Type I interferon treatment or pathogen infection. Its 17  kDa protein product, ISG15, was the first ubiquitin-like modifier identified, and is similar to a ubiquitin linear dimer. As ISG15 modifies proteins in a similar manner to ubiquitylation, protein conjugation by ISG15 is termed ISGylation. Some of the primary enzymes that promote ISGylation are also involved in ubiquitin conjugation. The process to remove ISG15 from its conjugated proteins, termed de-ISGylation, is performed by a cellular ISG15-specific protease, ubiquitin-specific proteases with molecular mass 43 kDa (UBP43)/ubiquitin-specific proteases 18. Relative to ubiquitin, the biological function of ISG15 is still poorly understood, but ISG15 appears to play important roles in various biological and cellular functions. Therefore, there is growing interest in ISG15, as the study of free ISG15 and functional consequences of ISGylation/de-ISGylation may identify useful therapeutic targets. This review highlights recent discoveries and remaining questions important to understanding the biological functions of ISG15.

  11. Ophthalmological side effects of interferon therapy of chronic hepatitis C

    PubMed Central

    Medhat, Eman; Esmat, Gamal; Hamza, Eman; Abdel Aziz, Amr; Fouad Fathalah, Waleed; Zakaria, Zeinab; Mostafa, Sameh

    2016-01-01

    Background Egypt has one of the highest prevalence of hepatitis C virus (HCV) worldwide. Ophthalmological side effects are recognized complications of interferon (IFN) therapy. This study aimed to evaluate IFN-induced ophthalmological manifestations in patients receiving PEGylated interferon (PEG IFN) and ribavirin (RBV) and to assess the effect of IFN duration, response and systemic risk factors on the severity. Methods We retrospectively analyzed 100 patients with chronic HCV who were candidates for PEG-IFN and RBV therapy. All patients were subjected to clinical and ophthalmological examination, laboratory investigations, abdominal ultrasound, colored fundus photography and fundus fluorescein angiography, follow up was made at weeks 12, 24, and 48 of treatment. Results IFN-induced retinopathy had been found in (9/100; 9%), 5 (5/9; 55.5%) of them had bilateral lesions, (3/9; 33.3%) were treatment responders and (6/9; 66.6%) non responders. The time of retinopathy appearance was mainly at W12. Retinopathy was asymptomatic in most of the affected patients (7/9; 77.77%) and reversible, cotton wool spots was the major associated sign. Patients with older age, DM and or HTN, and non-responders to antiviral therapy were associated with more severe retinopathy. Conclusions Retinopathy is not a rare complication of IFN therapy for chronic HCV infection, but fortunately it’s asymptomatic and reversible. Ophthalmological assessment at base-line and at follow up during IFN treatment is very important. PMID:27275462

  12. Hepatitis B, interferon, and acne fulminans in a young girl

    PubMed Central

    Arora, Sandeep; Malik, Ajay; Kumar, Dharmendra; Sodhi, Neha

    2016-01-01

    Acne fulminans (AF) is a very rare severe form of acne seen in young males, characterized by a sudden and explosive onset of hemorrhagic pustules and ulceration on the trunk, systemic features in the form of fever, polyarthropathy, malaise, erythema nodosum and painful osteolytic bone involvement with leukocytosis, and an elevated erythrocyte sedimentation rate. Conventional treatment of AF includes corticosteroids or immunosuppressive agents for the initial phase followed by isotretinoin. Active hepatitis B infection with a high viral load precludes the administration of any immunosuppressive drugs. We present the case of an 18-year-old girl with a history of occasional acne who presented with AF of sudden onset following administration of interferon-alpha-2a for her recently detected hepatitis B infection. Management of hepatitis B was withheld in view of her general condition. The patient was managed with low dose isotretinoin with subsidence of lesions. AF in a young female precipitated by interferon and its management with isotretinoin in the presence of active hepatitis B infection make the case unique. PMID:27057488

  13. The Role of Type 1 Interferon in Systemic Sclerosis

    PubMed Central

    Wu, Minghua; Assassi, Shervin

    2013-01-01

    Systemic Sclerosis (Scleroderma, SSc) is an autoimmune disease characterized by vasculopathy, inflammation, and fibrosis that can lead to loss of organ function. Type I interferons (IFNs) are family of cytokines that mitigate the deleterious effects of viral and bacterial infections in the innate immunity system. Past several years, research efforts have been focused on the role of type I IFN and IFN-inducible genes in the pathogenesis of SSc. Polymorphisms in the Interferon regulatory factor (IRF)-5, IRF7, and IRF8 are associated with SSc, Similarly, polymorphism of Signal Transducer and Activator of Transcription (STAT)-4, has been established as a genetic risk factor of SSc. IRFs and STAT4 proteins are key activators of type I IFN signaling pathways. An IFN signature (increased expression and activation of IFN-regulated genes) has been observed in the peripheral blood and skin biopsy samples of patients with SSc. Furthermore, a plasma IFN-inducible chemokine score correlated with markers of disease severity and autoantibody subtypes in SSc. In this review, we summarize our current knowledge of the role of type I IFNs and IFN-inducible genes in the pathogenesis of SSc and their potential role as biomarkers and therapeutic targets. PMID:24046769

  14. Interferon Gamma Receptor: The Beginning of the Journey

    PubMed Central

    Blouin, Cédric M.; Lamaze, Christophe

    2013-01-01

    Our view of endocytosis and membrane trafficking of transmembrane receptors has dramatically changed over the last 20 years. Several new endocytic routes have been discovered and mechanistically characterized in mammalian cells. Long considered as a passive means to terminate signaling through down-regulation of the number of activated receptors at the plasma membrane, it is now established that receptor endocytosis and endosomal sorting can be directly linked to the regulation of intracellular signaling pathways. The functional links between membrane trafficking of interferon receptors and JAK/STAT signaling have recently begun to be unraveled. These studies raise the exciting possibility that a certain level of signal specificity can be achieved through endocytosis and selective localization of the activated complexes within cellular membranes. The ongoing development of high-resolution cell imaging techniques with better spatial and temporal resolution gives new means of deciphering the inherent complexity of membrane trafficking and signaling. This should help to better comprehend the molecular mechanisms by which endocytosis and endosomal sorting of interferon receptors can orchestrate signaling selectivity within the JAK/STAT pathway that can be activated by as many as 60 different cytokines, growth factors, and hormones. PMID:24027571

  15. Parsing the Interferon Transcriptional Network and Its Disease Associations.

    PubMed

    Mostafavi, Sara; Yoshida, Hideyuki; Moodley, Devapregasan; LeBoité, Hugo; Rothamel, Katherine; Raj, Towfique; Ye, Chun Jimmie; Chevrier, Nicolas; Zhang, Shen-Ying; Feng, Ting; Lee, Mark; Casanova, Jean-Laurent; Clark, James D; Hegen, Martin; Telliez, Jean-Baptiste; Hacohen, Nir; De Jager, Philip L; Regev, Aviv; Mathis, Diane; Benoist, Christophe

    2016-01-28

    Type 1 interferon (IFN) is a key mediator of organismal responses to pathogens, eliciting prototypical "interferon signature genes" that encode antiviral and inflammatory mediators. For a global view of IFN signatures and regulatory pathways, we performed gene expression and chromatin analyses of the IFN-induced response across a range of immunocyte lineages. These distinguished ISGs by cell-type specificity, kinetics, and sensitivity to tonic IFN and revealed underlying changes in chromatin configuration. We combined 1,398 human and mouse datasets to computationally infer ISG modules and their regulators, validated by genetic analysis in both species. Some ISGs are controlled by Stat1/2 and Irf9 and the ISRE DNA motif, but others appeared dependent on non-canonical factors. This regulatory framework helped to interpret JAK1 blockade pharmacology, different clusters being affected under tonic or IFN-stimulated conditions, and the IFN signatures previously associated with human diseases, revealing unrecognized subtleties in disease footprints, as affected by human ancestry.

  16. Prognostic significance of autoimmunity during treatment of melanoma with interferon.

    PubMed

    Krauze, Michal T; Tarhini, Ahmad; Gogas, Helen; Kirkwood, John M

    2011-07-01

    Since the pivotal cooperative group trials in the 1980's-90's,, high-dose interferon (HDI) has been the standard of adjuvant therapy. Despite multiple other trials evaluating potential new therapies in melanoma, HDI remains the only FDA-approved therapy for stage IIB and III melanoma. Initial reports from the more recent phase III international trials of modifications of the original HDI regimen linked the appearance of autoimmunity with improved outcomes of disease. Trials of high-dose interleukin-2, many years earlier, reported anecdotal observations that were consistent with the hypothesis that autoimmunity and clinical benefit of immunotherapies of melanoma are linked with one another. The only prospectively conducted study examining the appearance of clinical and laboratory evidence of autoimmunity during HDI therapy was published by Gogas and colleagues, demonstrating statistically significant impact on relapse-free survival and overall survival. Retrospectively conducted studies of different intermediate dosage regimens of interferon (IFN) have not fully confirmed the linkage of serological evidence of autoimmunity and improved survival outcomes. With the emergence of new immunotherapies in treatment of melanoma, this review highlights the importance of autoimmunity for future applications in melanoma and reviews significant differences of past studies evaluating the appearance of autoimmunity during IFN therapy in high-risk melanoma.

  17. Interferon but not MxB inhibits foamy retroviruses.

    PubMed

    Bähr, Ariane; Singer, Anna; Hain, Anika; Vasudevan, Ananda Ayyappan Jaguva; Schilling, Mirjam; Reh, Juliane; Riess, Maximilian; Panitz, Sylvia; Serrano, Vanessa; Schweizer, Matthias; König, Renate; Chanda, Sumit; Häussinger, Dieter; Kochs, Georg; Lindemann, Dirk; Münk, Carsten

    2016-01-15

    Foamy viruses (FV) are retroviruses that are widely distributed in primate and non-primate animal species. We tested here FV with capsids of simian and non-simian origin for sensitivity to interferon-β (IFN-β). Our data show significant inhibition of FV by IFN-β early in infection of human HOS and THP-1 but not of HEK293T cells. The post-entry restriction of FV was not mediated by the interferon-induced MxB protein that was recently identified as a capsid-interacting restriction factor targeting Human immunodeficiency virus (HIV) before integration. Neither the ectopic expression of MxA or MxB in HEK293T cells nor the lack of MxB expression in CRISPR/CAS MxB THP-1 knockout cells impacted the infection of the tested FV. IFN-β treated THP-1 and THP-1 KO MxB cells showed the same extend of restriction to FV. Together, the data demonstrate that IFN-β inhibits FV early in infection and that MxB is not a restriction factor of FV.

  18. Antiviral and antiproliferative effects of canine interferon-λ1.

    PubMed

    Ichihashi, Tomonori; Asano, Atsushi; Usui, Tatsufumi; Takeuchi, Takashi; Watanabe, Yasuko; Yamano, Yoshiaki

    2013-11-15

    Interferon (IFN)-λs, members of the type III IFN group, were recently identified in several vertebrates. Although IFN-λs have the potential to be utilized as antiviral and antitumor agents in veterinary medicine, the biological properties of IFN-λs have not yet been studied in companion animals. In this study, we analyzed the expression of canine IFN-λs and their receptors, produced a recombinant canine IFN-λ1 protein, and investigated its antiviral and antiproliferative activities using a canine kidney epithelial cell line, MDCK cells. MDCK cells were found to express type III IFN molecules, IFN-λ1 and IFN-λ3, and the receptors, IFNλR1 and IL10R2. IFN-λ1 was induced faster than IFN-λ3 by stimulation with poly (I:C). His-tagged IFN-λ1 protein expressed in Escherichia coli inhibited cytolytic plaque formation by influenza A virus infection, and induced the expression of interferon-stimulated genes, Mx1 and OAS1, in MDCK cells. In addition, recombinant IFN-λ1 inhibited the proliferation of MDCK cells slightly. These effects were observed in a dose-dependent manner. These results indicate that canine IFN-λ1 has antiviral effect, and suggest the potential applicability of canine IFN-λ1 as a therapeutic agent.

  19. Antiviral Effect of Interferon Lambda Against Lymphocytic Choriomeningitis Virus.

    PubMed

    Lukacikova, Lubomira; Oveckova, Ingrid; Betakova, Tatiana; Laposova, Katarina; Polcicova, Katarina; Pastorekova, Silvia; Pastorek, Jaromir; Tomaskova, Jana

    2015-07-01

    Lambda interferons inhibit replication of many viruses, but their role in the inhibition of lymphocytic choriomeningitis virus (LCMV) infection remains unclear. In this study, we examined the antiviral effects of interferon (IFN)-λ2 and IFN-λ3 against LCMV in A549 cells. We found that IFN-λ2 is a more potent inhibitor of LCMV strain MX compared with IFN-λ3, whereas both cytokines have similar antiviral effects against an immunosuppressive variant of LCMV, clone-13. We also demonstrated that the antiviral activity of IFN-λ2 is more effective if it is delivered early rather than after establishment of a long-term infection, suggesting that virus replication is only partially responsive to the cytokine. In agreement with this observation, we showed that LCMV infection significantly reduces IFNLR1 mRNA expression in infected cells. In addition, LCMV infection, to some extent, compromises the signal transduction pathway of IFN-λ2. This implies that IFN receptors as well as their downstream signaling components could be selectively targeted either directly by LCMV proteins or indirectly by cellular factor(s) that are induced or activated by LCMV infection.

  20. A controlled randomised trial of t-UDCA as adjuvant to interferon for treatment of chronic hepatitis C: an interferon sparing effect of t-UDCA.

    PubMed

    Gracielle, Pigozzi; Roberta, Sorbara; Ornella, Baisini; Luciana, Di; Alessandro, Reggiani; Daniela, Quattrocchi; Gianpaolo, Lorini; Grazia, De; Lamberto, Bettini; Anna, Cominotti; Maurizio, Favret; Alberto, Lanzini

    2002-08-01

    BACKGROUND: Combination of the cytoprotective effect of tauro-ursodeoxycholic acid (t-UDCA) with the antiviral effect of interferon may be more effective than interferon alone for treatment of chronic hepatitis C. METHODS: We randomised 106 patients with chronic hepatitis C to interferon 3 MU/m(2)/3 times per week given alone (regimen A, n=51) or in combination with t-UDCA 10 mg/kg/day (regimen B, n=55) for 6 months followed by IFN dose tapering for further 6 months. Control liver biopsies were obtained 6 months after stopping treatment. RESULTS: At the end of the trial a similar proportion of patients had normal serum alanine aminotransferase activity (ALT) levels (41 and 44%) and negative viremia (42 and 43%) with regimens A and B, respectively. The effect on liver histology was also similar, and the Knodell score decreased by 2.9+/-0.4 points with both regimens. During the dose tapering phase, the cumulative interferon dose to maintain ALT activity within the normal range was significantly lower for regimen B (142+/-4 million units, MU) than for regimen A (180+/-12 MU, P<0.005). CONCLUSIONS: Adjuvant t-UDCA exerts an 'interferon sparing effect' that may be of value for patients intolerant to high dose interferon.

  1. 78 FR 46593 - Prospective Grant of Start-up Exclusive License: Kits for the Detection of Human Interferon-Alpha...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-01

    ... the Detection of Human Interferon-Alpha Subtypes and Allotypes AGENCY: National Institutes of Health...-2008/0), titled ``Compositions for Detecting Human Interferon- Alpha Subtypes and Methods of Use'', to.... This technology relates to use of kits for the detection of human interferon-alpha subtypes and...

  2. Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier.

    PubMed

    Lazear, Helen M; Daniels, Brian P; Pinto, Amelia K; Huang, Albert C; Vick, Sarah C; Doyle, Sean E; Gale, Michael; Klein, Robyn S; Diamond, Michael S

    2015-04-22

    Although interferon-λ [also known as type III interferon or interleukin-28 (IL-28)/IL-29] restricts infection by several viruses, its inhibitory mechanism has remained uncertain. We used recombinant interferon-λ and mice lacking the interferon-λ receptor (IFNLR1) to evaluate the effect of interferon-λ on infection with West Nile virus, an encephalitic flavivirus. Cell culture studies in mouse keratinocytes and dendritic cells showed no direct antiviral effect of exogenous interferon-λ, even though expression of interferon-stimulated genes was induced. We observed no differences in West Nile virus burden between wild-type and Ifnlr1(-/-) mice in the draining lymph nodes, spleen, or blood. We detected increased West Nile virus infection in the brain and spinal cord of Ifnlr1(-/-) mice, yet this was not associated with a direct antiviral effect in mouse neurons. Instead, we observed an increase in blood-brain barrier permeability in Ifnlr1(-/-) mice. Treatment of mice with pegylated interferon-λ2 resulted in decreased blood-brain barrier permeability, reduced West Nile virus infection in the brain without affecting viremia, and improved survival against lethal virus challenge. An in vitro model of the blood-brain barrier showed that interferon-λ signaling in mouse brain microvascular endothelial cells increased transendothelial electrical resistance, decreased virus movement across the barrier, and modulated tight junction protein localization in a protein synthesis- and signal transducer and activator of transcription 1 (STAT1)-independent manner. Our data establish an indirect antiviral function of interferon-λ in which noncanonical signaling through IFNLR1 tightens the blood-brain barrier and restricts viral neuroinvasion and pathogenesis. Copyright © 2015, American Association for the Advancement of Science.

  3. Differential viral induction of distinct interferon-alpha genes by positive feedback through interferon regulatory factor-7.

    PubMed Central

    Marié, I; Durbin, J E; Levy, D E

    1998-01-01

    Interferon (IFN) genes are among the earliest transcriptional responses to virus infection of mammalian cells. Although the regulation of the IFNbeta gene has been well characterized, the induction of the large family of IFNalpha genes has remained obscure. We report that the IFNalpha genes can be divided into two groups: an immediate-early response gene (IFNalpha4) which is induced rapidly and without the need for ongoing protein synthesis; and a set of genes that display delayed induction, consisting of at least IFNalpha2, 5, 6 and 8, which are induced more slowly and require cellular protein synthesis. One protein that must be synthesized for induction of the delayed gene set is IFN itself, presumably IFNalpha4 or IFNbeta, which stimulates the Jak-Stat pathway through the IFN receptor, resulting in activation of the transcription factor interferon-stimulated gene factor 3 (ISGF3). Among the IFN-stimulated genes induced through this positive feedback loop is the IFN regulatory factor (IRF) protein, IRF7. Induction of IRF7 protein in response to IFN and its subsequent activation by phosphorylation in response to virus-specific signals, involving two C-terminal serine residues, are required for induction of the delayed IFNalpha gene set. PMID:9822609

  4. Production of interferons by dendritic cells, plasmacytoid cells, natural killer cells, and interferon-producing killer dendritic cells.

    PubMed

    Vremec, David; O'Keeffe, Meredith; Hochrein, Hubertus; Fuchsberger, Martina; Caminschi, Irina; Lahoud, Mireille; Shortman, Ken

    2007-02-01

    The capacity of mouse spleen conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs) to produce interferon-gamma (IFN-gamma) or IFN-alpha was assessed, and compared with that of natural killer (NK) cells and the recently identified interferon-producing killer dendritic cells (IKDCs), both of which are frequent contaminants in DC preparations. Fully developed cDCs or pDCs, if free of NK cells or IKDCs, showed little capacity for IFN-gamma production. However, an early developmental form of the CD4-8+ cDC subtype, and the Ly6C- Ly49Q- pDC subtype, both were able to produce moderate amounts of IFN-gamma, although less than IKDCs. In response to toll-like receptor 9 stimuli, both the Ly6C+ Ly49Q+ and the Ly6C- Ly49Q- pDC subtypes were effective producers of IFN-alpha. However, IKDCs, which efficiently produced IFN-gamma and showed immediate cytotoxicity on NK target cells, did not produce IFN-alpha under these conditions.

  5. Evasion of interferon responses by Ebola and Marburg viruses.

    PubMed

    Basler, Christopher F; Amarasinghe, Gaya K

    2009-09-01

    The filoviruses, Ebola virus (EBOV) and Marburg virus (MARV), cause frequently lethal viral hemorrhagic fever. These infections induce potent cytokine production, yet these host responses fail to prevent systemic virus replication. Consistent with this, filoviruses have been found to encode proteins VP35 and VP24 that block host interferon (IFN)-alpha/beta production and inhibit signaling downstream of the IFN-alpha/beta and the IFN-gamma receptors, respectively. VP35, which is a component of the viral nucleocapsid complex and plays an essential role in viral RNA synthesis, acts as a pseudosubstrate for the cellular kinases IKK-epsilon and TBK-1, which phosphorylate and activate interferon regulatory factor 3 (IRF-3) and interferon regulatory factor 7 (IRF-7). VP35 also promotes SUMOylation of IRF-7, repressing IFN gene transcription. In addition, VP35 is a dsRNA-binding protein, and mutations that disrupt dsRNA binding impair VP35 IFN-antagonist activity while leaving its RNA replication functions intact. The phenotypes of recombinant EBOV bearing mutant VP35s unable to inhibit IFN-alpha/beta demonstrate that VP35 IFN-antagonist activity is critical for full virulence of these lethal pathogens. The structure of the VP35 dsRNA-binding domain, which has recently become available, is expected to provide insight into how VP35 IFN-antagonist and dsRNA-binding functions are related. The EBOV VP24 protein inhibits IFN signaling through an interaction with select host cell karyopherin-alpha proteins, preventing the nuclear import of otherwise activated STAT1. It remains to be determined to what extent VP24 may also modulate the nuclear import of other host cell factors and to what extent this may influence the outcome of infection. Notably, the Marburg virus VP24 protein does not detectably block STAT1 nuclear import, and, unlike EBOV, MARV infection inhibits STAT1 and STAT2 phosphorylation. Thus, despite their similarities, there are fundamental differences by which

  6. [Determination of the species specificity of interferons in the translation of the their mRNA from various cell cultures].

    PubMed

    Nosik, D N; Novokhatskiĭ, A S; Liakh, L A; Khil'ko, S N; Aspetov, R D

    1983-01-01

    Interferons obtained on induction of human lymphocytes with Newcastle viruses and staphylococcal enterotoxin A and diploid fibroblast cells of human embryos with poly (I).poly (C), as well as translation products of interferon mRNA obtained from these cells were analysed serologically. It was shown that the main type of interferon produced by the cells depended on the cell culture and inductor nature. It was defined at the level of the respective gene depression. Effective translation of mRNA of the interferons of the 3 types makes possible production of cDNA and creation of bacterial plasmids coding the genetic information for the synthesis of human interferon.

  7. Cross-Species Antiviral Activity of Goose Interferons against Duck Plague Virus Is Related to Its Positive Self-Feedback Regulation and Subsequent Interferon Stimulated Genes Induction

    PubMed Central

    Zhou, Hao; Chen, Shun; Zhou, Qin; Wei, Yunan; Wang, Mingshu; Jia, Renyong; Zhu, Dekang; Liu, Mafeng; Liu, Fei; Yang, Qiao; Wu, Ying; Sun, Kunfeng; Chen, Xiaoyue; Cheng, Anchun

    2016-01-01

    Interferons are a group of antiviral cytokines acting as the first line of defense in the antiviral immunity. Here, we describe the antiviral activity of goose type I interferon (IFNα) and type II interferon (IFNγ) against duck plague virus (DPV). Recombinant goose IFNα and IFNγ proteins of approximately 20 kDa and 18 kDa, respectively, were expressed. Following DPV-enhanced green fluorescent protein (EGFP) infection of duck embryo fibroblast cells (DEFs) with IFNα and IFNγ pre-treatment, the number of viral gene copies decreased more than 100-fold, with viral titers dropping approximately 100-fold. Compared to the control, DPV-EGFP cell positivity was decreased by goose IFNα and IFNγ at 36 hpi (3.89%; 0.79%) and 48 hpi (17.05%; 5.58%). In accordance with interferon-stimulated genes being the “workhorse” of IFN activity, the expression of duck myxovirus resistance (Mx) and oligoadenylate synthetases-like (OASL) was significantly upregulated (p < 0.001) by IFN treatment for 24 h. Interestingly, duck cells and goose cells showed a similar trend of increased ISG expression after goose IFNα and IFNγ pretreatment. Another interesting observation is that the positive feedback regulation of type I IFN and type II IFN by goose IFNα and IFNγ was confirmed in waterfowl for the first time. These results suggest that the antiviral activities of goose IFNα and IFNγ can likely be attributed to the potency with which downstream genes are induced by interferon. These findings will contribute to our understanding of the functional significance of the interferon antiviral system in aquatic birds and to the development of interferon-based prophylactic and therapeutic approaches against viral disease. PMID:27438848

  8. Up-regulation of interferon-stimulated gene15 and its conjugates by tumor necrosis factor-α via type I interferon-dependent and -independent pathways.

    PubMed

    Chairatvit, Kongthawat; Wongnoppavich, Ariyaphong; Choonate, Sirinthip

    2012-09-01

    Interferon-stimulated gene15 (ISG15) is the first characterized ubiquitin-like protein, which is strongly induced by type I interferons (IFN-α/β), bacterial endotoxin, and cellular stress. Up-regulation of ISG15 is observed in several cancer cell types and is associated with cancer progression. As many cytokines can influence all stages of tumorigenesis, the elevated expression of ISG15 system may be regulated in cancer cells by inflammatory cytokines. In this study, we showed that TNF-α, but not TGF-β and IL-6, up-regulates levels of both ISG15 and its conjugates in human lung carcinoma A549 and human squamous carcinoma HSC4 cell lines. Induction of ISG15 and its conjugates by TNF-α was dose-dependent and required mediation of p38 MAP kinase and Jak1 through up-regulation of endogenous type I interferon expression. SB202190 (p38 MAPK inhibitor) and Jak1 inhibitor suppressed TNF-α-induced expression of ISG15 and its conjugates. However, only SB202190 inhibited the expression of type I interferons by TNF-α. Although B18R, a soluble type I interferon receptor, totally abolished the effect of exogenous IFN-β, it was unable to inhibit completely the TNF-α-induced ISG15 production. In addition, the initiation of ISG15 induction by TNF-α was detected earlier than that of IFN-β induction. Taken together, TNF-α elicits the induction of ISG15 and ISG15 conjugates not only via the autocrine stimulation of type I interferon expression, but also through a type I interferon-independent pathway. These data provide a possible link between inflammatory response and cancer progression.

  9. Cross-Species Antiviral Activity of Goose Interferons against Duck Plague Virus Is Related to Its Positive Self-Feedback Regulation and Subsequent Interferon Stimulated Genes Induction.

    PubMed

    Zhou, Hao; Chen, Shun; Zhou, Qin; Wei, Yunan; Wang, Mingshu; Jia, Renyong; Zhu, Dekang; Liu, Mafeng; Liu, Fei; Yang, Qiao; Wu, Ying; Sun, Kunfeng; Chen, Xiaoyue; Cheng, Anchun

    2016-07-18

    Interferons are a group of antiviral cytokines acting as the first line of defense in the antiviral immunity. Here, we describe the antiviral activity of goose type I interferon (IFNα) and type II interferon (IFNγ) against duck plague virus (DPV). Recombinant goose IFNα and IFNγ proteins of approximately 20 kDa and 18 kDa, respectively, were expressed. Following DPV-enhanced green fluorescent protein (EGFP) infection of duck embryo fibroblast cells (DEFs) with IFNα and IFNγ pre-treatment, the number of viral gene copies decreased more than 100-fold, with viral titers dropping approximately 100-fold. Compared to the control, DPV-EGFP cell positivity was decreased by goose IFNα and IFNγ at 36 hpi (3.89%; 0.79%) and 48 hpi (17.05%; 5.58%). In accordance with interferon-stimulated genes being the "workhorse" of IFN activity, the expression of duck myxovirus resistance (Mx) and oligoadenylate synthetases-like (OASL) was significantly upregulated (p < 0.001) by IFN treatment for 24 h. Interestingly, duck cells and goose cells showed a similar trend of increased ISG expression after goose IFNα and IFNγ pretreatment. Another interesting observation is that the positive feedback regulation of type I IFN and type II IFN by goose IFNα and IFNγ was confirmed in waterfowl for the first time. These results suggest that the antiviral activities of goose IFNα and IFNγ can likely be attributed to the potency with which downstream genes are induced by interferon. These findings will contribute to our understanding of the functional significance of the interferon antiviral system in aquatic birds and to the development of interferon-based prophylactic and therapeutic approaches against viral disease.

  10. Differences in interferon alpha and beta signaling. Interferon beta selectively induces the interaction of the alpha and betaL subunits of the type I interferon receptor.

    PubMed

    Platanias, L C; Uddin, S; Domanski, P; Colamonici, O R

    1996-09-27

    All Type I interferons (IFNalpha, IFNbeta, IFNomega) bind to the Type I IFN receptor (IFNR) and elicit a common set of signaling events, including activation of the Jak/Stat and IRS pathways. However, IFNbeta selectively induces the association of the alpha subunit of the Type I IFNR with p100, a tyrosyl phosphoprotein, to transduce IFNbeta-specific signals. Using antibodies raised against the different components of the Type I IFNR, we identified p100 as the long form of the beta subunit (betaL subunit) of the Type I IFNR. This was also confirmed in experiments with mouse L-929 cells transfected with truncated forms of betaL. Thus, IFNbeta stimulation of human cells or mouse L-929 transfectants expressing the human alpha and betaL subunits, selectively induces the formation of a signaling complex containing the alpha and betaL subunits of the receptor. The IFNbeta-regulated interaction of the alpha and betaL chains is rapid and transient and follows a similar time course with the tyrosine phosphorylation of these receptor components. These data demonstrate that the signaling specificity for different Type I IFNs is established early in the signaling cascade, at the receptor level, and results from distinct interactions between components of the Type I IFNR.

  11. Biological effects of chicken type III interferon on expression of interferon-stimulated genes in chickens: comparison with type I and type II interferons.

    PubMed

    Masuda, Yasumitsu; Matsuda, Akiko; Usui, Tatsufumi; Sugai, Toru; Asano, Atsushi; Yamano, Yoshiaki

    2012-11-01

    Interferons (IFNs) are key mediators that activate host defense mechanisms against viruses. The recently identified mammalian Type III IFN has biological effects similar to type I IFN. However, the biological effects of type III IFN have not yet been characterized in birds. We compared the effects of chicken type III IFN (IFN-λ) with type I (IFN-β) and type II (IFN-γ) IFNs on IFN-stimulated genes (ISGs) using recombinant proteins expressed in Escherichia coli. Recombinant chicken IFN-λ inhibited influenza virus replication and induced the mRNA expression of the ISGs, Mx and OAS, in chicken embryonic fibroblasts (CEFs) in a dose-dependent manner. However, the effective dose of IFN-λ was higher than that of IFN-β and IFN-γ. Furthermore, the effect of IFN-λ on induction of Mx and OAS was lesser than that of IFN-β, but comparable to that of IFN-γ. These results indicate that chicken IFN-λ has the potential to induce ISGs and inhibit viral replication in chicken cells.

  12. Role of Leptin and SOCS3 in Inhibiting the Type I Interferon Response During Obesity.

    PubMed

    Terán-Cabanillas, Elí; Hernández, Jesús

    2017-02-01

    Obesity provokes an imbalance in the immune system, including an aberrant type I interferon response during some viral infections and after TLR stimulation. SOCS3 overexpression and altered systemic leptin levels could be responsible for the reduced type I interferon production in people with obesity and, eventually, significantly increase the risk of viral infection. The aim of this study was to determine whether SOCS3- and leptin-induced tolerance are responsible for the reduced type I interferon production in people with obesity. SOCS3 overexpression in PBMCs from people with obesity was inhibited with the small interfering RNA (siRNA) assay, and leptin-induced tolerance was evaluated in PBMCs from non-obese volunte\\ers and U937 cells treated with TLR ligands. SOCS3, but not SOCS1, gene silencing via siRNA increased the type I interferon response in PBMCs obtained from people with obesity. On the other hand, leptin induced SOCS3 expression and inhibited type I interferons in PBMCs from healthy donors and in U937 monocytes stimulated with TLR ligands. Taken together, these results demonstrate that reduced type I interferon production in obesity is caused by SOCS3 overexpression as well as tolerance induced by leptin. Here, we demonstrate a key role of leptin and SOCS3 in inhibiting the type I interferon response during obesity.

  13. Treatment of recurrent respiratory papillomatosis with human leukocyte interferon. Results of a multicenter randomized clinical trial.

    PubMed

    Healy, G B; Gelber, R D; Trowbridge, A L; Grundfast, K M; Ruben, R J; Price, K N

    1988-08-18

    Recurrent respiratory papillomatosis is a relentless disease of viral origin in which squamous papillomas frequently obstruct the respiratory tract of children and young adults. No therapy has been proved to be curative for this process. Recent reports have suggested that interferon may cure or dramatically control airway papillomatosis. We evaluated the efficacy of human leukocyte interferon in the treatment of respiratory papillomatosis. One hundred twenty-three patients were randomly assigned to receive treatment with either surgery plus interferon or surgery alone. Interferon (2 X 10(6) IU per square meter of body-surface area) was given daily for one week, then three times per week for one year; treatment was followed by a year of observation, without the drug. Both study groups underwent serial endoscopy to remove papillomas and to document the efficacy of treatment during the two years of study. During the first six months, the growth rate of papillomas in the interferon group was significantly lower than in the control group (P = 0.0007). This difference diminished during the second six months and was no longer statistically significant (P = 0.68). Our data do not show that interferon is either curative or of substantial value as an adjunctive agent in the long-term management of recurrent respiratory papillomatosis. The initial benefit of interferon is not sustained.

  14. Cutaneous Adverse Events Associated with Interferon-β Treatment of Multiple Sclerosis.

    PubMed

    Kolb-Mäurer, Annette; Goebeler, Matthias; Mäurer, Mathias

    2015-07-02

    Interferons are widely used platform therapies as disease-modifying treatment of patients with multiple sclerosis. Although interferons are usually safe and well tolerated, they frequently cause dermatological side effects. Here, we present a multiple sclerosis (MS) patient treated with interferon-β who developed new-onset psoriasis. Both her MS as well as her psoriasis finally responded to treatment with fumarates. This case illustrates that interferons not only cause local but also systemic adverse events of the skin. These systemic side effects might indicate that the Th17/IL-17 axis plays a prominent role in the immunopathogenesis of this individual case and that the autoimmune process might be deteriorated by further administration of interferons. In conclusion, we think that neurologists should be aware of systemic cutaneous side effects and have a closer look on interferon-associated skin lesions. Detection of psoriasiform lesions might indicate that interferons are probably not beneficial in the individual situation. We suggest that skin lesions may serve as biomarkers to allocate MS patients to adequate disease-modifying drugs.

  15. Cutaneous Adverse Events Associated with Interferon-β Treatment of Multiple Sclerosis

    PubMed Central

    Kolb-Mäurer, Annette; Goebeler, Matthias; Mäurer, Mathias

    2015-01-01

    Interferons are widely used platform therapies as disease-modifying treatment of patients with multiple sclerosis. Although interferons are usually safe and well tolerated, they frequently cause dermatological side effects. Here, we present a multiple sclerosis (MS) patient treated with interferon-β who developed new-onset psoriasis. Both her MS as well as her psoriasis finally responded to treatment with fumarates. This case illustrates that interferons not only cause local but also systemic adverse events of the skin. These systemic side effects might indicate that the Th17/IL-17 axis plays a prominent role in the immunopathogenesis of this individual case and that the autoimmune process might be deteriorated by further administration of interferons. In conclusion, we think that neurologists should be aware of systemic cutaneous side effects and have a closer look on interferon-associated skin lesions. Detection of psoriasiform lesions might indicate that interferons are probably not beneficial in the individual situation. We suggest that skin lesions may serve as biomarkers to allocate MS patients to adequate disease-modifying drugs. PMID:26147425

  16. Regulation of 2', 5'-oligoadenylate synthetase gene expression by interferons and platelet-derived growth factor

    SciTech Connect

    Garcia-Blanco, M.A. ); Lengyel, P. . Dept. of Molecular Biophysics and Biochemistry); Morrison, E.; BrownLee, C.; Stiles, C.D. ); Williams, B.R.G. )

    1989-03-01

    In murine BALB/c 3T3 cell cultures, either beta interferon or platelet-derived growth factor (PDGF) enhanced expression of the 2', 5-oligoadenylate synthetase mRNA and protein. The time course of induction in response to beta inteferon was similar to that in response to PDGF. Of several growth factors known to be present in clotted blood serum (i.e., epidermal growth factor, transforming growth factor beta, and PDGF), only PDGF enhanced expression of 2', 5-oligoadenylate synthetase. The linkage of an interferon response element-containing segment from the 5'-flanking region of a human or murine 2'-5'-oligoadenylate synthetase gene made a heterologous gene responsive to interferon. The expression of such a gene construct in transfected cells was also induced by PDGF. Induction by PDGF was inhibited by mono- or polyclonal antibodies to murine interferon, which suggested that induction by PDGF requires interferon. Both PDGF and interferon induced nuclear factors that bound to this interferon response element-containing segment in vitro.

  17. Natural interferon-beta treatment for patients with chronic hepatitis C in Japan

    PubMed Central

    Sasaki, Reina; Kanda, Tatsuo; Nakamoto, Shingo; Haga, Yuki; Nakamura, Masato; Yasui, Shin; Jiang, Xia; Wu, Shuang; Arai, Makoto; Yokosuka, Osamu

    2015-01-01

    Chronic hepatitis C virus (HCV) infection can cause liver cirrhosis and hepatocellular carcinoma (HCC). Several studies have demonstrated that the eradication of HCV reduces the occurrence of HCC. In Japan, as many people live to an advanced age, HCV-infected patients are also getting older, and the age at HCC diagnosis has also increased. Although older HCV-infected patients have a risk of developing HCC, the treatment response to peginterferon-alpha plus ribavirin therapy is relatively poor in these patients because of drop-out or discontinuation of this treatment due to adverse events. It is established that the mechanism of action between interferon-alpha and interferon-beta is slightly different. Short-term natural interferon-beta monotherapy is effective for patients with acute hepatitis C and patients infected with HCV genotype 2 and low viral loads. Natural interferon-beta plus ribavirin for 48 wk or for 24 wk are also effective for some patients with HCV genotype 1 or HCV genotype 2. Natural interferon-beta plus ribavirin has been used for certain “difficult-to-treat” HCV-infected patients. In the era of direct-acting anti-virals, natural interferon-beta plus ribavirin may be one of the therapeutic options for special groups of HCV-infected patients. In the near future, signal transduction pathways of interferon-beta will inform further directions. PMID:26052401

  18. Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade.

    PubMed

    Benci, Joseph L; Xu, Bihui; Qiu, Yu; Wu, Tony J; Dada, Hannah; Twyman-Saint Victor, Christina; Cucolo, Lisa; Lee, David S M; Pauken, Kristen E; Huang, Alexander C; Gangadhar, Tara C; Amaravadi, Ravi K; Schuchter, Lynn M; Feldman, Michael D; Ishwaran, Hemant; Vonderheide, Robert H; Maity, Amit; Wherry, E John; Minn, Andy J

    2016-12-01

    Therapeutic blocking of the PD1 pathway results in significant tumor responses, but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB) and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. The highly virulent variola and monkeypox viruses express secreted inhibitors of type I interferon

    PubMed Central

    Fernández de Marco, María del Mar; Alejo, Alí; Hudson, Paul; Damon, Inger K.; Alcami, Antonio

    2010-01-01

    Variola virus (VARV) caused smallpox, one of the most devastating human diseases and the first to be eradicated, but its deliberate release represents a dangerous threat. Virulent orthopoxviruses infecting humans, such as monkeypox virus (MPXV), could fill the niche left by smallpox eradication and the cessation of vaccination. However, immunomodulatory activities and virulence determinants of VARV and MPXV remain largely unexplored. We report the molecular characterization of the VARV- and MPXV-secreted type I interferon-binding proteins, which interact with the cell surface after secretion and prevent type I interferon responses. The proteins expressed in the baculovirus system have been purified, and their interferon-binding properties characterized by surface plasmon resonance. The ability of these proteins to inhibit a broad range of interferons was investigated to identify potential adaptation to the human immune system. Furthermore, we demonstrate by Western blot and activity assays the expression of the type I interferon inhibitor during VARV and MPXV infections. These findings are relevant for the design of new vaccines and therapeutics to smallpox and emergent virulent orthopoxviruses because the type I interferon-binding protein is a major virulence factor in animal models, vaccination with this protein induces protective immunity, and its neutralization prevents disease progression.—Fernández de Marco, M. M., Alejo, A., Hudson, P., Damon, I. K., Alcami, A. The highly virulent variola and monkeypox viruses express secreted inhibitors of type I interferon. PMID:20019241

  20. The Regulation of Type I Interferon Production by Paramyxoviruses

    PubMed Central

    Goodbourn, Stephen

    2009-01-01

    Experimentally, paramyxoviruses are conventionally considered good inducers of type I interferons (IFN-α/β), and have been used as agents in the commercial production of human IFN-α. However, in the last few years it has become clear that viruses in general mount a major challenge to the IFN system, and paramyxoviruses are no exception. Indeed, most paramyxoviruses encode mechanisms to inhibit both the production of, and response to, type I IFN. Here we review our knowledge of the type I IFN-inducing signals (by so-called pathogen-associated molecular patterns, or PAMPs) produced during paramyxovirus infections, and discuss how paramyxoviruses limit the production of PAMPs and inhibit the cellular responses to PAMPs by interfering with the activities of the pattern recognition receptors (PRRs), mda-5, and RIG-I, as well as downstream components in the type I IFN induction cascades. PMID:19702509

  1. The role of interferons in the treatment of malignant neoplasms.

    PubMed Central

    Murren, J. R.; Buzaid, A. C.

    1989-01-01

    Interferons (IFNs) are proteins with a wide range of biological effects. IFNs have antiviral and antiproliferative properties. They modulate both the immune system and the expression of cell phenotype. In the past decade, the IFNs have received intense clinical scrutiny. Alpha IFN is the best studied and displays activity in many neoplastic diseases; it has shown the most promise in the hematological cancers although several solid tumors, including epidemic Kaposi's sarcoma, renal cell carcinoma, and melanoma, respond. No neoplastic disease, however, has been cured by the IFNs. IFN seems to be most active in the setting of minimal residual disease, and clinical studies evaluating its role in the adjuvant setting are under way. Other areas of research include trials combining IFN with cytotoxic drugs or other biological response modifiers, and maintenance IFN to prolong remissions following successful induction therapy. PMID:2479178

  2. Glucocorticosteroids enhance replication of respiratory viruses: effect of adjuvant interferon

    PubMed Central

    Thomas, Belinda J.; Porritt, Rebecca A.; Hertzog, Paul J.; Bardin, Philip G.; Tate, Michelle D.

    2014-01-01

    Glucocorticosteroids (GCS) are used on a daily basis to reduce airway inflammation in asthma and chronic obstructive pulmonary disease (COPD). This treatment is usually escalated during acute disease exacerbations, events often associated with virus infections. We examined the impact of GCS on anti-viral defences and virus replication and assessed supplementary interferon (IFN) treatment. Here, we report that treatment of primary human airway cells in vitro with GCS prior to rhinovirus (RV) or influenza A virus (IAV) infection significantly reduces the expression of innate anti-viral genes and increases viral replication. Mice given intranasal treatment with GCS prior to IAV infection developed more severe disease associated with amplified virus replication and elevated inflammation in the airways. Adjuvant IFN treatment markedly reduced GCS-amplified infections in human airway cells and in mouse lung. This study demonstrates that GCS cause an extrinsic compromise in anti-viral defences, enhancing respiratory virus infections and provides a rationale for adjuvant IFN treatment. PMID:25417801

  3. Post-Transcriptional Control of the Interferon System

    PubMed Central

    Khabar, Khalid S. A.; Young, Howard A.

    2007-01-01

    The interferon (IFN) system is a well-controlled network of signaling, transcriptional, and post-transcriptional processes that orchestrate host defense against microbes. The IFN response comprises a multi-array of IFN-stimulated gene products that mediate a variety of biological processes designed to control infection and regulate specific immune responses. In this review, we focus on post-transcriptional mechanisms of gene regulation that occur during the course of IFN induction and during the response of cells to IFN. Post-transcriptional mechanisms involve different levels of regulation such as mRNA stability, alternative splicing, and translation. Such controls offer a fine tuning mechanism for efficient and rapid response and as a negative feedback control in IFN biosynthesis and response. PMID:17408842

  4. Type I Interferon in Chronic Virus Infection and Cancer.

    PubMed

    Snell, Laura M; McGaha, Tracy L; Brooks, David G

    2017-08-01

    Type I interferons (IFN-Is) are emerging as key drivers of inflammation and immunosuppression in chronic infection. Control of these infections requires IFN-I signaling; however, prolonged IFN-I signaling can lead to immune dysfunction. IFN-Is are also emerging as double-edged swords in cancer, providing necessary inflammatory signals, while initiating feedback suppression in both immune and cancer cells. Here, we review the proinflammatory and suppressive mechanisms potentiated by IFN-Is during chronic virus infections and discuss the similar, newly emerging dichotomy in cancer. We then discuss how this understanding is leading to new therapeutic concepts and immunotherapy combinations. We propose that, by modulating the immune response at its foundation, it may be possible to widely reshape immunity to control these chronic diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. [Conjunctival squamous cell carcinoma: paradoxical response to interferon eyedrops].

    PubMed

    Mata, E; Conesa, E; Castro, M; Martínez, L; de Pablo, C; González, M L

    2014-07-01

    A 67 year-old male seen for a longstanding corneal-conjunctival tumor. topical interferon α2b (IFN-α2b) 10 U/ml. A significant increase in lesion size was observed after 8 weeks. A surgical excision with cryotherapy was then performed. Pathological examination confirmed the diagnosis of squamous cell carcinoma. At this time the patient was found to have a positive HIV serology. Conjunctival intraepithelial neoplasia (CIN) is a pre-cancerous lesion of the ocular surface. Medical treatment of CIN is essentially with IFN-α2b due to its antiviral/antitumor properties. In patients with HIV, treatment response could be paradoxical. We recommend serology for HIV before treatment with topical IFN-α2b. Copyright © 2012 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.

  6. Interferon in resistance to bacterial and protozoan infections

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald; Gould, Cheryl L.; Kierszenbaum, Felipe; Degee, Antonie L. W.; Mansfield, John M.

    1986-01-01

    The effects of genetic differences in mouse strains on the modulation of protozoan infections by interferon (IFN) were investigated. In one set of experiments, three different strains of mice were injected with T. cruzi, and their sera were assayed at five time intervals for IFN titer. A greater quantity of IFN was produced by mouse strains that were susceptible to T. cruzi infection than by the more resistant strain. In another set of experiments, spleen cell cultures from inbred strains of mice were challenged with an antigen made from T.b. rhodesiense. The cells from mice resistant to infection, produced greater amounts of IFN-gamma than did cells from the susceptible mice. In a third set of experiments, it was found that mice injected with T.b. rhodesiense before being infected with a diabetogenic virus (EMC-D) were resistant to the effects of the virus and did not produce virus-specific antibody.

  7. HIV-1 and interferons: who's interfering with whom?

    PubMed

    Doyle, Tomas; Goujon, Caroline; Malim, Michael H

    2015-07-01

    The ability of interferons (IFNs) to inhibit HIV-1 replication in cell culture models has long been recognized, and the therapeutic administration of IFNα to HIV-1-infected patients who are not receiving antiretroviral therapy produces a clear but transient decrease in plasma viral load. Conversely, studies of chronic HIV-1 infection in humans and SIV-infected animal models of AIDS show positive correlations between elevated plasma levels of IFNs, increased expression of IFN-stimulated genes (ISGs), biomarkers of inflammation and disease progression. In this Review, we discuss the evidence that IFNs can control HIV-1 replication in vivo and debate the controversial role of IFNs in promoting the pathological sequelae of chronic HIV-1 infection.

  8. A purchaser experience of managing new expensive drugs: interferon beta.

    PubMed Central

    Rous, E.; Coppel, A.; Haworth, J.; Noyce, S.

    1996-01-01

    Interferon beta is a new and expensive drug for treating multiple sclerosis. One published trial has shown that it reduces the exacerbation rate in patients who have relapsing-remitting disease without important disability. This paper describes the development of a strategy for purchasing the drug in one region of England before its licensing. Purchasers felt unable to decline funding for this marginally effective drug and thereby undertake explicit rationing. To ensure prescribing was within the guidelines, a vast communication network had to be sustained with managers, general practitioners, neurologists, the Multiple Sclerosis Society, and professional advisers in all the purchasing authorities. The workload involved was considerable. The dilemma of rationing in a public service with a high political profile is demonstrated. PMID:8916757

  9. Secretion of human interferon alpha 2b by Streptomyces lividans.

    PubMed

    Pimienta, E; Fando, R; Sánchez, J C; Vallin, C

    2002-02-01

    Biologically active human interferon alpha 2b (HuIFNalpha-2b) was secreted into the culture medium by Streptomyces lividans transformed with recombinant plasmids coding for HuIFNalpha-2b fused to the Streptomyces exfoliatus M11 lipase A signal sequence. Levels were low, 15 or 100 ng/ml, depending on the plasmid used. Neither processed nor unprocessed HuIFNalpha-2b was detected in cell lysates of the transformants secreting the recombinant product. However, the secreted recombinant product was found to partially degrade when cultures reached the stationary phase by the action of an, as yet, unidentified mycelium-associated factor. Experimental evidence suggests that the degrading factor is related to mycelium-associated proteolytic activity.

  10. Immune Alterations in Patients with Anti-Interferon-γ Autoantibodies

    PubMed Central

    Chruewkamlow, Nuttapol; Mahasongkram, Kodchakorn; Pata, Supansa; Chaiwarith, Romanee; Salee, Parichart; Supparatpinyo, Khuanchai; Kasinrerk, Watchara

    2016-01-01

    Autoantibodies against interferon-gamma (IFN-γ) can cause immunodeficiency and are associated with various opportunistic infections. In the present study, we investigated other cellular immune parameters for a better understanding of the immunodeficiency condition in the patients. The numbers of WBC, monocytes and NK cells were increased in patients with anti-IFN-γ autoantibodies (AAbs). Upon TCR activation, T cell proliferation and IL-2 receptor of the patients remained intact. Nonetheless, the Th1 cytokine (IFN-γ and TNF-α) production was up-regulated. The production of Th2 (IL-4) and Th17 (IL-17) cytokines was unchanged. We suggest that, in addition to the presence of anti-IFN-γ autoantibodies, alterations in the cellular immune functions may also contribute to this immunodeficiency. PMID:26727515

  11. Immunogenicity of Human Interferon-Beta-Containing Pharmaceuticals.

    PubMed

    Nazarov, V D; Lapin, S V; Mazing, A V; Evdoshenko, E P; Totolian, A A

    2016-11-01

    Multiple sclerosis is a severe autoimmune disease with inflammatory component that continues to be resistant to treatment. One of the approaches retarding its progression is based on using nonspecific therapy with human interferon-beta (IFN-β)-containing pharmaceuticals. Neutralizing antibodies (NAbs) against genetically engineered pharmaceuticals developed by the patient's immune system, which reduce their therapeutic and biological activity, pose a serious problem. Cell lines sensitive to IFN-β activity also quantifying NAb level are applied because direct measurement of IFN-β antiviral activity is complicated. This study was aimed at standardization and validation of a reporter cell system for measuring anti-human IFN-β NAb titers, and evaluation data were obtained with samples from 33 patients with multiple sclerosis.

  12. Interferon-inducible effector mechanisms in cell-autonomous immunity.

    PubMed

    MacMicking, John D

    2012-04-25

    Interferons (IFNs) induce the expression of hundreds of genes as part of an elaborate antimicrobial programme designed to combat infection in all nucleated cells - a process termed cell-autonomous immunity. As described in this Review, recent genomic and subgenomic analyses have begun to assign functional properties to novel IFN-inducible effector proteins that restrict bacteria, protozoa and viruses in different subcellular compartments and at different stages of the pathogen life cycle. Several newly described host defence factors also participate in canonical oxidative and autophagic pathways by spatially coordinating their activities to enhance microbial killing. Together, these IFN-induced effector networks help to confer vertebrate host resistance to a vast and complex microbial world.

  13. Monitoring the antiviral effect of alpha interferon on individual cells.

    PubMed

    Kim, Chon Saeng; Jung, Jong Ha; Wakita, Takaji; Yoon, Seung Kew; Jang, Sung Key

    2007-08-01

    An infectious hepatitis C virus (HCV) cDNA clone (JFH1) was generated recently. However, quantitative analysis of HCV infection and observation of infected cells have proved to be difficult because the yield of HCV in cell cultures is fairly low. We generated infectious HCV clones containing the convenient reporters green fluorescent protein (GFP) and Renilla luciferase in the NS5a-coding sequence. The new viruses responded to antiviral agents in a dose-dependent manner. Responses of individual cells containing HCV to alpha interferon (IFN-alpha) were monitored using GFP-tagged HCV and time-lapse confocal microscopy. Marked variations in the response to IFN-alpha were observed among HCV-containing cells.

  14. Interferons and viruses: an evolutionary arms race of molecular interactions

    PubMed Central

    Hoffmann, Hans-Heinrich; Schneider, William M.; Rice, Charles M.

    2015-01-01

    Over half a century has passed since interferons (IFNs) were discovered and shown to inhibit virus infection in cultured cells. Since then, researchers have steadily brought to light the molecular details of IFN signaling, catalogued their pleiotropic effects on cells, and harnessed their therapeutic potential for a variety of maladies. While advances have been plentiful, several fundamental questions have yet to be answered and much complexity remains to be unraveled. We explore the current knowledge surrounding four main questions: are type I IFN subtypes differentially produced in response to distinct pathogens? How are IFN subtypes distinguished by cells? What are the mechanisms and consequences of viral antagonism? Lastly, how can the IFN response be harnessed to improve vaccine efficacy? PMID:25704559

  15. Saccharin derivatives as inhibitors of interferon-mediated inflammation.

    PubMed

    Csakai, Adam; Smith, Christina; Davis, Emily; Martinko, Alexander; Coulup, Sara; Yin, Hang

    2014-06-26

    A series of novel, saccharin-based antagonists have been identified for the interferon signaling pathway. Through in vitro high-throughput screening with the Colorado Center for Drug Discovery (C2D2) Pilot Library, we identified hit compound 1, which was the basis for extensive structure-activity relationship studies. Our efforts produced a lead anti-inflammatory compound, tert-butyl N-(furan-2-ylmethyl)-N-{4-[(1,1,3-trioxo-2,3-dihydro-1λ(6),2-benzothiazol-2-yl)methyl]benzoyl}carbamate CU-CPD103 (103), as a potent inhibitor using an established nitric oxide (NO) signaling assay. With further studies of its inhibitory mechanisms, we demonstrated that 103 carries out this inhibition through the JAK/STAT1 pathway, providing a drug-like small molecule inflammation suppressant for possible therapeutic uses.

  16. Molecular study of the interferon genes in chronic myeloid leukemia.

    PubMed

    Larripa, I; Giere, I; Slavutsky, I; Diaz, M

    1995-08-01

    The interferons alpha, beta, and w (IFNA, IFNB, IFNW), are a family of genes that have been mapped on the short arm of chromosome 9 (9p21-22). Deletions of genetic material on 9p are frequently observed in hematological diseases, particularly in lymphoid neoplasias. In this paper we have performed the molecular studies of IFNA and IFNB genes in chronic myeloid leukemia (CML) in order to determine if the deletions of these genes are prevalent in this pathology. Forty CML patients, Philadelphia positive or with BCR/ABL rearrangement, were studied at diagnosis. The analysis of IFNA and IFNB genes was performed by Southern and dot blot techniques. Homozygous or hemizygous deletions of IFNA and IFNB genes could not be detected, indicating that deletions of these genes would not be present or would be a very infrequent event in the chronic phase of the CML patients.

  17. Interferon and the fear of needles: a case report.

    PubMed

    López, Maria; Moreno, Laura; Dosal, Angelina; Pujol, Marta Maria; Vergara, Mercedes; Gil, Montserrat

    2011-01-01

    The treatment of viral hepatitis C infection uses a combination of pegylated interferon and ribavirin. Psychological preparation of the patient is vital to ensure adherence to the treatment. In our center, the nurse prepares this treatment according to an established educative protocol; however, some patients have special needs that require individualized attention. One such situation observed by the nurse is that the patients frequently admit to the fear of needle puncture (the peginterferon treatment is administered subcutaneously) and are unable to inject themselves. We describe a representative case and the care plan to manage the patient's fear so that the patient acquires confidence in his or her ability to self-inject. This facilitates autonomy and coresponsibility for the treatment, and the nurse can develop care approaches to combat the patient's fear of needles.

  18. Type I Interferons and Natural Killer Cell Regulation in Cancer

    PubMed Central

    Müller, Lena; Aigner, Petra; Stoiber, Dagmar

    2017-01-01

    Type I interferons (IFNs) are known to mediate antitumor effects against several tumor types and have therefore been commonly used in clinical anticancer treatment. However, how IFN signaling exerts its beneficial effects is only partially understood. The clinically relevant activity of type I IFNs has been mainly attributed to their role in tumor immune surveillance. Different mechanisms have been postulated to explain how type I IFNs stimulate the immune system. On the one hand, they modulate innate immune cell subsets such as natural killer (NK) cells. On the other hand, type I IFNs also influence adaptive immune responses. Here, we review evidence for the impact of type I IFNs on immune surveillance against cancer and highlight the role of NK cells therein. PMID:28408907

  19. Interferon γ limits the effectiveness of melanoma peptide vaccines

    PubMed Central

    Cho, Hyun-Il; Lee, Young-Ran

    2011-01-01

    The development of effective therapeutic vaccines to generate tumor-reactive cytotoxic T lymphocytes (CTLs) continues to be a top research priority. However, in spite of some promising results, there are no clear examples of vaccines that eradicate established tumors. Most vaccines are ineffective because they generate low numbers of CTLs and because numerous immunosuppressive factors abound in tumor-bearing hosts. We designed a peptide vaccine that produces large numbers of tumor-reactive CTLs in a mouse model of melanoma. Surprisingly, CTL tumor recognition and antitumor effects decreased in the presence of interferon γ (IFNγ), a cytokine that can provide therapeutic benefit. Tumors exposed to IFNγ evade CTLs by inducing large amounts of noncognate major histocompatibility complex class I molecules, which limit T-cell activation and effector function. Our results demonstrate that peptide vaccines can eradicate large, established tumors in circumstances under which the inhibitory activities of IFNγ are curtailed. PMID:20889921

  20. Interferon in resistance to bacterial and protozoan infections

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald; Gould, Cheryl L.; Kierszenbaum, Felipe; Degee, Antonie L. W.; Mansfield, John M.

    1986-01-01

    The effects of genetic differences in mouse strains on the modulation of protozoan infections by interferon (IFN) were investigated. In one set of experiments, three different strains of mice were injected with T. cruzi, and their sera were assayed at five time intervals for IFN titer. A greater quantity of IFN was produced by mouse strains that were susceptible to T. cruzi infection than by the more resistant strain. In another set of experiments, spleen cell cultures from inbred strains of mice were challenged with an antigen made from T.b. rhodesiense. The cells from mice resistant to infection, produced greater amounts of IFN-gamma than did cells from the susceptible mice. In a third set of experiments, it was found that mice injected with T.b. rhodesiense before being infected with a diabetogenic virus (EMC-D) were resistant to the effects of the virus and did not produce virus-specific antibody.

  1. Interferons, Signal Transduction Pathways, and the Central Nervous System

    PubMed Central

    Nallar, Shreeram C.

    2014-01-01

    The interferon (IFN) family of cytokines participates in the development of innate and acquired immune defenses against various pathogens and pathogenic stimuli. Discovered originally as a proteinaceous substance secreted from virus-infected cells that afforded immunity to neighboring cells from virus infection, these cytokines are now implicated in various human pathologies, including control of tumor development, cell differentiation, and autoimmunity. It is now believed that the IFN system (IFN genes and the genes induced by them, and the factors that regulate these processes) is a generalized alarm of cellular stress, including DNA damage. IFNs exert both beneficial and deleterious effects on the central nervous system (CNS). Our knowledge of the IFN-regulated processes in the CNS is far from being clear. In this article, we reviewed the current understanding of IFN signal transduction pathways and gene products that might have potential relevance to diseases of the CNS. PMID:25084173

  2. Interferons and the Immunogenic Effects of Cancer Therapy

    PubMed Central

    Minn, Andy J.

    2015-01-01

    Much of our understanding on resistance mechanisms to conventional cancer therapies such as chemotherapy and radiation has focused on cell intrinsic properties that antagonize the detrimental effects of DNA and other cellular damage. However, it is becoming clear that the immune system and/or innate immune signaling pathways can integrate with these intrinsic mechanisms to profoundly influence treatment efficacy. In this context, recent evidence indicates that interferon (IFN) signaling has an important role in this integration by influencing immune and intrinsic/non-immune determinants of therapy response. However, IFN signaling can be both immunostimulatory and immunosuppressive, and the factors determining these outcomes in different disease settings are unclear. Here I discuss the regulation and molecular events in cancer that are associated with these dichotomous functions. PMID:26604042

  3. Interferon and hormone sensitivity of endocrine-related tumors.

    PubMed

    Sica, G; Iacopino, F; Recchia, F

    1996-02-01

    Interferons (IFNs) have been shown to enhance both in vitro and in vivo the antiproliferative activity of some hormones and anti-hormones which mainly act via steroid receptors. We discuss some of the mechanisms which could be involved in determining this effect in breast, endometrial and prostatic cancer cells, with a particular emphasis on steroid receptor modulation, reduction of the expression of epidermal growth factor receptors and, finally, down-regulation of some oncogenes. It seems that under appropriate conditions IFN might produce changes in cancer cells that enhance or restore hormone sensitivity. Nevertheless, available clinical data are too few to allow any conclusion to be drawn and this problem merits further investigations.

  4. Interferon gamma release assay compared with the tuberculin skin test for latent tuberculosis detection in pregnancy.

    PubMed

    Worjoloh, Ayaba; Kato-Maeda, Midori; Osmond, Dennis; Freyre, Rachel; Aziz, Natali; Cohan, Deborah

    2011-12-01

    To estimate agreement and correlation between the tuberculin skin test and an interferon gamma release assay for detecting latent tuberculosis (TB) infection in pregnant women. We conducted a cross-sectional study of pregnant women initiating prenatal care at a university-affiliated public hospital between January 5, 2009, and March 15, 2010. Eligible women received a questionnaire about TB history and risk factors as well as the tuberculin skin test and phlebotomy for the interferon gamma release assay. Agreement and correlation between tests were estimated, and different cutoffs for interferon gamma release assay positivity were used to assess effect on agreement. Furthermore, predictors of test positivity and test discordance were evaluated using multivariable analysis. Of the 220 enrolled women, 199 (90.5%) returned for tuberculin skin test evaluation. Over 70% were Hispanic and 65% were born in a country with high TB prevalence. Agreement between the tuberculin skin test and interferon gamma release assay was 77.39 (κ=0.26). This agreement was not significantly changed using different cutoffs for the assay. Birth bacille Calmette-Guérin vaccination was associated with tuberculin skin test positivity (odds ratio [OR] 4.33, 95% confidence interval [CI] 1.4-13.48, P=.01), but not interferon gamma release assay positivity. There were no statistically significant predictors of the tuberculin skin test and interferon gamma release assay result discordance; however, birth in a high-prevalence country was marginally associated with tuberculin skin test-positive and interferon gamma release assay-negative results (OR 2.94, 95% CI 0.86-9.97 P=.08). Comparing the tuberculin skin test and interferon gamma release assay results in pregnancy, concordance and agreement were poor. Given that much is still unknown about the performance of interferon gamma release assays in pregnancy, further research is necessary before the tuberculin skin test is abandoned for screening of

  5. Interferon Gamma Release Assay Compared With Tuberculin Skin Test for Latent Tuberculosis Detection in Pregnancy

    PubMed Central

    Worjoloh, Ayaba; –Maeda, Midori Kato; Osmond, Dennis; Freyre, Rachel; Aziz, Natali; Cohan, Deborah

    2011-01-01

    Objective To estimate agreement and correlation between the tuberculin skin test and an interferon gamma release assay for detecting latent tuberculosis (TB) infection in pregnant women. Methods We conducted a cross-sectional study of pregnant women initiating prenatal care at a university-affiliated public hospital between January 5, 2009 and March 15, 2010. Eligible women received a questionnaire about tuberculosis history and risk factors, as well as the tuberculin skin test and phlebotomy for the interferon gamma release assay. Agreement and correlation between tests were estimated, and different cut-offs for interferon gamma release assay positivity were used to assess effect on agreement. Furthermore, predictors of test positivity and test discordance were evaluated using multivariable analysis. Results Of the 220 enrolled women, 199 (90.5%) returned for tuberculin skin test evaluation. Over 70% were Hispanic and 65% were born in a country with high tuberculosis prevalence. Agreement between tuberculin skin test and interferon gamma release assay was 77.39 (k=0.26). This agreement was not significantly changed using different cut-offs for the assay. Birth bacille Calmette-Guérin vaccination was associated with tuberculin skin test positivity (OR 4.33, 95%CI 1.4–13.48, p=0.01), but not interferon gamma release assay positivity. There were no statistically significant predictors of tuberculin skin test and interferon gamma release assay result discordance, however birth in high prevalence country was marginally associated with tuberculin skin test positive and interferon gamma release assay negative results (OR 2.94, 95% CI 0.86–9.97, p=0.08). Conclusion Comparing tuberculin skin test and interferon gamma release assay results in pregnancy, concordance and agreement were poor. Given that much is still unknown about the performance of interferon gamma release assays in pregnancy, further research is necessary before tuberculin skin test is abandoned for

  6. A new mass-spectrometric C-terminal sequencing technique finds a similarity between gamma-interferon and alpha 2-interferon and identifies a proteolytically clipped gamma-interferon that retains full antiviral activity.

    PubMed Central

    Rose, K; Simona, M G; Offord, R E; Prior, C P; Otto, B; Thatcher, D R

    1983-01-01

    A novel mass-spectrometric technique is described that permits the identification of the C-terminal peptide of a protein. The technique involves the incorporation of 18O into all alpha-carboxy groups liberated during enzyme-catalysed partial hydrolysis of the protein, followed by mass spectrometry to identify as the C-terminal peptide the only peptide that did not incorporate any 18O. The technique has been used to identify the true C-terminal tryptic peptide of a bacterially produced gamma-interferon and to distinguish it from a peptide produced by anomalous tryptic cleavage. It was found that a closely similar sequence segment of bacterially produced alpha 2-interferon undergoes an analogous cleavage. The technique was also used to identify the C-terminus of a clipped gamma-interferon that retains full antiviral activity. PMID:6418141

  7. Long-term therapy of interferon-alpha induced pulmonary arterial hypertension with different PDE-5 inhibitors: a case report

    PubMed Central

    Jochmann, Nicoline; Kiecker, Felix; Borges, Adrian C; Hofmann, Maja A; Eddicks, Stephan; Sterry, Wolfram; Baumann, Gert; Trefzer, Uwe

    2005-01-01

    background Interferon alpha2 is widely used in hepatitis and high-risk melanoma. Interferon-induced pulmonary arterial hypertension as a side effect is rare. Case presentation We describe a melanoma patient who developed severe pulmonary arterial hypertension 30 months after initiation of adjuvant interferon alpha2b therapy. Discontinuation of interferon did not improve pulmonary arterial hypertension. This patient could be treated successfully with phosphodiesterase-5 inhibitor therapy. Conclusion This is only the 5th case of interferon-induced pulmonary arterial hypertension and the first documented case where pulmonary arterial hypertension was not reversible after termination of interferon alpha2 therapy. If interferon alpha2 treated patients develop respiratory symptoms, pulmonary arterial hypertension should be considered in the differential diagnosis. For these patients phosphodiesterase-5 inhibitors, e.g. sildenafil or vardenafil, could be an effective therapeutic approach. PMID:16138923

  8. Bortezomib sensitizes human glioblastoma cells to induction of apoptosis by type I interferons through NOXA expression and Mcl-1 cleavage.

    PubMed

    Wang, Ruishan; Davidoff, Andrew M; Pfeffer, Lawrence M

    2016-09-09

    Glioblastomas are highly invasive and aggressive primary brain tumors. Type I interferons have significant, pleiotropic anticancer activity. However, through various pathways many cancers become interferon-resistant, limiting interferon's clinical utility. In this study, we demonstrated that the proteasomal inhibitor bortezomib sensitized human glioblastoma cells to the antiproliferative action of interferons, which involved the induction of caspase-dependent apoptosis but not necroptosis. We found that death ligands such as TRAIL (TNF-related apoptosis-inducing ligand) were not involved in interferon/bortezomib-induced apoptosis, although interferon induced TRAIL expression. However, apoptosis was induced through an intrinsic pathway involving increased NOXA expression and Mcl-1 cleavage. Our findings may provide an important rationale for combining type I interferons with bortezomib for glioblastoma therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Clinical implications of interferon-γ genetic and epigenetic variants

    PubMed Central

    Smith, Nicola L D; Denning, David W

    2014-01-01

    Interferon-γ (IFN-γ) is an integral and critical molecule of the immune system, with multiple functions, mostly related to the T helper type 1 (Th1) response to infection. It is critical for defence against mycobacterial infection and is of increasing interest in defence against fungi. In this article, we review the genetic and epigenetic variants affecting IFN-γ expression and investigate its role in disease, with an emphasis on fungal diseases such as invasive and chronic pulmonary aspergillosis. Over 347 IFN-γ gene variants have been described, in multiple ethnic populations. Many appear to confer a susceptibility to disease, especially tuberculosis (TB) and hepatitis, but also some non-infectious conditions such as aplastic anaemia, cervical cancer and psoriasis. Several epigenetic modifications are also described, increasing IFN-γ expression in Th1 lymphocytes and reducing IFN-γ expression in Th2 lymphocytes. Recombinant IFN-γ administration is licensed for the prophylaxis of infection (bacterial and fungal) in patients with the phagocyte functional deficiency syndrome chronic granulomatous disease, although the benefits appear limited. Interferon-γ therapy is given to patients with profound defects in IFN-γ and interleukin-12 production and appears to be beneficial for patients with invasive aspergillosis and cryptococcal meningitis, but the studies are not definitive. A high proportion of patients with chronic pulmonary aspergillosis are poor producers of IFN-γ in response to multiple stimuli and could also benefit from IFN-γ administration. The investigation and management of patients with possible or demonstrated IFN-γ deficiency in adulthood is poorly studied and could be greatly enhanced with the integration of genetic data. PMID:25052001

  10. Type III Interferons in Hepatitis C Virus Infection

    PubMed Central

    Boisvert, Maude; Shoukry, Naglaa H.

    2016-01-01

    The interferon (IFN)-λ family of type III cytokines includes the closely related interleukin (IL)-28A (IFN-λ2), IL-28B (IFN-λ3), and IL-29 (IFN-λ1). They signal through the Janus kinases (JAK)-signal transducers and activators of transcription pathway and promote an antiviral state by the induction of expression of several interferon-stimulated genes (ISGs). Contrary to type I IFNs, the effect of IFN-λ cytokines is largely limited to epithelial cells due to the restricted pattern of expression of their specific receptor. Several genome-wide association studies have established a strong correlation between polymorphism in the region of IL-28B gene (encoding for IFN-λ3) and both spontaneous and therapeutic IFN-mediated clearance of hepatitis C virus (HCV) infection, but the mechanism(s) underlying this enhanced viral clearance are not fully understood. IFN-λ3 directly inhibits HCV replication, and in vitro studies suggest that polymorphism in the IFN-λ3 and its recently identified overlapping IFN-λ4 govern the pattern of ISGs induced upon HCV infection of hepatocytes. IFN-λ can also be produced by dendritic cells, and apart from its antiviral action on hepatocytes, it can regulate the inflammatory response of monocytes/macrophages, thus acting at the interface between innate and adaptive immunity. Here, we review the current state of knowledge about the role of IFN-λ cytokines in mediating and regulating the immune response during acute and chronic HCV infections. PMID:28066437

  11. RelA-Induced Interferon Response Negatively Regulates Proliferation

    PubMed Central

    Kochupurakkal, Bose S.; Wang, Zhigang C.; Hua, Tony; Culhane, Aedin C.; Rodig, Scott J.; Rajkovic-Molek, Koraljka; Lazaro, Jean-Bernard; Richardson, Andrea L.; Biswas, Debajit K.; Iglehart, J. Dirk

    2015-01-01

    Both oncogenic and tumor-suppressor activities are attributed to the Nuclear Factor kappa B (NF-kB) pathway. Moreover, NF-kB may positively or negatively regulate proliferation. The molecular determinants of these opposing roles of NF-kB are unclear. Using primary human mammary epithelial cells (HMEC) as a model, we show that increased RelA levels and consequent increase in basal transcriptional activity of RelA induces IRF1, a target gene. Induced IRF1 upregulates STAT1 and IRF7, and in consort, these factors induce the expression of interferon response genes. Activation of the interferon pathway down-regulates CDK4 and up-regulates p27 resulting in Rb hypo-phosphorylation and cell cycle arrest. Stimulation of HMEC with IFN-γ elicits similar phenotypic and molecular changes suggesting that basal activity of RelA and IFN-γ converge on IRF1 to regulate proliferation. The anti-proliferative RelA-IRF1-CDK4 signaling axis is retained in ER+/HER2- breast tumors analyzed by The Cancer Genome Atlas (TCGA). Using immuno-histochemical analysis of breast tumors, we confirm the negative correlation between RelA levels and proliferation rate in ER+/HER2- breast tumors. These findings attribute an anti-proliferative tumor-suppressor role to basal RelA activity. Inactivation of Rb, down-regulation of RelA or IRF1, or upregulation of CDK4 or IRF2 rescues the RelA-IRF1-CDK4 induced proliferation arrest in HMEC and are points of disruption in aggressive tumors. Activity of the RelA-IRF1-CDK4 axis may explain favorable response to CDK4/6 inhibition observed in patients with ER+ Rb competent tumors. PMID:26460486

  12. Mechanisms of mRNA translation of interferon stimulated genes.

    PubMed

    Joshi, Sonali; Kaur, Surinder; Kroczynska, Barbara; Platanias, Leonidas C

    2010-01-01

    Over the last two decades, a lot of research work has been focused on the interferon (IFN)-regulated JAK-STAT pathway and understanding the mechanisms governing the transcription of interferon stimulated genes (ISGs). Evidence suggests that the JAK-STAT pathway alone does not account in its entirety for mediating cellular responses to IFNs. There is emerging evidence that non-Stat pathways play important roles in mediating signals for the generation of IFN-responses. Various studies have underscored the importance of mitogen activated protein kinases (MAPKs), especially p38 and ERK1/2, as well as the PI 3'K/AKT pathway in transmitting signals that are of critical importance for the biological effects of IFNs. Besides regulating the transcription of ISGs in some cases, engagement of these signaling pathways by the IFN-receptor (IFNR) associated complexes also plays an important role in mediating the translation of ISGs. The mechanisms regulating mRNA translation of ISGs is an area of ongoing active research and a lot more efforts will be required to complete our understanding of the various cellular elements involved in this process. In this review we highlight the mechanisms regulating translation of ISGs. We focus on the proteins regulated by the PI 3'K/AKT pathway, their role in mediating mRNA translation of ISGs and the functional consequences of this regulation. In addition, MAPKs are known to regulate the phosphorylation of various eukaryotic initiation factors and we summarize the roles of eIF4B and eIF4E phosphorylations on the translation of ISGs. The emerging roles of microRNAs in mRNA translation of ISGs are also discussed.

  13. Arenavirus nucleoprotein targets interferon regulatory factor-activating kinase IKKε.

    PubMed

    Pythoud, Christelle; Rodrigo, W W Shanaka I; Pasqual, Giulia; Rothenberger, Sylvia; Martínez-Sobrido, Luis; de la Torre, Juan Carlos; Kunz, Stefan

    2012-08-01

    Arenaviruses perturb innate antiviral defense by blocking induction of type I interferon (IFN) production. Accordingly, the arenavirus nucleoprotein (NP) was shown to block activation and nuclear translocation of interferon regulatory factor 3 (IRF3) in response to virus infection. Here, we sought to identify cellular factors involved in innate antiviral signaling targeted by arenavirus NP. Consistent with previous studies, infection with the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) prevented phosphorylation of IRF3 in response to infection with Sendai virus, a strong inducer of the retinoic acid-inducible gene I (RIG-I)/mitochondrial antiviral signaling (MAVS) pathway of innate antiviral signaling. Using a combination of coimmunoprecipitation and confocal microscopy, we found that LCMV NP associates with the IκB kinase (IKK)-related kinase IKKε but that, rather unexpectedly, LCMV NP did not bind to the closely related TANK-binding kinase 1 (TBK-1). The NP-IKKε interaction was highly conserved among arenaviruses from different clades. In LCMV-infected cells, IKKε colocalized with NP but not with MAVS located on the outer membrane of mitochondria. LCMV NP bound the kinase domain (KD) of IKKε (IKBKE) and blocked its autocatalytic activity and its ability to phosphorylate IRF3, without undergoing phosphorylation. Together, our data identify IKKε as a novel target of arenavirus NP. Engagement of NP seems to sequester IKKε in an inactive complex. Considering the important functions of IKKε in innate antiviral immunity and other cellular processes, the NP-IKKε interaction likely plays a crucial role in arenavirus-host interaction.

  14. Clinical implications of interferon-γ genetic and epigenetic variants.

    PubMed

    Smith, Nicola L D; Denning, David W

    2014-12-01

    Interferon-γ (IFN-γ) is an integral and critical molecule of the immune system, with multiple functions, mostly related to the T helper type 1 (Th1) response to infection. It is critical for defence against mycobacterial infection and is of increasing interest in defence against fungi. In this article, we review the genetic and epigenetic variants affecting IFN-γ expression and investigate its role in disease, with an emphasis on fungal diseases such as invasive and chronic pulmonary aspergillosis. Over 347 IFN-γ gene variants have been described, in multiple ethnic populations. Many appear to confer a susceptibility to disease, especially tuberculosis (TB) and hepatitis, but also some non-infectious conditions such as aplastic anaemia, cervical cancer and psoriasis. Several epigenetic modifications are also described, increasing IFN-γ expression in Th1 lymphocytes and reducing IFN-γ expression in Th2 lymphocytes. Recombinant IFN-γ administration is licensed for the prophylaxis of infection (bacterial and fungal) in patients with the phagocyte functional deficiency syndrome chronic granulomatous disease, although the benefits appear limited. Interferon-γ therapy is given to patients with profound defects in IFN-γ and interleukin-12 production and appears to be beneficial for patients with invasive aspergillosis and cryptococcal meningitis, but the studies are not definitive. A high proportion of patients with chronic pulmonary aspergillosis are poor producers of IFN-γ in response to multiple stimuli and could also benefit from IFN-γ administration. The investigation and management of patients with possible or demonstrated IFN-γ deficiency in adulthood is poorly studied and could be greatly enhanced with the integration of genetic data.

  15. Interferon lambda inhibits dengue virus replication in epithelial cells.

    PubMed

    Palma-Ocampo, Helen K; Flores-Alonso, Juan C; Vallejo-Ruiz, Verónica; Reyes-Leyva, Julio; Flores-Mendoza, Lilian; Herrera-Camacho, Irma; Rosas-Murrieta, Nora H; Santos-López, Gerardo

    2015-09-28

    In viral disease, infection is controlled at the cellular level by type I interferon (IFN-I), but dengue virus (DENV) has the ability to inhibit this response. Type III interferon, also known as lambda IFN (IFN-III or IFN-λ), is a complementary pathway to the antiviral response by IFN-I. This work analyzed the IFN-λ (IFN-III) mediated antiviral response against DENV serotype 2 (DENV-2) infection. Dengue fever patients were sampled to determine their IFN-λ levels by ELISA. To study the IFN-λ response during DENV infection we selected the epithelial cell line C33-A, and we demonstrated that it is permissive to DENV-2 infection. The effect of IFN-λ on virus replication was determined in these cells, in parallel to the expression of IFN-stimulated genes (ISGs), and Suppressor of Cytokine Signaling (SOCS), genes measured by RT-qPCR. We found increased (~1.8 times) serological IFN-λ in dengue fever patients compared to healthy blood donors. IFN-λ inhibited DENV-2 replication in a dose-dependent manner in vitro. The reduction of viral titer corresponded with increased ISG mRNA levels (MX1 and OAS1), with the highest inhibition occurring at ISG's peak expression. Presence of IFN-negative regulators, SOCS1 and SOCS3, during DENV-2 infection was associated with reduced IFN-λ1 expression. Evidence described here suggests that IFN-λ is a good candidate inhibitor of viral replication in dengue infection. Mechanisms for the cellular and organismal interplay between DENV and IFN- λ need to be further studied as they could provide insights into strategies to treat this disease. Furthermore, we report a novel epithelial model to study dengue infection in vitro.

  16. Antiproliferative Properties of Type I and Type II Interferon.

    PubMed

    Bekisz, Joseph; Baron, Samuel; Balinsky, Corey; Morrow, Angel; Zoon, Kathryn C

    2010-03-30

    The clinical possibilities of interferon (IFN) became apparent with early studies demonstrating that it was capable of inhibiting tumor cells in culture and in vivo using animal models. IFN gained the distinction of being the first recombinant cytokine to be licensed in the USA for the treatment of a malignancy in 1986, with the approval of IFN-α2a (Hoffman-La Roche) and IFN-α2b (Schering-Plough) for the treatment of Hairy Cell Leukemia. In addition to this application, other approved antitumor applications for IFN-α2a are AIDS-related Kaposi's Sarcoma and Chronic Myelogenous Leukemia (CML) and other approved antitumor applications for IFN-α2b are Malignant Melanoma, Follicular Lymphoma, and AIDS-related Kapoisi's Sarcoma. In the ensuing years, a considerable number of studies have been conducted to establish the mechanisms of the induction and action of IFN's anti-tumor activity. These include identifying the role of Interferon Regulatory Factor 9 (IRF9) as a key factor in eliciting the antiproliferative effects of IFN-α as well as identifying genes induced by IFN that are involved in recognition of tumor cells. Recent studies also show that IFN-activated human monocytes can be used to achieve >95% eradication of select tumor cells. The signaling pathways by which IFN induces apoptosis can vary. IFN treatment induces the tumor suppressor gene p53, which plays a role in apoptosis for some tumors, but it is not essential for the apoptotic response. IFN-α also activates phosphatidylinositol 3-kinase (PI3K), which is associated with cell survival. Downstream of PI3K is the mammalian target of rapamycin (mTOR) which, in conjunction with PI3K, may act in signaling induced by growth factors after IFN treatment. This paper will explore the mechanisms by which IFN acts to elicit its antiproliferative effects and more closely examine the clinical applications for the anti-tumor potential of IFN.

  17. Expression of bioactive recombinant bovine interferon-gamma using baculovirus.

    PubMed

    Gentilomi, Giovanna; Lelli, Rossella; D'Angelo, Mirella; Langella, Vincenzo; Monaco, Federica; Portanti, Ottavio; Luciani, Mirella; Mirasoli, Mara; Roda, Aldo; Zerbini, Marialuisa; Musiani, Monica

    2006-01-01

    The precise role of bovine interferon-gamma (BoIFN-gamma) in disease and therapy is still poorly defined. Clearly it is involved in defence against parasites, bacteria, viruses and possibly tumor cells. This paper reports the expression of BoIFN-gamma in a baculovirus system to generate a fully functional recombinant protein. Bovine interferon-gamma cDNA was cloned from mitogen stimulated peripheral blood mononuclear cell (PBMC) RNA utilizing the reverse transcription-polymerase chain reaction (RT-PCR). The cDNA open reading frame (ORF) encoding for a putative 166 amino acid protein (22KDa) was cloned and expressed into baculovirus transfer vector pBlueBac 4.5/V5 His. This vector was co-transfected with Autografa californica multiple nuclear polyhedrosis virus (AcMNPV) DNA into Spodoptera frugiperda cells (Sf9) and the recombinant virus, named AcBoIFN-gamma, was then recovered. Recombinant BoIFN-gamma (rBoIFN-gamma His) was accumulated in the serum-free medium of AcBoIFN-gamma-infected cells. The nickel affinity spin column purified rBoIFN-gamma His was shown to be a glycosylated 20-22 KDa protein as confirmed by SDS-PAGE glycan determination and showed antiviral activity in vitro against the bovine viral diarrhoea-mucosal disease virus (BVD/MD). The production of this bioactive rBoIFN-gamma His will allow us to explore this cytokine as a potential vaccine adjuvant or therapeutic agent for bovine diseases.

  18. Diagnostics for resource-limited settings in the era of interferon-free HCV therapy.

    PubMed

    Cooke, G S; Hill, A M

    2015-05-01

    The field of hepatitis C (HCV) therapy is moving inexorably towards a time when interferon is no longer part of routine HCV treatment. 2015 will see at least two interferon-free directly acting antiviral (DAA) treatments licensed in Europe and the USA. For those parts of the world that can afford it, this will mean the potential for treatment of those who have either failed interferon-based therapy or have been unable to tolerate the side-effects that commonly accompany treatment. © 2015 John Wiley & Sons Ltd.

  19. A Recombinant Adenovirus Expressing Ovine Interferon Tau Prevents Influenza Virus-Induced Lethality in Mice

    PubMed Central

    Pascual, E.; Avia, M.; Rangel, G.; de Molina, A.; Alejo, A.; Sevilla, N.

    2016-01-01

    Ovine interferon tau (IFN-τ) is a unique type I interferon with low toxicity and a broad host range in vivo. We report the generation of a nonreplicative recombinant adenovirus expressing biologically active IFN-τ. Using the B6.A2G-Mx1 mouse model, we showed that single-dose intranasal administration of recombinant Ad5-IFN-τ can effectively prevent lethality and disease induced by highly virulent hv-PR8 influenza virus by activating the interferon response and preventing viral replication. PMID:26739058

  20. Assay of bovine interferons in cultures of the porcine cell line IB-RS-2.

    PubMed Central

    Ahl, R; Rump, A

    1976-01-01

    An assay for bovine interferons has been developed using the porcine cell line IB-RS-2 and a bovine enterovirus, CBV-D, as challenge virus. The method is based on estimation of cytopathic effect measured by uptake of neutral red. Teh assay is simple, sensitive, and reproducible. A comparative test of different viruses in IB-RS-2 cells and secondary calf kidney cells revealed that the sensitivity of a virus to interferon can vary up to 1,000-fold in the two cell systems. Vesicular stomatitis virus was found to be rather insensitive to interferon in IB-RS-2 cells. PMID:184049

  1. Interferon signaling remains functional during henipavirus infection of human cell lines.

    PubMed

    Virtue, Elena R; Marsh, Glenn A; Wang, Lin-Fa

    2011-04-01

    Henipaviruses encode several proteins from the P gene, of which V and W have been demonstrated by gene-based transfection studies to antagonize the innate immune response, blocking both type I interferon production and signaling. This study examines the effects of henipavirus infection on the innate immune response in human cell lines. We report that henipavirus infection does not result in interferon production, with the virus antagonizing this response. In contrast to published transfection studies, our study found that the interferon signaling pathways are only partially blocked by henipavirus infection of human cell lines.

  2. Interferon-γ release assay for tuberculosis screening of healthcare workers at a Korean tertiary hospital.

    PubMed

    Park, Hye Yun; Jeon, Kyeongman; Suh, Gee Young; Kwon, O Jung; Chung, Doo Ryeon; Yoonchang, Sung Won; Kang, Eun-Suk; Koh, Won-Jung

    2010-12-01

    The aim of this study was to evaluate the annual incidence of tuberculosis infection among newly employed doctors and nurses in Korea. The annual incidence of tuberculosis infection ranged from 3.3% to 5.7%, based on the definition of conversion of an interferon-γ release assay, which suggests that stricter preventive strategies against nosocomial TB infection should be employed. Follow-up interferon-γ levels measured after 3 months of isoniazid and rifampicin treatment showed considerable variation. Therefore, serial testing with interferon-γ release assays after treatment of latent TB infection may be insufficient for evaluating the effects of treatment due to the variable responses.

  3. Studies on the replication of Mayaro virus grown in interferon treated cells.

    PubMed

    Rebello, M C; Fonseca, M E; Marinho, J O; Rebello, M A

    1994-01-01

    Mayaro virus grown in interferon treated infected cells has been characterized with regard to its ability to replicate in vertebrate (TC7) and invertebrate (Aedes albopictus) cells. Virus purified from interferon treated TC7 cells adsorbs and penetrates to the same extent as the control virus. During infection, these virus particles caused inhibition of host protein synthesis and synthesized the same spectrum of viral proteins as normal virus. This population however, was apparently more sensitive to interferon treatment. Electron microscopy of TC7 cells showed the presence of numerous aberrant virus particles budding from the plasma membrane.

  4. New developments in the Induction and Antiviral Effectors of Type I Interferon

    PubMed Central

    Liu, Su-Yang; Sanchez, David Jesse; Cheng, Genhong

    2013-01-01

    Type I Interferons are cytokines of the innate immune system that induce antiviral protein expression in response to viral infection. Various proteins and pathways have been shown to recognize nucleic acids ligands especially from RNA viruses. Here, we will review recent developments including transcription of DNA virus genomes into RNA ligands, and the recognition of viruses by TLR2 for interferon induction. The induced IFNs activate many interferon stimulated genes (ISGs) that have direct anti-viral effects. Recent studies have identified IFITM proteins as the first ISG to inhibit viral entry processes and revealed mechanistic understanding of known anti-viral ISGs such as ISG15 and Viperin. PMID:21123041

  5. Interferon-α and pericardial injury: a case report and literature review

    PubMed Central

    Hakim, Fayaz A; Singh, Sujata; Pandit, Anil; Alegria, Jorge R; Camoriano, John; Stanton, Melissa L; Mookadam, Farouk

    2014-01-01

    Interferon- α (IFN-α) alone or in combination with other chemotherapeutic agents has been used in the management of many malignant and non-malignant conditions. Pericarditis with or without pericardial effusion has been reported with IFN-α therapy, and available literature is limited to case reports. Pericardial constriction after interferon use has not been described in the published literature to date. We performed a systematic review of literature to address the demographic features, clinical presentation, diagnosis, treatment and outcome of interferon-related pericardial injury. PMID:27326167

  6. [A short history of beta-interferon therapy of multiple sclerosis].

    PubMed

    Stock, G; Horowski, R

    2001-09-15

    Basic sciences including biotechnology and diagnostic imaging as well as dedicated and substantial clinical research have contributed to the progress in the therapy of multiple sclerosis (MS) which is no longer an orphan disease. Pivotal studies using interferon beta-1b for early and later phases of MS are described in their historical context. In addition, possible mechanisms of action of interferon beta-1b and new directions for future research are discussed. Interferon beta-1b already now has become a global standard for the expected further therapeutic progress.

  7. Virus infection and interferon can activate gene expression through a single synthetic element, but endogenous genes show distinct regulation.

    PubMed

    Raj, N B; Engelhardt, J; Au, W C; Levy, D E; Pitha, P M

    1989-10-05

    Virus inducible elements (IE) in promoters of mouse alpha-interferon and human beta 1-interferon genes contain multiple copies of the hexanucleotide sequence AGT-GAA or its variants which are also found in the interferon-stimulated response element of genes transcriptionally induced by interferon. We have examined the similarities between virus and interferon induction of gene expression and the role of AGTGAA and AAT-GAA hexamers in these responses. Hybrid plasmids were constructed by inserting the IE region, the alpha 4 promoter, or the multiple copies of AGTGAA or AAT-GAA 5' to the inactive-45 human immunodeficiency-chloramphenicol acetyltransferase hybrid gene, and their inducible expression was studied in a transient expression assay. In L-cells, multiple hexamers were efficiently induced both by infection with Newcastle disease virus and by interferon treatment; while the alpha 4 promoter and the IE inducible region were induced predominantly by virus rather than by interferon. In order to dissociate the effect of virus and endogenous interferon on the induction process, we examined the gene expression in Vero cells, which have undergone homozygous deletion of type 1 interferon genes, and in VNPT-159 cells, which were derived from Vero cells by insertion of an inducible human interferon beta 1 gene. The results show that while the alpha 4 promoter was efficiently induced only by virus in both cell types, the constructs containing shorter segments of the IE were induced by both virus and interferon in Vero cells. However, the inducibility by interferon was not detected in VNPT-159 cells, suggesting that the presence of endogenous interferon suppresses interferon-induced expression of hexanucleotide repeats and the short inducible region. In contrast, virus inducibility of endogenous interferon-stimulated genes, ISG-15 and ISG-54, was about 100-fold more efficient in VNPT-159 cells than in Vero cells, suggesting that this induction is largely mediated through

  8. Importance of the loop connecting A and B helices of human interferon-gamma in recognition by interferon-gamma receptor.

    PubMed

    Lundell, D; Lunn, C A; Senior, M M; Zavodny, P J; Narula, S K

    1994-06-10

    Characterization of murine-human hybrid interferon-gamma (IFN-gamma) molecules suggests that substitution of the peptide connecting the A and B helices in human IFN-gamma with the murine sequence significantly blocks the protein's binding to the human interferon-gamma receptor. Mutagenesis showed that this effect is localized to the central part of this A-B loop peptide, particularly Ser20, Asp21, Val22, and Ala23. One mutant, IFN-gamma/A23E,D24E,N25K, was examined by NMR. This "EEK" mutation does not significantly alter the conformation of interferon-gamma, suggesting that the effects of these mutations are not the result of global conformational changes. The A-B loop is near histidine 111, a residue previously shown to be important in receptor-ligand interaction (Lunn, C. A., Fossetta, J., Dalgarno, D., Murgolo, N., Windsor, W., Zavodny, P. J., Narula, S. K., and Lundell, D. (1992) Protein Eng. 5, 253-257). We show that copper forms a complex between histidine 19 in the A-B loop and histidine 111. This metal complex lacks the ability to interact with the interferon-gamma receptor. These results suggest that the A-B loop contains important structural information needed for receptor-ligand binding and hence biological activity of human interferon-gamma.

  9. Inhibition of alpha interferon but not gamma interferon signal transduction by phorbol esters is mediated by a tyrosine phosphatase.

    PubMed Central

    Petricoin, E; David, M; Igarashi, K; Benjamin, C; Ling, L; Goelz, S; Finbloom, D S; Larner, A C

    1996-01-01

    Previous studies have indicated that the expression of viral oncoproteins, cell transformation, or phorbol ester treatment of cells can inhibit alpha/beta interferon (IFN-alpha/beta)-induced gene expression. The mechanisms by which these promoters of cell growth exert their inhibitory effects vary, but in most instances they involve a disruption of the IFN-alpha/beta-induced transcription complex ISGF3 such that the DNA-binding component of this complex (the 48-kDa ISGF3gamma protein) does not bind to the interferon-stimulated response element (ISRE). In this report, we demonstrated that phorbol ester treatment of human peripheral blood monocytes dramatically inhibits activation of IFN-alpha/B-stimulated early response genes but by a mechanism which does not involve abrogation of the ISRE binding of ISGF3gamma. Phorbol ester treatment of monocytes inhibited IFN alpha-stimulated tyrosine phosphorylation of the transcription factors Stat1alpha, Stat2, and Stat3 and of the tyrosine kinase Tyk2 but had no effect on IFN-gamma activation of Stat1alpha. IFNalpha-stimulated tyrosine phosphorylation of Jak1 and the alpha subunit of the IFN-alpha receptor were unaffected by phorbol 12-myristate 13-acetate (PMA). Moreover, PMA caused the dephosphorylation of Tyk2 but not of Jak1, which was activated by IFN. Pretreatment of cells with vanadate prevented the effects of PMA with regard to PMA-induced Tyk2 dephosphorylation. These observations suggest that PMA exerts its inhibitory effects by activation of a tyrosine phosphatase which selectively regulates Tyk2 but not Jak1 activity. PMID:8657115

  10. LGP2 downregulates interferon production during infection with seasonal human influenza A viruses that activate interferon regulatory factor 3.

    PubMed

    Malur, Meghana; Gale, Michael; Krug, Robert M

    2012-10-01

    LGP2, a member of the RIG-I-like receptor family, lacks the amino-terminal caspase activation recruitment domains (CARDs) required for initiating the activation of interferon regulatory factor 3 (IRF3) and interferon (IFN) transcription. The role of LGP2 in virus infection is controversial, and the only LGP2 experiments previously carried out with mammalian influenza A viruses employed an attenuated, mouse-adapted H1N1 A/PR/8/34 (PR8) virus that does not encode the NS1 protein. Here we determine whether LGP2 has a role during infection with wild-type, nonattenuated influenza A viruses that have circulated in the human population, specifically two types of seasonal influenza A viruses: (i) H3N2 and H1N1 viruses that activate IRF3 and IFN transcription and (ii) recent H1N1 viruses that block these two activations. In human cells infected with an H3N2 virus that activates IRF3, overexpression of LGP2 or its repressor domain decreased STAT1 activation and IFN-β transcription approximately 10-fold. Overexpression of LGP2 also caused a 10-fold decrease of STAT1 activation during infection with other seasonal influenza A viruses that activate IRF3. Using LGP2(+/+) and LGP2(-/-) mouse cells, we show that endogenous LGP2 decreased IFN production during H3N2 virus infection 3- to 4-fold. In contrast, in both mouse and human cells infected with H1N1 viruses that do not activate IRF3, LGP2 had no detectable role. These results demonstrate that LGP2 downregulates IFN production during infection by seasonal influenza A viruses that activate IRF3 and IFN transcription. It is intriguing that LGP2, a host protein induced during influenza A virus infection, downregulates the host antiviral IFN response.

  11. Role of Interferon Regulatory Factor 3 in Type I Interferon Responses in Rotavirus-Infected Dendritic Cells and Fibroblasts▿

    PubMed Central

    Douagi, Iyadh; McInerney, Gerald M.; Hidmark, Åsa S.; Miriallis, Vassoula; Johansen, Kari; Svensson, Lennart; Karlsson Hedestam, Gunilla B.

    2007-01-01

    The main pathway for the induction of type I interferons (IFN) by viruses is through the recognition of viral RNA by cytosolic receptors and the subsequent activation of interferon regulatory factor 3 (IRF-3), which drives IFN-α/β transcription. In addition to their role in inducing an antiviral state, type I IFN also play a role in modulating adaptive immune responses, in part via their effects on dendritic cells (DCs). Many viruses have evolved mechanisms to interfere with type I IFN induction, and one recently reported strategy for achieving this is by targeting IRF-3 for degradation, as shown for rotavirus nonstructural protein 1 (NSP1). It was therefore of interest to investigate whether rotavirus-exposed DCs would produce type I IFN and/or mature in response to the virus. Our results demonstrate that IRF-3 was rapidly degraded in rotavirus-infected mouse embryonic fibroblasts (MEFs) and type I IFN was not detected in these cultures. In contrast, rotavirus induced type I IFN production in myeloid DCs (mDCs), resulting in their activation. Type I IFN induction in response to rotavirus was reduced in mDCs from IRF-3−/− mice, indicating that IRF-3 was important for mediating the response. Exposure of mDCs to UV-treated rotavirus induced significantly higher type I IFN levels, suggesting that rotavirus-encoded functions also antagonized the response in DCs. However, in contrast to MEFs, this action was not sufficient to completely abrogate type I IFN induction, consistent with a role for DCs as sentinels for virus infection. PMID:17215281

  12. Induction of interferon and interferon-induced antiviral effector genes following a primary bovine herpesvirus-1 (BHV-1) respiratory infection.

    PubMed

    Osman, Rahwa; Gonzalez-Cano, Patricia; Brownlie, Robert; Griebel, Philip J

    2017-07-01

    Invitro investigations have identified a variety of mechanisms by which herpesviruses evade interferon-stimulated antiviral effector mechanisms. However, these immune evasion mechanisms have not been evaluated during a bovine herpesvirus-1 (BHV-1) infection. This study investigated the transcription and secretion of type I and II interferons (IFNs) and the transcription of IFN-stimulated genes (ISGs) during a primary BHV-1 infection of the upper respiratory tract (URT) in naïve calves. IFN-α, -β and -γ transcription in nasal turbinates and protein levels in nasal secretions increased following infection. Increased IFN type I and II secretion was detected 3 days post-infection (p.i.) and IFN production increased in parallel with virus shedding. Expression of ISGs, including Mx1, OAS and BST-2, also increased significantly (P<0.05) in nasal turbinates on day 3 p.i. and elevated ISG expression persisted throughout the period of viral shedding. In contrast, RNAase L gene expression was not induced during the BHV-1 infection in the nasal turbinates, but was induced on day 10 p.i. in the trachea. In vitro studies confirmed that recombinant bovine (rBo)IFN-α, -β and -γ induced expression of Mx1, OAS and BST-2, but decreased RNAse L transcript in bovine epithelial cells. Relative to vesicular stomatitisvirus (VSV), BHV-1 was resistant to the antiviral activity of rBoIFN-α and -γ, but treatment of epithelial cells with 10 ng rBoIFN-β ml-1 effected an 80 % inhibition of BHV-1 replication and complete inhibition of VSV replication. These observations confirm that the transcription and translation of type I and II IFNs increase during BHV-1 infection, while the transcription of some ISGs is not inhibited.

  13. Virus-activated interferon regulatory factor 7 upregulates expression of the interferon-regulated BST2 gene independently of interferon signaling.

    PubMed

    Bego, Mariana G; Mercier, Johanne; Cohen, Eric A

    2012-04-01

    BST-2/tetherin is an interferon (IFN)-inducible host restriction factor that inhibits the release of many enveloped viruses and functions as a negative-feedback regulator of IFN production by plasmacytoid dendritic cells. Currently, mechanisms underlying BST2 transcriptional regulation by type I IFN remain largely unknown. Here, we demonstrate that the BST2 promoter is a secondary target of the IFN cascade and show that a single IRF binding site is sufficient to render this promoter responsive to IFN-α. Interestingly, expression of IRF-1 or virus-activated forms of IRF-3 and IRF-7 stimulated the BST2 promoter even under conditions where type I IFN signaling was inhibited. Indeed, vesicular stomatitis virus could directly upregulate BST-2 during infection of mouse embryonic fibroblasts through a process that required IRF-7 but was independent from the type I IFN cascade; however, in order to achieve optimal BST-2 induction, the type I IFN cascade needed to be engaged through activation of IRF-3. Furthermore, using human peripheral blood mononuclear cells, we show that BST-2 upregulation is part of an early intrinsic immune response since TLR8 and TLR3 agonists, known to trigger pathways that mediate activation of IRF proteins, could upregulate BST-2 prior to engagement of the type I IFN pathway. Collectively, our findings reveal that BST2 is activated by the same signals that trigger type I IFN production, outlining a regulatory mechanism ensuring that production of type I IFN and expression of a host restriction factor involved in the IFN negative-feedback loop are closely coordinated.

  14. Effect of standard interferon and ribavirin on haemoglobin level in hepatitis-C patients.

    PubMed

    Shakeel Ahmad, Jadoon; Ashfaa, Ahmed; Habib Ahmad, Jadoon

    2014-01-01

    The standard treatment for HCV infection involves combination therapy with pegylated interferon and ribavirin. The study was conducted to determine the effect of standard interferon and ribavirin on the haemoglobin level in patients treated for hepatitis-C. PCR confirmed 58 patients of chronic hepatitis-C treated with standard interferon and ribavirin for six months were included in this case series study. The patients were followed up monthly. Haemoglobin was measured by Sysmex Haematology analyser at monthly interval to study change in its level. The study found decrease in the mean haemoglobin levels during the six months treatment. when the mean of baseline haemoglobin was compared with the mean haemoglobin of six months treatment, a decrease of 2.05 gm/dl was observed and the result was statistically significant (p=0.000). Six months treatment of chronic hepatitis-C with standard interferon and ribavirin decreases haemoglobin to a significant level causing anaemia in susceptible patients.

  15. Oropharyngeal pemphigus in a patient with chronic hepatitis C during interferon alpha-2a therapy.

    PubMed

    Marinho, R T; Johnson, N W; Fatela, N M; Serejo, F S; Glória, H; Raimundo, M O; Velosa, J F; Ramalho, F J; Moura, M C

    2001-07-01

    There are a few reports in the literature concerning pemphigus induced by interferon given for hepatitis C. We present the case of a 28-year-old woman with post-transfusional chronic hepatitis C who developed ulcers and vesicles on her tongue, cheeks, posterior oropharynx and vocal cords 5 months after beginning treatment with recombinant interferon alpha-2a. The direct and indirect immunofluorescence was diagnostic of pemphigus vulgaris. The drug was promptly withdrawn; the patient was medicated with prednisolone and azathioprine and recovered only 3 months later. Although there are several publications describing the occurrence of other autoimmune diseases in patients receiving interferon alpha therapy, this is the first report of a pemphigus induced by interferon in hepatitis C patients involving oropharyngeal and laryngeal mucosae without cutaneous involvement.

  16. Interferon alpha-2a as alternative treatment for conjunctival squamous cell carcinoma.

    PubMed

    Cruzado-Sánchez, D; Salas-Diaz, M; Tellez, W A; Alvarez-Matos, S E; Serpa-Frías, S

    2017-05-15

    A 35 year-old male patient with a history of HIV infection characterized by progressive tumour growth in bulbar conjunctiva of the left eye, corresponding to conjunctival squamous cell carcinoma that responded to treatment with interferon alpha-2a. Interferon alpha-2b has been used at conjunctival level as a topical immunomodulator treatment, with complete remission of epithelial neoplasms being observed. However, there have not been any previous publications on the use of interferon alpha-2a, which differs from interferon alpha-2b in a single amino acid, for the treatment of conjunctival squamous cell carcinoma. Copyright © 2017 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

  17. [Expression of gamma interferon during HPV and Chlamydia trachomatis infection in cervical samples].

    PubMed

    Colín-Ferreyra, María Del Carmen; Mendieta-Zerón, Hugo; Romero-Figueroa, María Del Socorro; Martínez-Madrigal, Migdania; Martínez-Pérez, Sergio; Domínguez-García, María Victoria

    2015-02-01

    The aim of this study was to mesure the expression of gamma interferon in HPV and Chlamydia trachomatis infection in squamous intraepithelial lesions. Samples from 100 patients diagnosed by colposcopy with or without squamous intraepithelial lesions were used in the present study. Each patient was found to be infected by HPV and C.trachomatis. Relative gamma interferon mRNA expression was assessed using a real-time reverse transcriptase PCR assay (RT-PCR). The relative units of expression of gamma interferon mRNA were 13, 1.8 and 0.3, for HPV and C.trachomatis co-infection, or HPV or C.trachomatis infection, respectively. HPV and C.trachomatis could overstimulate the expression of gamma interferon. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  18. Effect of interferon on concentrations of cyclic nucleotides in cultured cells.

    PubMed Central

    Tovey, M G; Rochette-Egly, C; Castagna, M

    1979-01-01

    Constant intracellular concentrations of both adenosine 3',5'-cyclic-monophosphate (cyclic AMP) and guanosine 3',5'-cyclic-monophosphate (cyclic GMP) were obtained when leukemia L1210 cells were cultivated under steady-state conditions in the chemostat. In this sensitive and controlled system addition of mouse interferon resulted in a rapid (5-10 min) increase in the intracellular concentration of cyclic GMP, which preceded by several hours an increase in the intracellular concentration of cyclic AMP. In contrast to the effect of interferon, addition of prostaglandin E1 induced a rapid increase in the intracellular concentration of cyclic AMP without markedly affecting the intracellular concentration of cyclic GMP. It is suggested that the rapid effect of interferon on cyclic GMP plays a role in mediating some of the effects of interferon on cells. PMID:226987

  19. Retinopathy in chronic hepatitis C patients during interferon treatment with ribavirin

    PubMed Central

    Jain, K; Lam, W; Waheeb, S; Thai, Q; Heathcote, J

    2001-01-01

    AIM—To assess the ocular effect of interferon alfa 2b prescribed with ribavirin in patients undergoing therapy for chronic hepatitis C.
METHODS—19 patients with chronic hepatitis C who satisfied the follow up criteria were assessed for ocular complications using slit lamp biomicroscopy and indirect ophthalmoscopy before, during, and after the treatment at regular intervals.
RESULTS—8/19 patients, while on treatment, developed an asymptomatic retinopathy. Among these 3/8 were relapsers and 5/9 were non-responders to interferon monotherapy. All retinal changes faded, often while the patients continued the therapy. There was no significant association in occurrence of retinopathy with haematological and/or biochemical changes.
CONCLUSION—Retinopathy was more common in interferon monotherapy non-responders than relapsers when treated with interferon alfa 2b with the addition of ribavirin. The changes were transient, disappearing while the patients were still being treated.

 PMID:11567959

  20. Isotopic labeling of mouse interferon by incorporation of radioactive amino acids during synthesis

    SciTech Connect

    DeMaeyer-Guignard, J.; Cachard, A.; DeMaeyer, E.

    1982-07-30

    Mouse interferon produced by C-243 cells induced with Newcastle disease virus was isotopically labeled by adding either (/sup 35/S)methionine or a /sup 14/C-labeled amino acid mixture to the culture medium. A method combining butyric acid and theophylline treatment and resulting in high interferon yields was used. Following purification by two-step affinity chromatography on poly(U) and antibody columns, the resulting material was analyzed on SDS-PAGE. The migration pattern of radioactivity and interferon coincided well and autoradiography revealed three major bands at migration distances corresponding, respectively, to 35, 28, and 22 K. Interferon represented 3.8% of all (/sup 35/S)methionine-labeled proteins and 2.6% of all /sup 14/C-amino acid-labeled proteins released into the medium.

  1. Production of cloned human leukocyte interferon by Bacillus subtilis: optimal production is connected with restrained growth.

    PubMed Central

    Meyer, H P; Fiechter, A

    1985-01-01

    Bacillus subtilis, transformed with a plasmid containing the human alpha-2 (leukocyte) interferon gene, was cultivated in batch and continuous culture in a complex medium. In continuous culture with dissolved oxygen of less than 10% of air saturation, the extracellular interferon titer decreased sharply when the growth rate was lower or higher than the optimal one (mu = 0.14 h-1). Thus, a relatively low growth rate was best for extracellular interferon production, and oxygen limitation enhanced interferon production. The mean output rate in batch culture after successful harvest was 20 X 10(6) IU/liter per h and the maximal output rate in continuous culture was 14 X 10(6) IU/liter per h. PMID:3931551

  2. Impact of interferon therapy on the natural history of hepatitis C virus related cirrhosis

    PubMed Central

    Gramenzi, A; Andreone, P; Fiorino, S; Camma, C; Giunta, M; Magalotti, D; Cursaro, C; Calabrese, C; Arienti, V; Rossi, C; Di, F; Zoli, M; Craxi, A; Gasbarrini, G; Bernardi, M

    2001-01-01

    BACKGROUND—The role of interferon treatment on the natural history of hepatitis C virus related cirrhosis is under debate.
AIM—To evaluate the effect of interferon on the clinical course of compensated hepatitis C virus related cirrhosis.
PATIENTS AND METHODS—Seventy two cirrhotic patients treated with interferon and 72 untreated controls matched treated patients with for quinquennia of age, sex, and Child-Pugh's score were enrolled in a prospective non-randomised controlled trial. Treated patients received leucocytic interferon alfa, with an escalating schedule for 12 months. The incidence and risk (Cox regression analysis) of clinical complications (hepatocellular carcinoma, ascites, jaundice, variceal bleeding, and encephalopathy) and death were calculated.
RESULTS—Over median follow up periods of 55 months for treated and 58 for untreated subjects, seven and nine patients, respectively, died, and 20 and 32, respectively, developed at least one clinical complication (ns). Hepatocellular carcinoma developed in six treated and 19 untreated patients (p=0.018). Seven treated patients showed sustained aminotranferase normalisation and none died or developed complications. Clinical complications were significantly associated with low albumin, bilirubin, and prothrombin activity while hepatocellular carcinoma was significantly related to no treatment with interferon, oesophageal varices, and high α fetoprotein levels. By stratified analysis, the beneficial effect of interferon was statistically evident only in patients with baseline α fetoprotein levels ⩾20 ng/ml.
CONCLUSIONS—Interferon does not seem to affect overall or event free survival of patients with hepatitis C virus related cirrhosis while it seems to prevent the development of hepatocellular carcinoma. Patients who achieved sustained aminotransferase normalisation survived and did not develop any complications during follow up.


Keywords: hepatocellular carcinoma

  3. Successful management of chronic multifocal Q fever Osteomyelitis with adjuvant interferon-gamma therapy.

    PubMed

    Neth, Olaf Werner; Falcon, Dolores; Peromingo, Estrella; Soledad Camacho, Maria; Rodríguez-Gallego, Carlos; Obando, Ignacio

    2011-09-01

    We present a 3-year-old girl who had chronic recurrent multifocal osteomyelitis caused by Coxiella burnetii despite long-term dual antibiotic therapy. Excellent clinical response was achieved and sustained when immunomodulatory therapy with interferon-γ was initiated. This is the case of a first child who was successfully treated with interferon-γ as adjuvant therapy for chronic multifocal Q fever osteomyelitis.

  4. Inhibited interferon-gamma but normal interleukin-3 production from rats flown on the Space Shuttle

    NASA Technical Reports Server (NTRS)

    Gould, Cheryl L.; Lyte, Mark; Williams, Joann; Mandel, Adrian D.; Sonnenfeld, Gerald

    1987-01-01

    Rats were flown on Space Shuttle SL-3 for one week. When spleen cells were removed from these rats and challenged with concanavalin-A, interferon-gamma production was severely inhibited, while interleukin-3 production was unaffected compared to ground-based control rats. These data indicate that there is a defect in interferon-gamma production in rats that have been exposed to spaceflight. This defect could contribute to, and be one reason for, immunosuppression observed after spaceflight.

  5. [Production of type I interferons in the body exposed to yeast RNA-tiloron molecular complexes].

    PubMed

    Karpov, A V; Zholobak, N M

    1996-01-01

    Molecular complexes forming as a result of interaction between yeast RNA preparations with 2,7-bis[-(diethylaminoethoxy)-fluorene]-9-on dihydrochloride (tilorone) administered parenterally to mice cause the appearance of interferon in high titers compatible to those induced by standard inductors of polyribonucleotide origin, poly(I)-poly(C) and larifan. Some physiologic conditions of interferonogenesis have been studied. The above molecular complexes in the dose range used experimentally were completely nontoxic. Hence, these complexes are promising agents for interferon induction.

  6. Role of interferon-γ and cytotoxic T lymphocytes in intraocular tumor rejection

    PubMed Central

    Ligocki, Ann J.; Brown, Joseph R.; Niederkorn, Jerry Y.

    2015-01-01

    The eye is normally an immunosuppressive environment. This condition is better known as immune privilege and protects the eye from immune-mediated inflammation of tissues that cannot regenerate. However, immune privilege creates a dilemma for the eye when intraocular neoplasms arise. In some cases, immune privilege is suspended, resulting in the immune rejection of intraocular tumors. This study employed a mouse model in which interferon-γ–dependent intraocular tumor rejection occurs. We tested the hypothesis that this rejection requires interferon-γ for the generation and functional capacity of cytotoxic T lymphocyte–mediated rejection of intraocular tumors. Tumors grew progressively in the eyes of interferon-γ knockout mice, even though the mice generated tumor-specific cytotoxic T lymphocyte responses in the periphery. However, interferon-γ knockout mice rejected tumors that were introduced into extraocular sites. Subcutaneous tumor immunization before intraocular challenge led to tumor rejection and preservation of the eye in wild-type mice. By contrast, tumors grew progressively in the eyes of interferon-γ knockout mice despite their ability to generate peripheral tumor-specific cytotoxic T lymphocytes as well as the capacity of CD8+ T cells to enter the eye as shown by the presence of CD8 and perforin message and CD3+CD8+ leukocytes within the tumor-bearing eye. We found that cytotoxic T lymphocytes generated in wild-type mice and adoptively transferred into interferon-γ knockout mice mediated the rejection of intraocular tumors in interferon-γ knockout hosts. The results indicate that interferon-γ is critical for the initial priming and differentiation of cytotoxic T lymphocytes residing in the periphery to produce the most effect antitumor function within the eye. PMID:26578649

  7. Development of Systemic Lupus Erythematosus Following Interferon-α Therapy for Hepatitis C Infection.

    PubMed

    Khalil-Ur-Rehman; Khokhar, Nasir

    2016-03-01

    Interferon-alpha (IFN-α) therapy has been associated with de novo development of systemic lupus erythematosus (SLE). We report a 48-year woman with chronic hepatitis C, who developed low grade fever, joint aches and pains, painful mouth ulcers, shortness of breath, dry cough and pleuritic chest pain after 2 months of completion of treatment with pegylated interferon-alpha. These clinical manifestations and the relevant immunologic investigations were in favour of SLE. She responded well to corticosteroids and hydroxychloroquine treatment.

  8. alpha Interferon: the potential drug of adjuvant therapy: past achievements and future challenges.

    PubMed

    Bonnem, E M

    1991-01-01

    This paper aims to summarize current experience with alpha interferon and provide direction for future study. There are four areas in which alpha interferon has proven or potential activity: antiviral, premalignant, adjuvant and advanced disease settings. The three main viral diseases in which interferon alfa-2b has been shown to have activity are chronic viral hepatitis, acquired immunodeficiency syndrome, and human papilloma virus infections. In vitro studies suggest that alpha interferon may inhibit transformation of some premalignant conditions into malignant disease; e.g., vaginal intraepithelial neoplasia. In the adjuvant setting, it is possible that a biological response modifier, such as alpha interferon, may have a role in helping the immune system to destroy residual tumour cells following tumour bulk reduction with radiation or chemotherapy. A higher response rate has been seen in patients with small tumour bulk compared to those with large tumour bulk (e.g., malignant melanoma, ovarian carcinoma), and in patients with early, rather than late, disease (e.g., chronic myelogenous leukaemia, hairy cell leukaemia, multiple myeloma, non-Hodgkin's lymphoma). This may be due to efficacy in a small tumour bulk setting or due to an immunoadjuvant role. In advanced disease, the question is how best to exploit the possible synergistic effects between alpha interferon and other therapeutic modalities. The optimum dose, schedule and patient populations for combined treatment have yet to be determined. The major objective of this paper is to determine how best to capitalize upon the current state of knowledge to build for future trials of alpha interferon, and to determine whether the existing data suggest an adjuvant role for interferon after initial tumour regression.

  9. Gamma-interferon alters globin gene expression in neonatal and adult erythroid cells

    SciTech Connect

    Miller, B.A.; Perrine, S.P.; Antognetti, G.; Perlmutter, D.H.; Emerson, S.G.; Sieff, C.; Faller, D.V.

    1987-06-01

    The effect of gamma-interferon on fetal hemoglobin synthesis by purified cord blood, fetal liver, and adult bone marrow erythroid progenitors was studied with a radioligand assay to measure hemoglobin production by BFU-E-derived erythroblasts. Coculture with recombinant gamma-interferon resulted in a significant and dose-dependent decrease in fetal hemoglobin production by neonatal and adult, but not fetal, BFU-E-derived erythroblasts. Accumulation of fetal hemoglobin by cord blood BFU-E-derived erythroblasts decreased up to 38.1% of control cultures (erythropoietin only). Synthesis of both G gamma/A gamma globin was decreased, since the G gamma/A gamma ratio was unchanged. Picograms fetal hemoglobin per cell was decreased by gamma-interferon addition, but picograms total hemoglobin was unchanged, demonstrating that a reciprocal increase in beta-globin production occurred in cultures treated with gamma-interferon. No toxic effect of gamma-interferon on colony growth was noted. The addition of gamma-interferon to cultures resulted in a decrease in the percentage of HbF produced by adult BFU-E-derived cells to 45.6% of control. Fetal hemoglobin production by cord blood, fetal liver, and adult bone marrow erythroid progenitors, was not significantly affected by the addition of recombinant GM-CSF, recombinant interleukin 1 (IL-1), recombinant IL-2, or recombinant alpha-interferon. Although fetal progenitor cells appear unable to alter their fetal hemoglobin program in response to any of the growth factors added here, the interaction of neonatal and adult erythroid progenitors with gamma-interferon results in an altered expression of globin genes.

  10. Inhibited interferon-gamma but normal interleukin-3 production from rats flown on the Space Shuttle

    NASA Technical Reports Server (NTRS)

    Gould, Cheryl L.; Lyte, Mark; Williams, Joann; Mandel, Adrian D.; Sonnenfeld, Gerald

    1987-01-01

    Rats were flown on Space Shuttle SL-3 for one week. When spleen cells were removed from these rats and challenged with concanavalin-A, interferon-gamma production was severely inhibited, while interleukin-3 production was unaffected compared to ground-based control rats. These data indicate that there is a defect in interferon-gamma production in rats that have been exposed to spaceflight. This defect could contribute to, and be one reason for, immunosuppression observed after spaceflight.

  11. Parkinsonism in Patients With Chronic Hepatitis C Treated With Interferons: Case Reports and Review of the Literature.

    PubMed

    Wangensteen, Kirk J; Krawitt, Edward L; Hamill, Robert W; Boyd, James T

    2016-01-01

    Interferons are a set of cytokines that activate antiviral responses by the body's immune cells and have been a mainstay of treatment of hepatitis C. Well-known neuropsychiatric effects of interferons include depression, irritability, and impaired concentration. A condition reported rarely in association with this treatment is parkinsonism. We report 2 patients who developed parkinsonism in conjunction with treatment of hepatitis C with alpha interferons. The first is a 51-year-old man who developed intermittent rest and postural tremor during treatment with pegylated interferon alpha ribavirin, and amantadine, with resolution of the symptoms after completing a 36-week course. Similar tremor recurred 3 years later with progressive parkinsonism, compatible with Parkinson disease (PD). The second patient is a 71-year-old man who developed postural tremor 8 weeks into a regimen of consensus interferon. Tremor resolved at completion of 48 weeks of interferon. Pegylated interferon alpha and ribavirin were started 2 years later because of lack of sustained virologic response. At 24 weeks of treatment, postural tremor returned along with features and a progressive course compatible with PD. Thus, both patients presented here developed (rest and/or postural) tremor during interferon therapy followed by delayed onset of parkinsonism. We identified 10 other cases in the literature of parkinsonism/PD associated with interferon administration. This report reviews the clinical presentation and potential pathophysiological mechanisms and recommends that physicians who prescribe interferon be vigilant for symptoms of PD in their patients.

  12. Results of interferon-based treatments in Alaska Native and American Indian population with chronic hepatitis C

    PubMed Central

    Livingston, Stephen E.; Townshend-Bulson, Lisa J.; Bruden, Dana J. T.; Homan, Chriss E.; Gove, James E.; Plotnik, Julia N.; Simons, Brenna C.; Spradling, Philip R.; McMahon, Brian J.

    2016-01-01

    Background There have been few reports of hepatitis C virus (HCV) treatment results with interferon-based regimens in indigenous populations. Objective To determine interferon-based treatment outcome among Alaska Native and American Indian (AN/AI) population. Design In an outcomes study of 1,379 AN/AI persons with chronic HCV infection from 1995 through 2013, we examined treatment results of 189 persons treated with standard interferon, interferon plus ribavirin, pegylated interferon plus ribavirin and triple therapy with a protease inhibitor. For individuals treated with pegylated interferon and ribavirin, the effect of patient characteristics on response was also examined. Results Sustained virologic response (SVR) with standard interferon was 16.7% (3/18) and with standard interferon and ribavirin was 29.7% (11/37). Of 119 persons treated with pegylated interferon and ribavirin, 61 achieved SVR (51.3%), including 10 of 46 with genotype 1 (21.7%), 38 of 51 with genotype 2 (74.5%) and 13 of 22 with genotype 3 (59.1%). By multivariate analysis, SVR in the pegylated interferon group was associated with female sex (p=0.002), estimated duration of infection (p=0.034) and HCV genotype (p<0.0001). There was a high discontinuation rate due to side effects in those treated with pegylated interferon and ribavirin for genotype 1 (52.2%). Seven of 15 genotype 1 patients treated with pegylated interferon, ribavirin and telaprevir or boceprevir achieved SVR (46.7%). Conclusions We had success with pegylated interferon-based treatment of AN/AI people with genotypes 2 and 3. However, there were low SVR and high discontinuation rates for those with genotype 1. PMID:27029671

  13. SIMIAN IMMUNODEFICIENCY VIRUS INFECTION IN THE BRAIN AND LUNG LEADS TO DIFFERENTIAL TYPE I INTERFERON SIGNALING DURING ACUTE INFECTION*

    PubMed Central

    Alammar, Luna; Gama, Lucio; Clements, Janice E.

    2011-01-01

    Using an accelerated and consistent simian immunodeficiency virus (SIV) pigtailed macaque model of HIV associated neurological disorders, we have demonstrated that virus enters the brain during acute infection. However, neurological symptoms do not manifest until late stages of infection, suggesting that immunological mechanisms exist within the central nervous system (CNS) that control viral replication and associated inflammation. We have shown that interferon beta, a type I interferon central to viral innate immunity, is a major cytokine present in the brain during acute infection and is responsible for limiting virus infection and inflammatory cytokine expression. However, the induction and role of interferon alpha in the CNS during acute SIV infection has never been examined in this model. In the classical model of interferon signaling, interferon beta signals through the interferon α/β receptor, leading to expression of interferon alpha. Surprisingly, although interferon beta is up regulated during acute SIV infection, we found that interferon alpha is down regulated. We demonstrate that this down regulation is coupled with a suppression of signaling molecules downstream of the interferon receptor, namely tyk2, STAT1 and IRF7, as indicated by either lack of protein phosphorylation, lack of nuclear accumulation, or transcriptional and/or translational repression. In contrast to brain, interferon alpha is up regulated in lung and accompanied by activation of tyk2 and STAT1. These data provide a novel observation that during acute SIV infection in the brain there is differential signaling through the interferon α/β receptor that fails to activate expression of interferon alpha in the brain. PMID:21368232

  14. Retinopathy during interferon-β treatment for multiple sclerosis: case report and review of the literature.

    PubMed

    Gaetani, Lorenzo; Menduno, Paola S; Cometa, Francesco; Di Gregorio, Maria; Sarchielli, Paola; Cagini, Carlo; Calabresi, Paolo; Di Filippo, Massimiliano

    2016-03-01

    The onset of new visual symptoms in patients with multiple sclerosis is often associated with a neuro-ophthalmologic manifestation of the disease. However, other possible differential diagnoses need to be ruled out, including drug-induced retinal side effects. Although uncommon, retinal side effects of interferon-beta formulations may occur, and need to be promptly recognized and treated by neurologists. In this manuscript, we report the case of a 37-year-old woman affected by multiple sclerosis diagnosed with interferon beta-associated retinopathy and we review the literature with regard to the epidemiology, clinical presentation, management and follow-up of interferon beta-associated retinopathy. Interferon-beta induced retinopathy seems to be an uncommon and a dose-related side effect in multiple sclerosis patients. Retinopathy tends to completely resolve after treatment discontinuation. Neurologists must be aware that immune-modulatory drugs, in particular interferon beta, have been reported to cause retinal side effects. In multiple sclerosis patients complaining of new visual symptoms during interferon-beta treatment, it is thus advisable to perform an ophthalmological assessment to rule out and properly manage retinopathy.

  15. Cure of hepatitis C virus infection without interferon alfa: scientific basis and current clinical evidence.

    PubMed

    Thomas, David L

    2014-01-01

    Cure of hepatitis C virus (HCV) infection is achievable without interferon alfa through the use of new direct-acting antiviral (DAA) drugs. In this era of interferon alfa-sparing therapy, however, interferon alfa sensitivity still matters, even as it turns out, if interferon alfa is not used. Inclusion of ribavirin in the treatment regimen remains a factor in treatment response, as does duration of treatment. HCV genotype and subtype remain relevant considerations in choosing a treatment regimen, and viral resistance may emerge when treatment fails. The potency and barrier to resistance of new DAAs and the use of appropriately designed interferon alfa-sparing combinations can overcome obstacles to cure posed by HCV resistance, interferon alfa resistance, and differences in response based on HCV genotype and subtype. Studies demonstrating the use of new DAAs to overcome these obstacles are discussed. This article summarizes a presentation by David L. Thomas, MD, MPH, at the IAS-USA continuing education program held in New York, New York, in June 2013.

  16. 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.

  17. [Formulation of an oral solid dosage form containing human interferon-alpha].

    PubMed

    Kristo, Katalin; Bajdik, János; Márki, Arpád; Eros, István; Falkay, György; Hödi, Klára

    2008-01-01

    The main objective of this study was to process the human alpha-interferon for the solid dosage form. The first step was the preparation of the intermediate product for the tablet making. Fluid bed apparatus with top spray method was applied for the layering of powdered cellulose with human alpha-interferon solutions. The intermediate product was compressed into tablet and an enteric solvent coating of the tablets was made in a fluid bed apparatus with Wurster method. The physical parameters were detected. These fitted the Ph. Eur. and the mechanical properties of the tablets were appropriate for coating in fluid bed apparatus. The tablets agree with the requirements of Ph. Eur. and the active agent was not dissolved in gastric juice. An animal test was also performed. The human alpha-interferon in the blood of the animals was detected with ELISA method. The human alpha-interferon specific kit was used. The active ingredient dissolved from the tablets was absorbed from the ileum. The solid dosage form containing human alpha-interferon was prepared; this can make oral application of human alpha-interferon possible.

  18. Effect of alpha interferon on glucose and alanine transport by rat renal brush border membrane vesicles

    SciTech Connect

    Batuman, V.; Chadha, I. New Jersey Medical School, Newark )

    1990-01-01

    To investigate the pathogenetic mechanisms of interferon nephrotoxicity, we studied the effect of recombinant interferon alfa-2b on the uptake of {sup 14}C-D-glucose and {sup 14}C-L-alanine by rat renal brush-border-membrane vesicles. Interferon significantly inhibited 20 sec. sodium-dependent and 5 and 10 min. equilibrium uptake of both glucose and alanine. The inhibitory effect was dose dependent with maximum effect achieved at interferon concentration of 5 {times} 10{sup {minus}8}M in the uptake media. The half-maximal inhibitory concentrations, IC{sub 50}, of interferon on glucose uptake was 1.8 {times} 10{sup {minus}8}M, and 5.4 {times} 10{sup {minus}9}M on alanine uptake. Dixon plot analysis of uptake data was consistent with pure non-competitive inhibition. The inhibition constants, K{sub i}, 1.5 {times} 10{sup {minus}8}M for glucose uptake, and 7.3 {times} 10{sup {minus}9}M for alanine uptake, derived from Dixon plots were in close agreement with the IC{sub 50}s calculated from the semilog dose response curves. These observations reveal that direct interactions at the proximal tubule cell membrane are involved in the pathogenesis of interferon nephrotoxicity, and that its mechanism of nephrotoxicity is similar to that of other low molecular weight proteins.

  19. Human B lymphocytes produce leukocyte interferon after interaction with foreign cells.

    PubMed Central

    Weigent, D A; Langford, M P; Smith, E M; Blalock, J E; Stanton, G J

    1981-01-01

    Enriched human B-cell populations cocultivated with xenogeneic or allogeneic tumor cells produced 1,000 to 10,000 U of leukocyte interferon per ml. In contrast, cocultivation of enriched plastic-adherent or T-cell populations with xenogeneic or allogeneic cells produced only 10 to 30 U of interferon. The population of cells producing the interferon absorbed to nylon wool and not sheep erythrocytes. They showed a strong mitogenic response to the B-cell mitogen Escherichia coli lipopolysaccharide but not the T-cell mitogen staphylococcal enterotoxin A. In addition, treatment of this cell population with goat anti-human immunoglobulin M and complement depleted the cell population synthesizing the interferon. Together, these in vitro findings strongly suggest that the cells producing most of the interferon after interacting with foreign cells belong to the B-cell population. These results also suggest that the cells that produce most of the leukocyte interferon after interacting in vivo with tumors or other cells made foreign to the body by certain viruses most likely belong to the B-lymphocyte population. PMID:6166556

  20. [The treatment of renal cell carcinoma with recombinant human leukocyte interferon].

    PubMed

    Kawamura, J; Yamauchi, T; Hashimura, T; Yoshida, O; Kohnami, T; Tomoyoshi, T; Ogura, K; Fukuyama, T; Nakagawa, K

    1985-03-01

    Recombinant human leukocyte (alpha) interferon was administered i.m. at the initial dose of 3 X 10(6) U/day to 27 patients with measurable metastatic renal cell carcinoma during the past 2 years. The results of 22 of these patients were evaluable. Three patients (13.6%) showed partial response; 3 patients (13.6%), minor response; 7 patients (31.8%), no change; and 9 patients (40.9%), progressive disease. Major toxicity consisted of fever (55.5%), anorexia (44.4%), malaise (22.2%), elevation of GOT/GPT (48.1%), leukopenia (44.4%) and thrombocytopenia (29.6%). When the 3 patients who showed stabilization (S) and the 2 patients who showed mixed effects (ME) among the 7 patients who showed no change are classified into the responded group, half the patients had some response to interferon. Characteristics of these responders (PR + MR + ME + S) were good performance status, relatively longer disease-free interval, metastases limited to the lungs or metastasis to lungs and one other organ excluding the liver, and frequency of interferon-induced thrombocytopenia. Interferon administration is still being continued to 4 patients on an outpatient basis, 5 patients are hospitalized and 13 patients have died. In conclusion, patients with pulmonary metastases seem to be the best responding group for interferon treatment in renal cell carcinoma and further trials, especially combined regimens with chemotherapy and/or other kinds of interferon should be tested.

  1. Inhibition of Interferon Induction and Action by the Nairovirus Nairobi Sheep Disease Virus/Ganjam Virus

    PubMed Central

    Holzer, Barbara; Bakshi, Siddharth; Bridgen, Anne; Baron, Michael D.

    2011-01-01

    The Nairoviruses are an important group of tick-borne viruses that includes pathogens of man (Crimean Congo hemorrhagic fever virus) and livestock animals (Dugbe virus, Nairobi sheep disease virus (NSDV)). NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam virus). We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU) found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other than ubiquitin and ISG15 may be involved in the actions of the viral OTU. PMID:22163042

  2. Management of chronic hepatitis C treatment failures: role of consensus interferon

    PubMed Central

    Gonzalez, Stevan A; Keeffe, Emmet B

    2009-01-01

    A significant proportion of patients with chronic hepatitis C virus (HCV) infection who undergo antiviral therapy have persistent or recurrent viremia and fail to achieve a sustained virologic response (SVR). Factors associated with treatment failure include HCV genotype 1 infection, high serum HCV RNA levels, and advanced fibrosis. Consensus interferon (CIFN) is a synthetic type I interferon derived from a consensus sequence of the most common amino acids found in naturally occurring alpha interferon subtypes. Several prospective clinical studies have demonstrated that CIFN may be a treatment option in patients who have failed prior interferon-based therapy, including those who have failed combination therapy with standard interferon or peginterferon plus ribavirin. Daily CIFN in combination with ribavirin may be an effective regimen in this setting; however, optimal dose and treatment duration of CIFN therapy have not been well established. Patients who achieve viral suppression during prior interferon-based therapy and those who do not have advanced fibrosis have a greater likelihood of achieving a SVR with CIFN retreatment. Individualized therapy targeting specific patient groups will be an important consideration in the successful management of prior treatment failures. Additional prospective studies are required in order to identify optimal treatment strategies for the use of CIFN in these patients. PMID:19707403

  3. Sensitivity of PEGylated interferon detection by anti-polyethylene glycol (PEG) antibodies depends on PEG length.

    PubMed

    Cheng, Ta-Chun; Chuang, Kuo-Hsiang; Chen, Michael; Wang, Hsin-Ell; Tzou, Shey-Cherng; Su, Yu-Cheng; Chuang, Chih-Hung; Kao, Chien-Han; Chen, Bing-Mae; Chang, Long-Sen; Roffler, Steve R; Cheng, Tian-Lu

    2013-08-21

    Attachment of poly(ethylene glycol) to proteins can mask immune epitopes to increase serum half-life, reduce immunogenicity, and enhance in vivo biological efficacy. However, PEGylation mediated epitope-masking may also limit sensitivity and accuracy of traditional ELISA. We previously described an anti-PEG-based sandwich ELISA for universal assay of PEGylated molecules. Here, we compared the quantitative assessment of PEGylated interferons by anti-PEG and traditional anti-interferon sandwich ELISA. The detection limits for PEG-Intron (12k-PEG) and Pegasys (40k-PEG) were 1.9 and 0.03 ng/mL for anti-PEG ELISA compared to 0.18 and 0.42 ng/mL for traditional anti-interferon sandwich ELISA. These results indicate that the anti-PEG sandwich ELISA was insensitive to PEGylation mediated epitope-masking and the sensitivity increased in proportion to the length of PEG. By contrast, PEG-masking interfered with detection by traditional anti-interferon sandwich ELISA. Human and mouse serum did not affect the sensitivity of anti-PEG ELISA but impeded traditional anti-interferon sandwich ELISA. The anti-PEG sandwich ELISA was comparable to anti-interferon sandwich ELISA and radioassay of 131I-Pegasys in pharmacokinetic studies in mice. The anti-PEG sandwich ELISA provides a sensitive, accurate, and convenient quantitative measurement of PEGylated protein drugs.

  4. Expert recommendations on the application of interferon for chronic hepatitis B.

    PubMed

    Wan, Mo Bin; Weng, Xin Hua

    2013-12-01

    To help the clinicians correctly and scientifically apply interferon for the treatment of chronic hepatitis B, more than 40 experts majored in infectious and liver diseases updated the 'Expert recommendations on the treatment of chronic hepatitis B with interferon (2007)' following a systematic literature review, summary of clinical experiences and thorough consultation and discussion. The updated expert recommendations primarily included fundamental new knowledge of the use of interferon and individualized interferon therapy. Specifically, we provided recommendations for implementing optimized therapeutic regimens based on quantitative changes in hepatitis B surface antigen and hepatitis B virus DNA levels 24 weeks after interferon therapy. The updated expert recommendations provided itemized details and supplement for the Guidelines for the Prevention and Treatment of Chronic Hepatitis B and they also offer a basis for individualized therapy of chronic hepatitis B with interferon. © 2013 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

  5. The highly virulent variola and monkeypox viruses express secreted inhibitors of type I interferon.

    PubMed

    Fernández de Marco, María del Mar; Alejo, Alí; Hudson, Paul; Damon, Inger K; Alcami, Antonio

    2010-05-01

    Variola virus (VARV) caused smallpox, one of the most devastating human diseases and the first to be eradicated, but its deliberate release represents a dangerous threat. Virulent orthopoxviruses infecting humans, such as monkeypox virus (MPXV), could fill the niche left by smallpox eradication and the cessation of vaccination. However, immunomodulatory activities and virulence determinants of VARV and MPXV remain largely unexplored. We report the molecular characterization of the VARV- and MPXV-secreted type I interferon-binding proteins, which interact with the cell surface after secretion and prevent type I interferon responses. The proteins expressed in the baculovirus system have been purified, and their interferon-binding properties characterized by surface plasmon resonance. The ability of these proteins to inhibit a broad range of interferons was investigated to identify potential adaptation to the human immune system. Furthermore, we demonstrate by Western blot and activity assays the expression of the type I interferon inhibitor during VARV and MPXV infections. These findings are relevant for the design of new vaccines and therapeutics to smallpox and emergent virulent orthopoxviruses because the type I interferon-binding protein is a major virulence factor in animal models, vaccination with this protein induces protective immunity, and its neutralization prevents disease progression.

  6. Bim Nuclear Translocation and Inactivation by Viral Interferon Regulatory Factor

    PubMed Central

    Choi, Young Bong; Nicholas, John

    2010-01-01

    Viral replication efficiency is in large part governed by the ability of viruses to counteract pro-apoptotic signals induced by infection of the host cell. Human herpesvirus 8 (HHV-8) uses several strategies to block the host's innate antiviral defenses via interference with interferon and apoptotic signaling. Contributors include the four viral interferon regulatory factors (vIRFs 1–4), which function in dominant negative fashion to block cellular IRF activities in addition to targeting IRF signaling-induced proteins such as p53 and inhibiting other inducers of apoptosis such as TGFβ receptor-activated Smad transcription factors. Here we identify direct targeting by vIRF-1 of BH3-only pro-apoptotic Bcl-2 family member Bim, a key negative regulator of HHV-8 replication, to effect its inactivation via nuclear translocation. vIRF-1-mediated relocalization of Bim was identified in transfected cells, by both immunofluorescence assay and western analysis of fractionated cell extracts. Also, co-localization of vIRF-1 and Bim was detected in nuclei of lytically infected endothelial cells. In vitro co-precipitation assays using purified vIRF-1 and Bim revealed direct interaction between the proteins, and Bim-binding residues of vIRF-1 were mapped by deletion and point mutagenesis. Generation and experimental utilization of Bim-refractory vIRF-1 variants revealed the importance of vIRF-1:Bim interaction, specifically, in pro-replication and anti-apoptotic activity of vIRF-1. Furthermore, blocking of the interaction with cell-permeable peptide corresponding to the Bim-binding region of vIRF-1 confirmed the relevance of vIRF-1:Bim association to vIRF-1 pro-replication activity. To our knowledge, this is the first report of an IRF protein that interacts with a Bcl-2 family member and of nuclear sequestration of Bim or any other member of the family as a means of inactivation. The data presented reveal a novel mechanism utilized by a virus to control replication

  7. The Role of Type I Interferon Subtypes and Interferon-Gamma in Type I Interferon Diabetes Inhibitory Activity in the NOD Mouse.

    PubMed

    Sobel, Douglas; Ahvazi, Behrouz; Pontzer, Carol

    2016-04-01

    As in bacterial infections and endotoxin shock, type I interferons (IFNs) also have complex and often opposing effects in various models of autoimmune disease. We have shown that type I IFN paradoxically inhibits autoimmune diabetes in the nonobese diabetic mouse (NOD) and biobreeding (BB) rat. We hypothesize that type I IFN activity differs by IFN subtype and interaction with IFN-gamma. We examined the structure-function relationship of the type I IFN molecule and the mechanism of its diabetes-sparing activity in the NOD mouse. While both recombinant human IFN-alpha A/D (bgl 11) (rHuIFN-alphaA/D) and ovine IFN-tauImod (ovIFN-tau) potently inhibited the development of diabetes (P < 0.01), neither recombinant human IFN-alpha B/D (rHuIFN-alphaB/D) nor recombinant human IFN-alpha consensus (CIFN) were efficacious. The activity of IFN subtypes correlate with their NH3-terminal amino acid sequences. All type I IFN save CIFN, which has no diabetes-sparing activity, inhibited the accessory cell function. IFN-tau administration decreased the expression of Fas and ICAM on total cells, class II MHC expression on B cells, and CD40L expression on T cells by 39%, 45%, 45%, and 60%, respectively. In addition, IFN-tau inhibited the development of diabetes in the NOD.IL4(null) but not the NOD.IFN-gamma(null) mice, suggesting a coordinated interaction between type I and type II IFNs to suppress diabetes development. Thus, the amino terminal portion of the type I IFN molecule influences its ability to inhibit the development of autoimmune diabetes in NOD mice. These data also support the contention that IFN-gamma may have a role in mediating the diabetes-sparing effect of high-dose type I IFNs by the inhibition of the IFN-gamma-inducible immune modulators, class II MHC, Fas, ICAM, and CD40L.

  8. The Peculiar Characteristics of Fish Type I Interferons.

    PubMed

    Boudinot, Pierre; Langevin, Christelle; Secombes, Christopher J; Levraud, Jean-Pierre

    2016-11-02

    Antiviral type I interferons (IFNs) have been discovered in fish. Genomic studies revealed their considerable number in many species; some genes encode secreted and non-secreted isoforms. Based on cysteine motifs, fish type I IFNs fall in two subgroups, which use two different receptors. Mammalian type I IFN genes are intronless while type III have introns; in fish, all have introns, but structurally, both subgroups belong to type I. Type I IFNs likely appeared early in vertebrates as intron containing genes, and evolved in parallel in tetrapods and fishes. The diversity of their repertoires in fish and mammals is likely a convergent feature, selected as a response to the variety of viral strategies. Several alternative nomenclatures have been established for different taxonomic fish groups, calling for a unified system. The specific functions of each type I gene remains poorly understood, as well as their interactions in antiviral responses. However, distinct induction pathways, kinetics of response, and tissue specificity indicate that fish type I likely are highly specialized, especially in groups where they are numerous such as salmonids or cyprinids. Unravelling their functional integration constitutes the next challenge to understand how these cytokines evolved to orchestrate antiviral innate immunity in vertebrates.

  9. Interferon induction and function at the mucosal surface.

    PubMed

    Durbin, Russell K; Kotenko, Sergei V; Durbin, Joan E

    2013-09-01

    Interferons (IFNs) are produced in response to virus infection and induce an antiviral state in virtually all cell types. In addition to upregulating the transcription of genes that inhibit virus replication, type I (or -α/β) IFNs also act to orchestrate the adaptive immune response to virus infection. Recently a new family of antiviral cytokines, the type III (or -λ) IFNs, has been identified that activate the same antiviral pathways via a distinct receptor. Although the identical transcription factor, IFN-stimulated gene factor 3 is activated by either IFN-α/β or IFN-λ signaling, differences in the induction and action of these two cytokine families are beginning to be appreciated. In this article, we review this emerging body of literature on the differing roles these cytokines play in host defense of the mucosal surface. Although many viruses enter the body through the respiratory and gastrointestinal tracts, we have focused the discussion on influenza A virus, respiratory syncytial virus, and rotavirus, three ubiquitous human pathogens that target the epithelial lining and are associated with a major disease burden.

  10. Type I Interferon Controls Propagation of Long Interspersed Element-1*

    PubMed Central

    Yu, Qiujing; Carbone, Christopher J.; Katlinskaya, Yuliya V.; Zheng, Hui; Zheng, Ke; Luo, Mengcheng; Wang, P. Jeremy; Greenberg, Roger A.; Fuchs, Serge Y.

    2015-01-01

    Type I interferons (IFN) including IFNα and IFNβ are critical for the cellular defense against viruses. Here we report that increased levels of IFNβ were found in testes from mice deficient in MOV10L1, a germ cell-specific RNA helicase that plays a key role in limiting the propagation of retrotransposons including Long Interspersed Element-1 (LINE-1). Additional experiments revealed that activation of LINE-1 retrotransposons increases the expression of IFNβ and of IFN-stimulated genes. Conversely, pretreatment of cells with IFN suppressed the replication of LINE-1. Furthermore, the efficacy of LINE-1 replication was increased in isogenic cell lines harboring inactivating mutations in diverse elements of the IFN signaling pathway. Knockdown of the IFN receptor chain IFNAR1 also stimulated LINE-1 propagation in vitro. Finally, a greater accumulation of LINE-1 was found in mice that lack IFNAR1 compared with wild type mice. We propose that LINE-1-induced IFN plays an important role in restricting LINE-1 propagation and discuss the putative role of IFN in preserving the genome stability. PMID:25716322

  11. Type I Interferons as Regulators of Lung Inflammation

    PubMed Central

    Makris, Spyridon; Paulsen, Michelle; Johansson, Cecilia

    2017-01-01

    Immune responses to lung infections must be tightly regulated in order to permit pathogen eradication while maintaining organ function. Exuberant or dysregulated inflammation can impair gas exchange and underlies many instances of lung disease. An important driver of inflammation in the lung is the interferon (IFN) response. Type I IFNs are antiviral cytokines that induce a large range of proteins that impair viral replication in infected cells. This cell-intrinsic action plays a crucial role in protecting the lungs from spread of respiratory viruses. However, type I IFNs have also recently been found to be central to the initiation of lung inflammatory responses, by inducing recruitment and activation of immune cells. This helps control virus burden but can cause detrimental immunopathology and contribute to disease severity. Furthermore, there is now increasing evidence that type I IFNs are not only induced after viral infections but also after infection with bacteria and fungi. The pro-inflammatory function of type I IFNs in the lung opens up the possibility of immune modulation directed against this antiviral cytokine family. In this review, the initiation and signaling of type I IFNs as well as their role in driving and maintaining lung inflammation will be discussed. PMID:28344581

  12. Electrochemical impedance spectroscopy based-on interferon-gamma detection

    NASA Astrophysics Data System (ADS)

    Li, Guan-Wei; Kuo, Yi-Ching; Tsai, Pei-I.; Lee, Chih-Kung

    2014-03-01

    Tuberculosis (TB) is an ancient disease constituted a long-term menace to public health. According to World Health Organization (WHO), mycobacterium tuberculosis (MTB) infected nearly a third of people of the world. There is about one new TB occurrence every second. Interferon-gamma (IFN-γ) is associated with susceptibility to TB, and interferongamma release assays (IGRA) is considered to be the best alternative of tuberculin skin test (TST) for diagnosis of latent tuberculosis infection (LTBI). Although significant progress has been made with regard to the design of enzyme immunoassays for IFN-γ, adopting this assay is still labor-intensive and time-consuming. To alleviate these drawbacks, we used IFN-γ antibody to facilitate the detection of IFN-γ. An experimental verification on the performance of IGRA was done in this research. We developed two biosensor configurations, both of which possess high sensitivity, specificity, and rapid IFN-γ diagnoses. The first is the electrochemical method. The second is a circular polarization interferometry configuration, which incorporates two light beams with p-polarization and s-polarization states individually along a common path, a four photo-detector quadrature configuration to arrive at a phase modulated ellipsometer. With these two methods, interaction between IFN-γ antibody and IFN-γ were explored and presented in detail.

  13. Interactions of the interferon system with cellular metabolism

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald

    1986-01-01

    The results of studies concerning the interaction of the interferon (Inf) system with the activities of carcinogens, tumor promoters, and cytochrome P-450 are presented. The results show that the addition of a tumor promoter (TPA or 4-O-methyl-TPA) to a tissue culture enhances virus-induced Inf-gamma production, suggesting a potential value of tumor promoters in the biosynthesis of commercial Inf. On the other hand, the carcinogens were reported to inhibit the induction of Inf-alpha/beta in cultured cells and in intact animals (with no effect on the administered or preformed Inf). The demonstration of a correlation between the carcinogenic potential of a compound and its inhibitive effect on Inf production suggests a possible use of the Inf production assay in the evaluation of the carcinogenicity of chemicals. In addition, it was shown that the induction of Inf-alpha/beta as well as the administration of this Inf depresses the levels of rat liver cytochrome P-450 which is responsible for binding lipophilic drugs, steroids, and carcinogens, thus increasing the toxicity of the respective chemical.

  14. The nucleocapsid protein of measles virus blocks host interferon response

    SciTech Connect

    Takayama, Ikuyo; Sato, Hiroki; Watanabe, Akira; Omi-Furutani, Mio; Sugai, Akihiro; Kanki, Keita; Yoneda, Misako; Kai, Chieko

    2012-03-01

    Measles virus (MV) belongs to the genus Morbillivirus of the family Paramyxoviridae. A number of paramyxoviruses inhibit host interferon (IFN) signaling pathways in host immune systems by various mechanisms. Inhibition mechanisms have been described for many paramyxoviruses. Although there are inconsistencies among previous reports concerning MV, it appears that P/V/C proteins interfere with the pathways. In this study, we confirmed the effects of MV P gene products of a wild MV strain on IFN pathways and examined that of other viral proteins on it. Interestingly, we found that N protein acts as an IFN-{alpha}/{beta} and {gamma}-antagonist as strong as P gene products. We further investigated the mechanisms of MV-N inhibition, and revealed that MV-N blocks the nuclear import of activated STAT without preventing STAT and Jak activation or STAT degradation, and that the nuclear translocation of MV-N is important for the inhibition. The inhibitory effect of the N protein was observed as a common feature of other morbilliviruses. The results presented in this report suggest that N protein of MV as well as P/V/C proteins is involved in the inhibition of host IFN signaling pathways.

  15. Conformation and activity of recombinant human fibroblast interferon-beta.

    PubMed

    Boublik, M; Moschera, J A; Wei, C; Kung, H F

    1990-04-01

    Conformation of highly purified recombinant human fibroblast interferon-beta (rHuIFN-beta) was correlated with its biological activity. The extent of ordered secondary structure was determined by circular dichroic (CD) spectroscopy in various buffer conditions to establish conditions of protein stability and its potential for helix formation. The highest "helicity" (about 50 +/- 5% of alpha-helices) and the highest antiviral activities (4-10 x 10(7) units/mg) were found in 50% ethylene glycol, 1 M NaCl and 0.05 M Na3PO4, pH 7.2 (Buffer I); 80 mM citric acid, 20 mM Na2HPO4, pH 2.9 (Buffer II); and 25 mM NH4OAc, 125 mM NaCl, pH 5.1 (Buffer III). Both helicity and antiviral activity of the IFN-beta decrease in parallel with denaturation by urea, heat, and/or by repeated cycles of freezing and thawing. Low pH (pH 2.9 Buffer II) exhibits a distinct stabilizing effect on the structure and antiviral activity of IFN-beta against heat denaturation.

  16. Interferon-gamma-release assay prevents unnecessary tuberculosis therapy.

    PubMed

    Schichter-Konfino, Vered; Halasz, Katalin; Grushko, Galia; Snir, Ayelet; Haj, Tharwat; Vadasz, Zahava; Kessel, Aharon; Potasman, Israel; Toubi, Elias

    2015-04-01

    The mass influx of immigrants from tuberculosis-endemic countries into Israel was followed by a considerable increase in the incidence of tuberculosis (TB). All contacts of active TB patients are obliged to be screened by tuberculin skin tests (TST) and, if found positive, prophylactic treatment is considered. To assess the utility of interferon-gamma (IFNγ)-release assay with a prolonged follow-up in preventing unnecessary anti-TB therapy in individuals with suspected false positive results. Between 2008 and 2012 the QuantiFERON TB gold-in-tube test (QFT-G) was performed in 278 sequential individuals who were mostly TST-positive and/or were in contact with an active TB patient. In all, whole blood was examined by the IFNγ-release assay. We correlated the TST diameter with the QFT-G assay and followed those patients with a negative assay. The QFT-G test was positive in only 72 (42%) of all 171 TST-positive individuals. There was no correlation between the diameter of TST and QFT-G positivity. Follow-up over 5 years was available in 128 (62%) of all QFT-G-negative individuals. All remained well and none developed active TB. A negative QFT-G test may obviate the need for anti-TB therapy in more than half of those with a positive TST.

  17. Molecular and Functional Characterization of Canine Interferon-Epsilon

    PubMed Central

    Yang, Limin; Xu, Lei; Li, Yun; Li, Jing; Bi, Yuhai

    2013-01-01

    In this study, we provide the first comprehensive annotation of the entire family of canine interferons (IFNs). Canine IFN-ɛ (IFNE), IFN-κ (IFNK), and IFN-λ (IFNL) were discovered for the first time. Ten functional and 2 truncated IFN-α (IFNA) pseudogenes were found in the genome, which also enriched the existing knowledge about canine IFNA. The canine type I IFN genes are clustered on chromosome 11, and their relative arrangements are illustrated. To further investigate the biological activity of canine IFNE, it was expressed and purified in Escherichia coli. Recombinant canine IFNE (rCaIFN-ɛ) displayed potent antiviral activity on both homologous and heterologous animal cells in vitro, indicating that rCaIFN-ɛ has more broad cross-species activity than recombinant canine IFNA (rCaIFN-α). The antiviral activities of rCaIFN-ɛ and rCaIFN-α7 against different viruses on MDCK cells were also evaluated. The antiviral activities of recombinant canine IFNK and IFNL were demonstrated using a VSV-MDCK virus-target cell system. rCaIFN-ɛ exhibited a significant anti-proliferative response against A72 canine tumor cells and MDCK canine epithelial cells in a dose-dependent manner. rCaIFN-α7 was approximately 16-fold more potent than rCaIFN-ɛ in promoting natural killer cell cytotoxicity activity. Further, rCaIFN-ɛ can activate the JAK-STAT signaling pathway. PMID:23964570

  18. Latent Mycobacterium tuberculosis Infection and Interferon-Gamma Release Assays.

    PubMed

    Pai, Madhukar; Behr, Marcel

    2016-10-01

    The identification of individuals with latent tuberculosis infection (LTBI) is useful for both fundamental understanding of the pathogenesis of disease and for clinical and public health interventions (i.e., to prevent progression to disease). Basic research suggests there is a pathogenetic continuum from exposure to infection to disease, and individuals may advance or reverse positions within the spectrum, depending on changes in the host immunity. Unfortunately, there is no diagnostic test that resolves the various stages within the spectrum of Mycobacterium tuberculosis infection. Two main immune-based approaches are currently used for identification of LTBI: the tuberculin skin test (TST) and the interferon-gamma release assay (IGRA). TST can use either the conventional purified protein derivative or more specific antigens. Extensive research suggests that both TST and IGRA represent indirect markers of M. tuberculosis exposure and indicates a cellular immune response to M. tuberculosis. The imperfect concordance between these two tests suggests that neither test is perfect, presumably due to both technical and biological reasons. Neither test can accurately differentiate between LTBI and active TB. Both IGRA and TST have low sensitivity in a variety of immunocompromised populations. Cohort studies have shown that both TST and IGRA have low predictive value for progression from infection to active TB. For fundamental applications, basic research is necessary to identify those at highest risk of disease with a positive TST and/or IGRA. For clinical applications, the identification of such biomarkers can help prioritize efforts to interrupt progression to disease through preventive therapy.

  19. The Peculiar Characteristics of Fish Type I Interferons

    PubMed Central

    Boudinot, Pierre; Langevin, Christelle; Secombes, Christopher J.; Levraud, Jean-Pierre

    2016-01-01

    Antiviral type I interferons (IFNs) have been discovered in fish. Genomic studies revealed their considerable number in many species; some genes encode secreted and non-secreted isoforms. Based on cysteine motifs, fish type I IFNs fall in two subgroups, which use two different receptors. Mammalian type I IFN genes are intronless while type III have introns; in fish, all have introns, but structurally, both subgroups belong to type I. Type I IFNs likely appeared early in vertebrates as intron containing genes, and evolved in parallel in tetrapods and fishes. The diversity of their repertoires in fish and mammals is likely a convergent feature, selected as a response to the variety of viral strategies. Several alternative nomenclatures have been established for different taxonomic fish groups, calling for a unified system. The specific functions of each type I gene remains poorly understood, as well as their interactions in antiviral responses. However, distinct induction pathways, kinetics of response, and tissue specificity indicate that fish type I likely are highly specialized, especially in groups where they are numerous such as salmonids or cyprinids. Unravelling their functional integration constitutes the next challenge to understand how these cytokines evolved to orchestrate antiviral innate immunity in vertebrates. PMID:27827855

  20. Gamma Interferon Release Assays for Detection of Mycobacterium tuberculosis Infection

    PubMed Central

    Denkinger, Claudia M.; Kik, Sandra V.; Rangaka, Molebogeng X.; Zwerling, Alice; Oxlade, Olivia; Metcalfe, John Z.; Cattamanchi, Adithya; Dowdy, David W.; Dheda, Keertan; Banaei, Niaz

    2014-01-01

    SUMMARY Identification and treatment of latent tuberculosis infection (LTBI) can substantially reduce the risk of developing active disease. However, there is no diagnostic gold standard for LTBI. Two tests are available for identification of LTBI: the tuberculin skin test (TST) and the gamma interferon (IFN-γ) release assay (IGRA). Evidence suggests that both TST and IGRA are acceptable but imperfect tests. They represent indirect markers of Mycobacterium tuberculosis exposure and indicate a cellular immune response to M. tuberculosis. Neither test can accurately differentiate between LTBI and active TB, distinguish reactivation from reinfection, or resolve the various stages within the spectrum of M. tuberculosis infection. Both TST and IGRA have reduced sensitivity in immunocompromised patients and have low predictive value for progression to active TB. To maximize the positive predictive value of existing tests, LTBI screening should be reserved for those who are at sufficiently high risk of progressing to disease. Such high-risk individuals may be identifiable by using multivariable risk prediction models that incorporate test results with risk factors and using serial testing to resolve underlying phenotypes. In the longer term, basic research is necessary to identify highly predictive biomarkers. PMID:24396134

  1. Interferon-Gamma Promotes Infection of Astrocytes by Trypanosoma cruzi

    PubMed Central

    Silva, Rafael Rodrigues; Mariante, Rafael M.; Silva, Andrea Alice; dos Santos, Ana Luiza Barbosa; Roffê, Ester; Santiago, Helton; Gazzinelli, Ricardo Tostes; Lannes-Vieira, Joseli

    2015-01-01

    The inflammatory cytokine interferon-gamma (IFNγ) is crucial for immunity against intracellular pathogens such as the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease (CD). IFNγ is a pleiotropic cytokine which regulates activation of immune and non-immune cells; however, the effect of IFNγ in the central nervous system (CNS) and astrocytes during CD is unknown. Here we show that parasite persists in the CNS of C3H/He mice chronically infected with the Colombian T. cruzi strain despite the increased expression of IFNγ mRNA. Furthermore, most of the T. cruzi-bearing cells were astrocytes located near IFNγ+ cells. Surprisingly, in vitro experiments revealed that pretreatment with IFNγ promoted the infection of astrocytes by T. cruzi increasing uptake and proliferation of intracellular forms, despite inducing increased production of nitric oxide (NO). Importantly, the effect of IFNγ on T. cruzi uptake and growth is completely blocked by the anti-tumor necrosis factor (TNF) antibody Infliximab and partially blocked by the inhibitor of nitric oxide synthesis L-NAME. These data support that IFNγ fuels astrocyte infection by T. cruzi and critically implicate IFNγ-stimulated T. cruzi-infected astrocytes as sources of TNF and NO, which may contribute to parasite persistence and CNS pathology in CD. PMID:25695249

  2. Fluoxetine regulates cell growth inhibition of interferon-α.

    PubMed

    Lin, Yu-Min; Yu, Bu-Chin; Chiu, Wen-Tai; Sun, Hung-Yu; Chien, Yu-Chieh; Su, Hui-Chen; Yen, Shu-Yang; Lai, Hsin-Wen; Bai, Chyi-Huey; Young, Kung-Chia; Tsao, Chiung-Wen

    2016-10-01

    Fluoxetine, a well-known anti-depression agent, may act as a chemosensitizer to assist and promote cancer therapy. However, how fluoxetine regulates cellular signaling to enhance cellular responses against tumor cell growth remains unclear. In the present study, addition of fluoxetine promoted growth inhibition of interferon-alpha (IFN-α) in human bladder carcinoma cells but not in normal uroepithelial cells through lessening the IFN-α-induced apoptosis but switching to cause G1 arrest, and maintaining the IFN-α-mediated reduction in G2/M phase. Activations and signal transducer and transactivator (STAT)-1 and peroxisome proliferator-activated receptor alpha (PPAR-α) were involved in this process. Chemical inhibitions of STAT-1 or PPAR-α partially rescued bladder carcinoma cells from IFN-α-mediated growth inhibition via blockades of G1 arrest, cyclin D1 reduction, p53 downregulation and p27 upregulation in the presence of fluoxetine. However, the functions of both proteins were not involved in the control of fluoxetine over apoptosis and maintained the declined G2/M phase of IFN-α. These results indicated that activation of PPAR-α and STAT-1 participated, at least in part, in growth inhibition of IFN-α in the presence of fluoxetine.

  3. Stochastic expression of the interferon-β gene.

    PubMed

    Zhao, Mingwei; Zhang, Jiangwen; Phatnani, Hemali; Scheu, Stefanie; Maniatis, Tom

    2012-01-01

    Virus infection of mammalian cells induces the production of high levels of type I interferons (IFNα and β), cytokines that orchestrate antiviral innate and adaptive immunity. Previous studies have shown that only a fraction of the infected cells produce IFN. However, the mechanisms responsible for this stochastic expression are poorly understood. Here we report an in depth analysis of IFN-expressing and non-expressing mouse cells infected with Sendai virus. Mouse embryonic fibroblasts in which an internal ribosome entry site/yellow fluorescent protein gene was inserted downstream from the endogenous IFNβ gene were used to distinguish between the two cell types, and they were isolated from each other using fluorescence-activated cell sorting methods. Analysis of the separated cells revealed that stochastic IFNβ expression is a consequence of cell-to-cell variability in the levels and/or activities of limiting components at every level of the virus induction process, ranging from viral replication and expression, to the sensing of viral RNA by host factors, to activation of the signaling pathway, to the levels of activated transcription factors. We propose that this highly complex stochastic IFNβ gene expression evolved to optimize both the level and distribution of type I IFNs in response to virus infection.

  4. Post-transcriptional regulation of interferons and their signaling pathways.

    PubMed

    Savan, Ram

    2014-05-01

    Interferons (IFNs) are low molecular weight cell-derived proteins that include the type I, II, and III IFN families. IFNs are critical for an optimal immune response during microbial infections while dysregulated expression can lead to autoimmune diseases. Given its role in disease, it is important to understand cellular mechanisms of IFN regulation. 3' untranslated regions (3' UTRs) have emerged as potent regulators of mRNA and protein dosage and are controlled through multiple regulatory elements including adenylate uridylate (AU)-rich elements (AREs) and microRNA (miRNA) recognition elements. These AREs are targeted by RNA-binding proteins (ARE-BPs) for degradation and/or stabilization through an ARE-mediated decay process. miRNA are endogenous, single-stranded RNA molecules ~22 nucleotides in length that regulate mRNA translation through the miRNA-induced silencing complex. IFN transcripts, like other labile mRNAs, harbor AREs in their 3' UTRs that dictate the turnover of mRNA. This review is a survey of the literature related to IFN regulation by miRNA, ARE-BPs, and how these complexes interact dynamically on the 3' UTR. Additionally, downstream effects of these post-transcriptional regulators on the immune response will be discussed. Review topics include past studies, current understanding, and future challenges in the study of post-transcriptional regulation affecting IFN responses.

  5. Distinct evolution process among type I interferon in mammals.

    PubMed

    Xu, Lei; Yang, Limin; Liu, Wenjun

    2013-05-01

    Interferon (IFN) is thought to play an important role in the vertebrate immune system, but systemic knowledge of IFN evolution has yet to be elucidated. To evaluate the phylogenic distribution and evolutionary history of type I IFNs, 13genomes were searched using BLASTn program, and a phylogenetic tree of vertebrate type I IFNs was constructed. In the present study, an IFNδ-like gene in the human genome was identified, refuting the concept that humans have no IFNδ genes, and other mammalian IFN genes were also identified. In the phylogenetic tree, the mammalian IFNβ, IFNɛ, and IFNκ formed a clade separate from the other mammalian type I IFNs, while piscine and avian IFNs formed distinct clades. Based on this phylogenetic analysis and the various characteristics of type I IFNs, the evolutionary history of type I IFNs was further evaluated. Our data indicate that an ancestral IFNα-like gene forms a core from which new IFNs divided during vertebrate evolution. In addition, the data suggest how the other type I IFNs evolved from IFNα and shaped the complex type I IFN system. The promoters of type I IFNs were conserved among different mammals, as well as their genic regions. However, the intergenic regions of type I IFN clusters were not conserved among different mammals, demonstrating a high selection pressure upon type I IFNs during their evolution.

  6. A peptide mimetic of human interferon (IFN)-beta.

    PubMed Central

    Sato, Atsushi; Sone, Saburo

    2003-01-01

    Type I interferons (IFNs) are cytokines that are used clinically as antiviral and antitumour agents. The interaction of IFNs with their heterodimeric type I IFN receptor comprised of IFNAR1 and IFNAR2 is a first step to inducing biological actions. Here, we describe the successful mimicry of IFN-beta by a peptide isolated by phage-display screening using a neutralizing anti-IFN-beta monoclonal antibody. The 15-mer peptide, designated SYR6, was shown to compete with IFN-beta for binding to type I IFN receptor in a concentration-dependent manner, and was shown to elicit antiviral activity on cultured cells. This antiviral activity was not eliminated in the presence of neutralizing monoclonal antibodies to IFN-alpha, -beta and -gamma, and a low concentration of soluble type I IFN receptor, suggesting that it was not due to IFN contamination or the induction of endogenous IFNs by SYR6. This peptide might be a potent agonist to provide a mechanism of activating heterodimeric cytokine receptors. PMID:12542398

  7. Nasal absorption of interferon: Enhancement by surfactant agents

    SciTech Connect

    Baglioni, C.; Phipps, R.J. )

    1990-10-01

    The effect of spraying the nasal mucosa with an aerosol of recombinant human interferon-alpha (IFN-alpha 2a) was studied in an animal model, the sheep, because cultures of sheep cells were found to be responsive to the antiviral activity of this IFN. Binding assays with {sup 125}I-labeled IFN-alpha 2a detected very few receptors in sheep nasal mucosa, but a membrane fraction prepared from this mucosa had abundant high-affinity receptors. Nasal mucosa homogenates were prepared from the turbinates of sheep that had been sprayed with IFN-alpha 2a aerosols, and the 2',5'-oligoadenylate (2-5A) activity induced in response was measured. To try to enhance the permeability of the mucosa, surfactant agents were added to the IFN and aerosols generated. There were measurable levels of 2-5A synthetase after aerosols with added sodium deoxycholate or, better, polyoxyethylene 9-lauryl ether. This latter surfactant was well tolerated in previous studies with intranasally administered insulin. The level of 2-5A synthetase induced was related to the dose of IFN, and the increased activity persisted up to 72 h after an IFN aerosol. These studies suggest that surfactant agents may make IFN aerosols much more effective for the prophylaxis of respiratory virus infections.

  8. Interferon-inducible GTPases in cell autonomous and innate immunity.

    PubMed

    Meunier, Etienne; Broz, Petr

    2016-02-01

    Detection and clearance of invading pathogens requires a coordinated response of the adaptive and innate immune system. Host cell, however, also features different mechanisms that restrict pathogen replication in a cell-intrinsic manner, collectively referred to as cell-autonomous immunity. In immune cells, the ability to unleash those mechanisms strongly depends on the activation state of the cell, which is controlled by cytokines or the detection of pathogen-associated molecular patterns by pattern-recognition receptors. The interferon (IFN) class of cytokines is one of the strongest inducers of antimicrobial effector mechanisms and acts against viral, bacterial and parasitic intracellular pathogens. This has been linked to the upregulation of several hundreds of IFN-stimulated genes, among them the so-called IFN-inducible GTPases. Two subfamilies of IFN-inducible GTPases, the immunity-related GTPases (IRGs) and the guanylate-binding proteins (GBPs), have gained attention due to their exceptional ability to specifically target intracellular vacuolar pathogens and restrict their replication by destroying their vacuolar compartment. Their repertoire has recently been expanded to the regulation of inflammasome complexes, which are cytosolic multi-protein complexes that control an inflammatory cell death called pyroptosis and the release of cytokines like interleukin-1β and interleukin-18. Here we discuss recent advances in understanding the function, the targeting and regulation of IRG and GBP proteins during microbial infections.

  9. Biological response modifiers: interferons, interleukins, recombinant products, liposomal products.

    PubMed

    Kruth, S A

    1998-03-01

    The concept of enhancing the normal immune response against infections and neoplasms has been considered for decades. The administration of various natural and synthetic products to simulate systemic infections has largely given over to the idea that specific cytokines can be used effectively when administered systemically. Interferons, interleukins, and hematopoietic growth factors may offer substantial clinical benefit in chronic viral infections, and cancers such as osteosarcoma, melanoma, and lymphosarcoma. Erythropoietin has been shown to have great utility in the management of chronic renal failure. At this point in time, only recombinant products derived from humans are commercially available, and they are expensive and not licensed for use in companion animals. Nevertheless, these products may have significant clinical impact on several highly fatal disorders of dogs and cats. When administered systemically, cytokines perturb complex regulatory pathways, and serious side effects may occur. Innovative delivery methods, such as liposomes, gene therapy, and even oral administration may increase the therapeutic index of these molecules. Biological response modification, cytokine biology, and associated delivery systems are rapidly changing fields, and the small animal veterinarian will need to watch for significant advances in these areas over the next several years.

  10. Gamma Interferon Is Dispensable for Neopterin Production In Vivo

    PubMed Central

    Sghiri, R.; Feinberg, J.; Thabet, F.; Dellagi, K.; Boukadida, J.; Ben Abdelaziz, A.; Casanova, J. L.; Barbouche, M. R.

    2005-01-01

    Previous studies have indicated that neopterin is synthesized in vitro by human monocyte-derived macrophages and dendritic cells upon stimulation with gamma interferon (IFN-γ). Neopterin production under specific conditions in vitro has also been obtained upon stimulation with IFN-α and/or IFN-β. However, it is unknown if any IFN-γ-independent neopterin synthesis is possible in vivo. In the present study we investigated the serum neopterin concentrations in patients affected by the syndrome of Mendelian susceptibility to mycobacterial disease (MSMD). Indeed, this syndrome is characterized by deeply impaired or absent IFN-γ production or function due to severe mutations in molecules involved in IFN-γ/interleukin-12 (IL-12)/IL-23-dependent pathway. Serum neopterin levels were measured by an enzyme-linked immunosorbent assay in 27 patients with MSMD. We found that serum neopterin levels are elevated in the complete absence of IFN-γ activity due either to a complete deficiency of its receptor or to deleterious mutations of IL-12 or its receptor. These data clearly indicate that, as reported from in vitro studies, other stimuli are able to induce neopterin synthesis in vivo. Consequently, neopterin cannot be used as means of diagnosis of MSMD due to IFN-γ-, IL-12-, and IL-23-dependent pathway defects. PMID:16339068

  11. Accumulation of guanylate binding proteins in patients treated with interferons.

    PubMed

    Cheng, Y S; Becker-Manley, M F; Rucker, R G; Borden, E C

    1988-06-01

    We have previously described an interferon (IFN)-induced protein with a molecular weight of 67,000. This protein has an affinity to guanylates and is thus called guanylate binding protein (GBP). The synthesis of GBP is inducible by IFNs in all human diploid fibroblast cell lines that we studied. To determine whether or not the GBP synthesis is IFN-inducible in humans as well as in cultured cells, we have studied the levels of GBP in the peripheral blood leukocytes (PBL) of patients treated with either type I or type II IFN. An increased GBP level was found the day immediately after treatment with either type of IFN, and the elevated GBP levels were maintained for at least 8 days. Among the patients studied, we found a higher level GBP accumulation (2.3x) in patients treated with IFN-beta than in those treated with IFN-gamma (1.6x). The increase of GBP in patients receiving IFN-gamma correlated with increases in class II histocompatibility antigens, HLA-DR and HLA-DQ in monocytes. Thus, the levels of GBP in peripheral blood leukocytes may be used as a parameter for the study of IFN responses in patients.

  12. Interferon-Inducible GTPases in Host Resistance, Inflammation and Disease.

    PubMed

    Pilla-Moffett, Danielle; Barber, Matthew F; Taylor, Gregory A; Coers, Jörn

    2016-08-28

    Cell-autonomous immunity is essential for host organisms to defend themselves against invasive microbes. In vertebrates, both the adaptive and the innate branches of the immune system operate cell-autonomous defenses as key effector mechanisms that are induced by pro-inflammatory interferons (IFNs). IFNs can activate cell-intrinsic host defenses in virtually any cell type ranging from professional phagocytes to mucosal epithelial cells. Much of this IFN-induced host resistance program is dependent on four families of IFN-inducible GTPases: the myxovirus resistance proteins, the immunity-related GTPases, the guanylate-binding proteins (GBPs), and the very large IFN-inducible GTPases. These GTPase families provide host resistance to a variety of viral, bacterial, and protozoan pathogens through the sequestration of microbial proteins, manipulation of vesicle trafficking, regulation of antimicrobial autophagy (xenophagy), execution of intracellular membranolytic pathways, and the activation of inflammasomes. This review discusses our current knowledge of the molecular function of IFN-inducible GTPases in providing host resistance, as well as their role in the pathogenesis of autoinflammatory Crohn's disease. While substantial advances were made in the recent past, few of the known functions of IFN-inducible GTPases have been explored in any depth, and new functions await discovery. This review will therefore highlight key areas of future exploration that promise to advance our understanding of the role of IFN-inducible GTPases in human diseases.

  13. Type I interferon response is delayed in human astrovirus infections.

    PubMed

    Guix, Susana; Pérez-Bosque, Anna; Miró, Lluïsa; Moretó, Miquel; Bosch, Albert; Pintó, Rosa M

    2015-01-01

    Type I interferon (IFN) activation and its subsequent effects are important in the response to viral infections. Here we show that human astroviruses (HAstVs), which are important agents of acute gastroenteritis in children, induce a mild and delayed IFN response upon infecting CaCo-2 cells. Although IFN-β mRNA is detected within infected cells and supernatant from infected cells show antiviral activity against the replication of other well-known IFN-sensitive viruses, these responses occur at late stages of infection once genome replication has taken place. On the other hand, HAstV replication can be partially reduced by the addition of exogenous IFN, and inhibition of IFN activation by BX795 enhances viral replication, indicating that HAstVs are IFN-sensitive viruses. Finally, different levels of IFN response were observed in cells infected with different HAstV mutants with changes in the hypervariable region of nsP1a/4, suggesting that nsP1a/4 genotype may potentially have clinical implications due to its correlation with the viral replication phenotype and the antiviral responses induced within infected cells.

  14. Rationale for stimulator of interferon genes-targeted cancer immunotherapy.

    PubMed

    Rivera Vargas, Thaiz; Benoit-Lizon, Isis; Apetoh, Lionel

    2017-02-17

    The efficacy of checkpoint inhibitor therapy illustrates that cancer immunotherapy, which aims to foster the host immune response against cancer to achieve durable anticancer responses, can be successfully implemented in a routine clinical practice. However, a substantial proportion of patients does not benefit from this treatment, underscoring the need to identify alternative strategies to defeat cancer. Despite the demonstration in the 1990's that the detection of danger signals, including the nucleic acids DNA and RNA, by dendritic cells (DCs) in a cancer setting is essential for eliciting host defence, the molecular sensors responsible for recognising these danger signals and eliciting anticancer immune responses remain incompletely characterised, possibly explaining the disappointing results obtained so far upon the clinical implementation of DC-based cancer vaccines. In 2008, STING (stimulator of interferon genes), was identified as a protein that is indispensable for the recognition of cytosolic DNA. The central role of STING in controlling anticancer immune responses was exemplified by observations that spontaneous and radiation-induced adaptive anticancer immunity was reduced in the absence of STING, illustrating the potential of STING-targeting for cancer immunotherapy. Here, we will discuss the relevance of manipulating the STING signalling pathway for cancer treatment and integrating STING-targeting based strategies into combinatorial therapies to obtain long-lasting anticancer immune responses.

  15. A new assay system for guinea pig interferon biological activity.

    PubMed

    Yamamoto, Toshiko; Jeevan, Amminikutty; Ohishi, Kazue; Nojima, Yasuhiro; Umemori, Kiyoko; Yamamoto, Saburo; McMurray, David N

    2002-07-01

    We have developed an assay system for guinea pig interferon (IFN) based on reduction of viral cytopathic effect (CPE) in various cell lines. CPE inhibition was detected optimally in the guinea pig fibroblast cell line 104C1 infected with encephalomyocarditis virus (EMCV). The amount of biologically active guinea pig IFN was quantified by estimating viable cell numbers colorimetrically by means of a tetrazolium compound, 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt (WST-1) and 1-methoxy-5-methylphenazinium methylsulfate (PMS). WST-1 color developed until stopped by the addition of sulfuric acid. This had no effect on the colorimetric assay, and the color was stable for at least 24 h. The acid also inactivated the EMCV and, thus, eliminated the viral hazard. Inhibition of CPE activity was highly correlated with the concentration of culture supernatants from BCG-vaccinated guinea pig splenocytes stimulated in vitro with tuberculin or an immunostimulatory oligoDNA. This assay detected guinea pig IFN and human IFN-alpha, but not IFN-gamma from human, mouse, rat, pig, or dog. This assay system has proved useful for the titration of guinea pig IFN, being easy to perform, free from viral hazard, relatively species specific, highly reproducible, and inexpensive.

  16. Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production.

    PubMed

    Nestle, Frank O; Conrad, Curdin; Tun-Kyi, Adrian; Homey, Bernhard; Gombert, Michael; Boyman, Onur; Burg, Günter; Liu, Yong-Jun; Gilliet, Michel

    2005-07-04

    Psoriasis is one of the most common T cell-mediated autoimmune diseases in humans. Although a role for the innate immune system in driving the autoimmune T cell cascade has been proposed, its nature remains elusive. We show that plasmacytoid predendritic cells (PDCs), the natural interferon (IFN)-alpha-producing cells, infiltrate the skin of psoriatic patients and become activated to produce IFN-alpha early during disease formation. In a xenograft model of human psoriasis, we demonstrate that blocking IFN-alpha signaling or inhibiting the ability of PDCs to produce IFN-alpha prevented the T cell-dependent development of psoriasis. Furthermore, IFN-alpha reconstitution experiments demonstrated that PDC-derived IFN-alpha is essential to drive the development of psoriasis in vivo. These findings uncover a novel innate immune pathway for triggering a common human autoimmune disease and suggest that PDCs and PDC-derived IFN-alpha represent potential early targets for the treatment of psoriasis.

  17. Interferon-α signaling promotes embryonic HSC maturation.

    PubMed

    Kim, Peter Geon; Canver, Matthew C; Rhee, Catherine; Ross, Samantha J; Harriss, June V; Tu, Ho-Chou; Orkin, Stuart H; Tucker, Haley O; Daley, George Q

    2016-07-14

    In the developing mouse embryo, the first hematopoietic stem cells (HSCs) arise in the aorta-gonad-mesonephros (AGM) and mature as they transit through the fetal liver (FL). Compared with FL and adult HSCs, AGM HSCs have reduced repopulation potential in irradiated adult transplant recipients but mechanisms underlying this deficiency in AGM HSCs are poorly understood. By co-expression gene network analysis, we deduced that AGM HSCs show lower levels of interferon-α (IFN-α)/Jak-Stat1-associated gene expression than FL HSCs. Treatment of AGM HSCs with IFN-α enhanced long-term hematopoietic engraftment and donor chimerism. Conversely, IFN-α receptor-deficient AGMs (Ifnαr1(-/-)), had significantly reduced donor chimerism. We identify adenine-thymine-rich interactive domain-3a (Arid3a), a factor essential for FL and B lymphopoiesis, as a key transcriptional co-regulator of IFN-α/Stat1 signaling. Arid3a occupies the genomic loci of Stat1 as well as several IFN-α effector genes, acting to regulate their expression. Accordingly, Arid3a(-/-) AGM HSCs had significantly reduced transplant potential, which was rescued by IFN-α treatment. Our results implicate the inflammatory IFN-α/Jak-Stat pathway in the developmental maturation of embryonic HSCs, whose manipulation may lead to increased potency of reprogrammed HSCs for transplantation.

  18. Inborn errors of anti-viral interferon immunity in humans

    PubMed Central

    Sancho-Shimizu, Vanessa; de Diego, Rebeca Perez; Jouanguy, Emmanuelle; Zhang, Shen-Ying; Casanova, Jean-Laurent

    2011-01-01

    The three types of interferon (IFNs) are essential for immunity against at least some viruses in the mouse model of experimental infections, type I IFNs displaying the broadest and strongest anti-viral activity. Consistently, human genetic studies have shown that type II IFN is largely redundant for immunity against viruses in the course of natural infections. The precise contributions of human type I and III IFNs remain undefined. However, various inborn errors of anti-viral IFN immunity have been described, which can result in either broad or narrow immunological and viral phenotypes. The broad disorders impair the response to (STAT1, TYK2) or the production of at least type I and type III IFNs following multiple stimuli (NEMO), resulting in multiple viral infections at various sites, including herpes simplex encephalitis (HSE). The narrow disorders impair exclusively (TLR3) or mostly (UNC-93B, TRIF, TRAF3) the TLR3-dependent induction of type I and III IFNs, leading to HSE in apparently otherwise healthy individuals. These recent discoveries highlight the importance of human type I and III IFNs in protective immunity against viruses, including the TLR3-IFN pathway in protection against HSE. PMID:22347990