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Sample records for peg interferon alpha

  1. Pharmacokinetic properties of a 40 kDa branched polyethylene glycol-modified form of consensus interferon-alpha (PEG-CIFN) in rhesus monkeys.

    PubMed

    Du, Yu; Tian, Hong; Gao, Xiang-Dong; Yao, Wen-Bing

    2008-11-01

    The pharmacokinetic properties of a branched 40 kDa polyethylene glycol (PEG) conjugate formulation of consensus interferon-alpha (CIFN) was evaluated in rhesus monkeys following subcutaneous administration. Four groups of rhesus monkeys (n=6 per group) received 1250, 300 and 150 microg/kg of PEG-CIFN and 150 microg/kg CIFN, respectively. Serum concentrations of the interferons were measured with an antiviral activity assay at various time points after administration. The PK profiles of the pooled data were described by a noncompartmental method. Peak concentration of PEG-CIFN was observed at 27-31 h, followed by a prolonged decay in comparison with the unmodified CIFN, the PEG-CIFN had a 4-5-fold longer terminal half-life. The apparent clearance (dose(sc)/AUC) decreased from 150 mL/h/kg for CIFN to 19.0-45.5 mL/h/kg for PEG-CIFNs. The AUC was lower for PEG-CIFN than that for CIFN at the 150 microg/kg. PMID:18985796

  2. Severe immune thrombocytopenia after peg-interferon-alpha2a, ribavirin and telaprevir treatment completion: A case report and systematic review of literature

    PubMed Central

    Arena, Rosario; Cecinato, Paolo; Lisotti, Andrea; Buonfiglioli, Federica; Calvanese, Claudio; Grande, Giuseppe; Montagnani, Marco; Azzaroli, Francesco; Mazzella, Giuseppe

    2015-01-01

    Mild to moderate autoimmune thrombocytopenia (AITP) is a common finding in patients receiving interferon-based antiviral treatment, due to bone marrow suppression. Here we report the case of a patient with chronic genotype 1b hepatitis C virus (HCV) infection treated with pegylated-interferon alpha-2a, ribavirin and telaprevir for 24 wk; the patient developed severe AITP three weeks after treatment withdrawal. We performed a systematic literature search in order to review all published cases of AITP related to HCV antiviral treatment. To our knowledge, this is the second case of AITP observed after antiviral treatment withdrawal. In most published cases AITP occurred during treatment; in fact, among 24 cases of AITP related to interferon-based antiviral treatment, only one occurred after discontinuation. Early diagnosis of AITP is a key factor in order to achieve an early interferon discontinuation; in the era of new direct antiviral agents those patients have to be considered for interferon-free treatment regimens. Prompt prescription of immuno-suppressant treatment (i.e., corticosteroids, immunoglobulin infusion and even rituximab for unresponsive cases) leads to favourable prognosis in most of cases. Physicians using interferon-based treatments should be aware that AITP can occur both during and after treatment, specially in the new era of interferon-free antiviral treatment. Finally, in the case of suspected AITP, presence of anti-platelet antibodies should be checked not only during treatment but also after discontinuation. PMID:26140092

  3. [Obtaining and characteristics of domestic preparation interferon alpha-2b with prolonged effect].

    PubMed

    Pokholenko, Ia A; Porubleva, L V; Dubeĭ, I Ia; Rebriev, A V; Sutugina, L P; Gromovoĭ, T Iu; Pokrovskiĭ, V A; Obolenskaia, M Iu; Chernykh, S I

    2008-01-01

    Pegylated interferon alpha-2b (PEG-IFN alpha-2b) is a domestic preparation of a modified recombinant interferon alpha-2b with prolonged effect. The preparation was obtained by N-terminal pegylation of IFN alpha-2b with polyethylene glycol (PEG). This paper presents the method of PEG-IFN alpha-2b synthesis and characteristics of the obtained product. PAAG electrophoresis, Western blot analysis and MALDI-TOF mass-spectrometry confirm that the preparation is an N-terminal pegylated IFN alpha-2b that contains no more than 10% of dipegylated IFN alpha-2b. The comparison of PEG-IFN alpha-2b with its foreign analogue has revealed the similarity of their biological activity and pharmacokinetic parameters. PMID:19351063

  4. Acute pancreatitis associated with pegylated interferon-alpha-2a therapy in chronic hepatitis C

    PubMed Central

    Choi, Jong Wook; Lee, June Sung; Paik, Woo Hyun; Song, Tae Jun; Kim, Jung Wook; Bae, Won Ki; Kim, Kyung-Ah; Kim, Jung Gon

    2016-01-01

    Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma. Combination therapy of pegylated interferon-alpha (PEG-IFN-α) and ribavirin (RBV) is a current standard treatment for chronic HCV infection in Korea, which has considerable adverse effects. Acute pancreatitis is a rare complication of PEG-IFN-α administration. We report a case of a 62-year-old female who experienced acute pancreatitis after 4 weeks of PEG-IFN-α-2a and RBV combination therapy for chronic HCV infection. The main cause of the acute pancreatitis in this case was probably PEG-IFN-α rather than RBV for several reasons. A few cases have been reported in which acute pancreatitis occurred during treatment with PEG-IFN-α-2b. This is the first report of acute pancreatitis associated with PEG-IFN-α-2a in Korea. PMID:27044768

  5. Alpha-interferon in the treatment of subacute sclerosing panencephalitis.

    PubMed

    Fayad, M N; Yamout, B I; Mroueh, S

    1997-11-01

    Subacute sclerosing panencephalitis is an inexorably progressive disease with no effective therapy. Recent trials of intrathecal and intraventricular alpha-interferon yielded controversial results. We tried intrathecal or intraventricular alpha-interferon in four patients with subacute sclerosing panencephalitis. None of them had evidence of improvement. We reviewed the previously published studies on the use of alpha-interferon in subacute sclerosing panencephalitis. Further international collaborative studies are needed to determine the role of alpha-interferon in the treatment of subacute sclerosing panencephalitis. PMID:9430312

  6. Quantification of different human alpha interferon subtypes and pegylated interferon activities by measuring MxA promoter activation.

    PubMed

    François, Catherine; Bernard, Isabelle; Castelain, Sandrine; Charleston, Bryan; Fray, Martin D; Capiod, Jean-Claude; Duverlie, Gilles

    2005-09-01

    Alpha interferons (alpha-IFNs) are potent biologically active proteins synthesized and secreted by somatic cells during viral infection. Quantification of alpha-IFN concentrations in biological samples is used for diagnosis. More recently, recombinant IFNs have been used as antiviral, antiproliferative, and immunomodulatory therapeutic agents, and particularly for the treatment of chronic hepatitis C virus infection. For this purpose, IFN has recently been coupled to polyethylene glycol (PEG) to improve the pharmacokinetic properties. The measure of alpha-IFN in biological samples from treated patients could be useful to ensure compliance to therapy and the true IFN activity in relation to viral decay during follow-up. In particular, it could be used to monitor the PEG-IFN concentration in patients treated for hepatitis C virus infection. The most frequently used test is a bioassay based on the antiviral property of the IFN, but the assay is not highly reproducible. Here, we present a reporter test based on MxA promoter activation of chloramphenicol acetyltransferase expression (Mx-CAT). MxA is an antiviral protein induced and tightly regulated by alpha-IFN. The Mx-CAT assay showed good reproducibility of 15% and was suitable to quantify PEG-IFN and numerous other alpha-IFN subtypes as well, despite a differential MxA promoter activation in relation with the subtype. A good correlation was obtained with the reporter assay and a commercial enzyme-linked immunosorbent assay on samples from treated patients. This test could be useful for monitoring IFN therapy of chronically infected hepatitis C virus-infected patients treated with the standard IFN, PEG-IFN, and probably forthcoming recombinant IFNs. PMID:16127052

  7. 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

  8. PEG-IFN Alpha but Not Ribavirin Alters NK Cell Phenotype and Function in Patients with Chronic Hepatitis C

    PubMed Central

    Markova, Antoaneta A.; Mihm, Ulrike; Schlaphoff, Verena; Lunemann, Sebastian; Filmann, Natalie; Bremer, Birgit; Berg, Thomas; Sarrazin, Christoph; Zeuzem, Stefan; Manns, Michael P.; Cornberg, Markus; Herrmann, Eva; Wedemeyer, Heiner

    2014-01-01

    Background Ribavirin (RBV) remains part of several interferon-free treatment strategies even though its mechanisms of action are still not fully understood. One hypothesis is that RBV increases responsiveness to type I interferons. Pegylated Interferon alpha (PEG-IFNa) has recently been shown to alter natural killer (NK) cell function possibly contributing to control of hepatitis C virus (HCV) infection. However, the effects of ribavirin alone or in combination with IFNa on NK cells are unknown. Methods Extensive ex vivo phenotyping and functional analysis of NK cells from hepatitis C patients was performed during antiviral therapy. Patients were treated for 6 weeks with RBV monotherapy (n = 11), placebo (n = 13) or PEG-IFNa-2a alone (n = 6) followed by PEG-IFNa/RBV combination therapy. The effects of RBV and PEG-IFNa-2a on NK cells were also studied in vitro after co-culture with K562 or Huh7.5 cells. Results Ribavirin monotherapy had no obvious effects on NK cell phenotype or function, neither ex vivo in patients nor in vitro. In contrast, PEG-IFNa-2a therapy was associated with an increase of CD56bright cells and distinct changes in expression profiles leading to an activated NK cell phenotype, increased functionality and decline of terminally differentiated NK cells. Ribavirin combination therapy reduced some of the IFN effects. An activated NK cell phenotype during therapy was inversely correlated with HCV viral load. Conclusions PEG-IFNa activates NK cells possibly contributing to virological responses independently of RBV. The role of NK cells during future IFN-free combination therapies including RBV remains to be determined. PMID:24751903

  9. 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

  10. Binding of human interferon alpha to cells of different sensitivities: studies with internally radiolabeled interferon retaining full biological activity.

    PubMed Central

    Yonehara, S; Yonehara-Takahashi, M; Ishii, A

    1983-01-01

    The characteristics of interferon binding to various cells with different interferon sensitivity were studied by using [3H]leucine-labeled, pure human interferon alpha from Namalwa cells. Scatchard analysis of the binding data on cells sensitive to interferon alpha (human FL and fibroblasts and bovine MDBK) indicated the presence of two kinds of binding sites with high and low affinities. The binding constants of the high-affinity sites in these cells were similar (4 X 10(10) to 11 X 10(10) M-1). Cells insensitive to human interferon alpha (human HEC-1 and mouse L cells) were shown to have only low-affinity sites, suggesting that high-affinity binding sites are indispensable for interferon sensitivity and represent interferon receptors. However, the number of sites in three human diploid fibroblast strains and one strain trisomic for chromosome 21 were not proportionally correlated to the interferon sensitivity of the cells. The high-affinity binding to human cells was completely inhibited by both nonradioactive human interferons alpha and beta in a similar manner, but binding to bovine MDBK cells, on which human interferon beta is practically inactive, was inhibited effectively only by interferon alpha and not by beta. These results suggest that the receptor for human interferon alpha is common to human interferon beta in human cells, whereas the receptor on bovine cells binds only human interferon alpha. PMID:6300453

  11. [Autoimmunization induced by interferon alpha therapy in chronic hepatitis C].

    PubMed

    Rocca, Pierre; Codes, Liana; Chevallier, Michèle; Trépo, Christian; Zoulim, Fabien

    2004-11-01

    We report the case of a 56 year-old woman with post-transfusion chronic hepatitis C who presented with a severe ALT flare up associated with a rapid progression of liver fibrosis during interferon alpha 2b therapy. Several hypotheses were considered to explain the etiology of this ALT flare: there was no viral super infection by other hepatotropic viruses, no toxic hepatitis, no metabolic disease, and no other specific liver diseases could be identified. HLA typing showed a specific profile A1 B8 DR3 (risk factor of auto-immunization during interferon alpha therapy) with antinuclear antibodies and anti smooth muscle antibodies. This case suggests that auto-immunization induced by interferon alpha should be investigated in case of ALT flare that is not followed by an HCV breakthrough. PMID:15657545

  12. Remission of liver fibrosis by interferon-alpha 2b.

    PubMed

    Moreno, M G; Muriel, P

    1995-08-01

    Fibrosis is a dynamic process associated with the continuous deposition and resorption of connective tissue, mainly collagen. Therapeutic strategies are emerging by which this dynamic process can be modulated. Since interferons are known to inhibit collagen production, the aim of this study was to investigate if the administration of interferon-alpha 2b (IFN-alpha) can restore the normal hepatic content of collagen in rats with established fibrosis. Fibrosis was induced by prolonged bile duct ligation. IFN-alpha (100,000 IU/rat/day; s.c.) was administered to fibrotic rats for 15 days. Bile duct ligation increased liver collagen content 6-fold. In addition, serum and liver markers of hepatic injury increased significantly; liver histology showed an increase in collagen deposition, and the normal architecture was lost, with large zones of necrosis being observed frequently. IFN-alpha administration reversed to normal the values of all the biochemical markers measured and restored the normal architecture of the liver. Our results demonstrated that IFN-alpha is useful in reversing fibrosis and liver damage induced by biliary obstruction in the rat. However, further investigations are required to evaluate the therapeutic relevance of interferons on non-viral fibrosis and cholestasis. PMID:7646558

  13. Alpha-interferon in the treatment of nodular lymphomas.

    PubMed

    Urba, W J; Longo, D L

    1986-12-01

    Patients with nodular lymphoma initially respond to a number of therapies but relapse is common and inexorable with time, and despite further therapy, most patients will ultimately die of their lymphoma. The recent demonstration of their sensitivity to alpha-interferon is promising. The importance of this human antitumor effect is that it is presumably based on mechanisms different from conventional agents. Phase I trials of various doses and schedules of recombinant alpha-interferon have shown that effective serum levels can be obtained by intramuscular (IM), intravenous (IV), or subcutaneous (SC) routes. Virtually all patients experienced some degree of acute toxicity manifested by fever, chills, myalgia, and headache. Tolerance usually developed to acute adverse effects within the first few weeks of therapy, regardless of dose or schedule. Fatigue and anorexia were the most important adverse reactions, occurring during the first two weeks of treatment and generally persisting for the duration of therapy. Occasional adverse effects relating to the central nervous and cardiovascular systems have been reported. Primary laboratory abnormalities observed during treatment include decreases in hematologic parameters and elevations of liver function tests. The clinical efficacy of alpha-interferon, both natural and recombinant, has been demonstrated in both untreated and heavily pretreated patients with nodular lymphoma. The response rate has approached 50% in recent studies; however, less than half were complete responders. Future directions include combination of interferon with cytotoxic agents or other biological response modifiers and use as adjuvant therapy. PMID:3541218

  14. A comparative study of variants of pegylated interferon alpha in treatment of chronic HCV patients.

    PubMed

    El Sabaawy, Dalia; El-Haggar, Sahar; El-Bahrawy, Hoda; Waked, Imam; El-Said, Hala

    2015-06-01

    HCV infection presents a vast burden in the regions of high prevalence such as Egypt, where most HCV isolates are genotype 4b. Combined treatment of three variants of pegylated interferon and ribavirin is still the standard of care in Egypt. However, no conclusive data confirming their efficacy are available. Here, 60 chronic HCV patients were randomized for ribavirin plus Peg Intron (PEG-IFNα-2b), Pegasys (PEG-IFNα-2a) or Reiveron Retard (PEG-IFNα-2a). Serum interferon and antibody (Ab) levels were measured, and responses and costs were compared. Serum interferon levels were higher in Pegasys group (1625.1 ng/mL) followed by Reiveron Retard (1076.5 ng/mL), and Peg Intron group (857.72 ng/mL). Moreover, Ab levels were the lowest in Reiveron Retard group (318.4 ng/mL), followed by Peg Intron (439.93 ng/mL), and Pegasys cases (610.83 ng/mL). The best 24-week response rates were detected in the Pegasys group (73.3%), followed by Peg Intron (66.67%), and Reiveron Retard (40%). Treatment with both Pegasys and Peg Intron were most cost-effective. Furthermore, Pegasys was superior in both 6-month response and serum interferon, despite having higher Ab levels (more antigenicity). Our data have notable clinical implications and suggest that Pegasys may be a superior choice of interferon therapy for chronic HCV under low socioeconomic conditions. PMID:25904442

  15. The early HCV RNA dynamics in patients with acute hepatitis C treated with pegylated interferon-alpha2b.

    PubMed

    De Rosa, Francesco G; Bargiacchi, Olivia; Audagnotto, Sabrina; Garazzino, Silvia; Cariti, Giuseppe; Veronese, Lorenzo; Raiteri, Riccardo; Calleri, Guido; Di Perri, Giovanni

    2006-01-01

    Interferon and pegylated interferon (peg-IFN) are highly effective in patients with acute hepatitis caused by hepatitis C virus (acute hepatitis C, AHC), but the optimal timing of treatment is still under debate. In this open-labelled, uncontrolled trial, 19 patients with AHC, including 12 intravenous drug users (IVDUs), were treated early in the course of the infection with peg-IFN-alpha2b for 12 weeks. Diagnosis was made according to standardized criteria. The HCV RNA decay was analysed during the first 4 weeks of treatment by quantitative branched-DNA and by qualitative RT-PCR. Of the patients, 11 (58%) had genotype 1. Sustained virological response (SVR) was achieved in 14 out of 19 patients (74%) and the mean time to achieve a negative RT-PCR for HCV RNA was 2.5 weeks. The SVR was associated by univariate analysis with peg-IFN dosage < or = 1.33 microg/kg/week (P = 0.026) and HCV RNA level at onset of therapy (P = 0.017). Using a logistic regression model, only peg-IFN dosage > or = 1.33 microg/kg/weekly was significantly associated with SVR (P = 0.0379, OR: 14.7; 95% CI: 1.16-185.2). The SVR was 100% and 83.3%, respectively, in genotype 1 and non-1 infected patients treated with a dosage equal to or higher than 1.33 microg/kg, compared with 40% and 50%, respectively, in those who received a lower dosage. Efforts should be made to propose a 12-week treatment with peg-IFN-alpha2b for AHC, and to maximize peg-IFN dosage. Early treatment is associated with early disappearance of HCV RNA. PMID:16640097

  16. Comparison of peg-interferon, ribavirin plus telaprevir vs simeprevir by propensity score matching

    PubMed Central

    Fujii, Hideki; Nishimura, Takeshi; Umemura, Atsushi; Nishikawa, Taichiro; Yamaguchi, Kanji; Moriguchi, Michihisa; Sumida, Yoshio; Mitsuyoshi, Hironori; Yokomizo, Chihiro; Tanaka, Saiyu; Ishikawa, Hiroki; Nishioji, Kenichi; Kimura, Hiroyuki; Takami, Shiro; Nagao, Yasuyuki; Takeuchi, Takayuki; Shima, Toshihide; Sawa, Yoshihiko; Minami, Masahito; Yasui, Kohichiroh; Itoh, Yoshito

    2015-01-01

    AIM: To compare efficacy of telaprevir (TVR) and simeprevir (SMV) combined with pegylated interferon (PEG-IFN) and ribavirin (RBV) while treating chronic hepatitis C (CHC). METHODS: In all, 306 CHC patients were included in this study. There were 159 patients in the TVR combination therapy group and 147 patients in the SMV combination therapy group. To evaluate pretreatment factors contributing to sustained virological response at 12 wk (SVR12), univariate and multivariate analyses were performed in TVR and SMV groups. To adjust for patient background between TVR and SMV groups, propensity score matching was performed. Virological response during treatment and SVR12 were evaluated. RESULTS: Overall rates of SVR12 [undetectable serum hepatitis C virus (HCV) RNA levels] were 79.2% and 69.4% in TVR and SMV groups, respectively. Patients in the SMV group were older, had higher serum HCV RNA levels, lower hemoglobin, higher prevalence of unfavorable interleukin-28B (IL28B) genotype (rs8099917), and poorer response to previous PEG-IFN and RBV treatment. Propensity score matching was performed to adjust for backgrounds (n = 104) and demonstrated SVR12 rates of 74.0% and 73.1% in the TVR and SMV groups, respectively. In the TVR group, discontinuation rates were higher because of adverse events; however, breakthrough and nonresponse was more frequent in the in SMV group. Multivariate analysis revealed IL28B genotype (rs8099917) as the only independent predictive factor of SVR12 in both groups. CONCLUSION: SVR12 rates were almost identical following propensity score matching. PMID:26668696

  17. Renal deposition of alpha interferon in systemic lupus erythematosus.

    PubMed Central

    Panem, S; Ordóñez, N; Vilcek, J

    1983-01-01

    Earlier studies from several laboratories showed that interferon-alpha (IFN-alpha) is present in the sera of a large percentage of patients with systemic lupus erythematosus (SLE). We now report the detection of IFN-alpha by indirect immunofluorescence in renal sections of three patients with SLE but not in six control kidneys. The immunofluorescence reaction was mediated by three hyperimmune antisera to IFN-alpha raised in three different species, but not by any preimmune serum. The reaction was specifically blocked by absorption of the anti-IFN-alpha sera with purified IFN-alpha made by recombinant DNA techniques or with IFN-alpha isolated from the serum of an SLE patient, but not by bovine serum albumin or human immunoglobulin G. In contrast, antisera to IFN-beta or IFN-gamma did not mediate immunofluorescence. The pattern of IFN-alpha deposition resembled that seen with anti-human immunoglobulin G, suggesting association with immune complexes. Immune complexes were then preparatively eluted from the homogenate of an SLE kidney by treatment with buffer at pH 2.8. Biologically active IFN was found in this eluate and was demonstrated to be IFN-alpha by specific neutralization with IFN antisera. These results extend the specific association of IFN-alpha with SLE. Images PMID:6413415

  18. 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

  19. Successful Treatment of Provisional Cutaneous Mastocytosis with Interferon Alpha.

    PubMed

    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

  20. Rheumatoid arthritis following PEG-interferon-alfa-2a plus ribavirin treatment for chronic hepatitis C: a case report and review of the literature

    PubMed Central

    2013-01-01

    Background The combination of Pegylated Interferon-alpha (PEG-IFN-α) and ribavirin is the current standard of care for the treatment of HCV infection. Unfortunately, IFN-α may lead to the induction or exacerbation of autoimmune diseases, such as psoriasis, thyroiditis, systemic lupus erythematosus and, rarely, rheumatoid arthritis (RA). Case presentation We report the case of a man affected with chronic hepatitis C (CHC) due to HCV genotype 3a infection, who developed RA after a complete course of PEG-IFN-α and ribavirin. Nine weeks after cessation of antiviral treatment, the patient developed symmetrical polyarthritis, with pain and edema in the wrists, knees, shoulders and metacarpophalangeal joints; magnetic resonance imaging detected initial bone erosions with juxta-articular osteopenia in wrist, knee and hand joints. Anti-cyclic citrullinated peptide (anti-CCP) antibodies were positive. Conclusions Autoimmune diseases, including RA, may occur when treating chronic hepatitis C with PEG-IFN-α and ribavirin; therefore, a close surveillance for the occurrence of autoimmune phenomena should be suggested in the setting of HCV management. PMID:24171974

  1. Mood and cognitive side effects of interferon-alpha therapy.

    PubMed

    Valentine, A D; Meyers, C A; Kling, M A; Richelson, E; Hauser, P

    1998-02-01

    The central nervous system side effects associated with interferon-alpha (IFN-alpha) therapy, including depression and cognitive changes, can compromise otherwise effective immunotherapy. The term "depression" has multiple meanings ranging from a feeling of sadness to a neuropsychiatric disorder with defined diagnostic criteria. A syndrome of mood disturbance with memory impairment, cognitive slowing, and impaired executive function is common with IFN-alpha therapy and is consistent with mild subcortical dementia. Cognitive deficits and mood disorder may occur independently, and in some cases depression is a reactive phenomenon. Risk factors for development of IFN-alpha neurotoxicity include duration of treatment, high-dose therapy, and prior cranial irradiation or neurologic illness. Past or current psychiatric illness also may put the patient at risk. Subtypes of major depression are associated with neuroendocrine and neurochemical alterations that are consistent with the observed activities of IFN-alpha. This may provide insight into the etiology of IFN-alpha neurotoxicity, as well as possible interventions. Assessment of the neuropsychiatric status of patients treated with IFN-alpha should be a standard of care. Possible pharmacologic interventions to decrease the neurotoxicity associated with IFN-alpha therapy include antidepressants, psychostimulants, and opioid antagonists. Preliminary clinical and research experience suggests that it is possible to effectively palliate IFN-alpha toxicity. PMID:9482539

  2. Treatment of carcinoid syndrome with recombinant interferon alpha-2a.

    PubMed

    Di Bartolomeo, M; Bajetta, E; Zilembo, N; de Braud, F; Di Leo, A; Verusio, C; D'Aprile, M; Scanni, A; Barduagni, M; Barduagni A [corrected to Barduagni, M

    1993-01-01

    The prognosis and the quality of life of patients with carcinoid tumors is related either to symptoms from the substances secreted or to progressive tumor growth. Medical treatment with cytotoxic agents is of marginal value for increasing life expectancy and reducing clinical symptoms. Recent studies with interferon have shown interesting results. In the present investigation, 22 patients with carcinoid tumors and syndrome were treated with recombinant interferon alpha-2a (r-IFN alpha-2a) at the dose of 6 x 10(6) IU intramuscularly daily for 8 weeks and three times weekly thereafter. The primary tumor was localized in the foregut (n = 11), midgut (n = 7), hindgut (n = 1), and unknown site (n = 3). Most cases had liver metastasis. Seventeen patients had elevated 5-hydroxyindoloacetic acid (5-HIAA) excretion and 5 had flushing and/or diarrhea as the only clinical manifestation. Six cases presented a complete syndrome (flushing, diarrhea and 5-HIAA excretion). Control of symptoms was obtained in 80% and a 5-HIAA level reduction in 58% of the patients. The interferon treatment was more effective for control of the carcinoid syndrome than for control of tumor growth. The treatment was well tolerated and fever, myalgia, anorexia and fatigue were the most frequent side-effects. PMID:7686766

  3. Intranasal application of alpha interferon reduces morbidity associated with low pathogenic avian influenza infection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Type I interferons, including interferon alpha (IFN-alpha), are expressed rapidly after viral infection, and represent a first line of defense initiated by the innate immune response. Following infection of chickens with avian influenza virus (AIV), transcription of IFN-alpha is quickly up regulate...

  4. Natural human interferon-alpha 2 is O-glycosylated.

    PubMed Central

    Adolf, G R; Kalsner, I; Ahorn, H; Maurer-Fogy, I; Cantell, K

    1991-01-01

    Natural human interferon alpha 2 (IFN-alpha 2) was isolated from a preparation of partially purified human leucocyte IFN by monoclonal-antibody immunoaffinity chromatography. The purified protein had a specific activity of 1.5 x 10(8) i.u./mg; it was estimated to constitute 10-20% of the total antiviral activity of leucocyte IFN. N-Terminal amino-acid-sequence analysis identified the subspecies IFN-alpha 2b and/or IFN-alpha 2c, whereas IFN-alpha 2a was not detectable. The structure of natural IFN-alpha 2 was found to differ from that of its recombinant (Escherichia coli-derived) equivalent. First, reverse-phase h.p.l.c. showed that natural IFN-alpha 2 was significantly more hydrophilic then expected. Secondly, the apparent molecular mass of the natural protein determined by SDS/PAGE was higher than that of recombinant IFN-alpha 2; incubation under mild alkaline conditions known to eliminate O-linked carbohydrates resulted in a reduction of the apparent molecular mass to that of the recombinant protein. On sequence analysis of proteolytic peptides, Thr-106 was found to be modified. These results suggested that Thr-106 of natural IFN-alpha 2 carries O-linked carbohydrates. Reverse-phase h.p.l.c. as well as SDS/PAGE of natural IFN-alpha 2 showed that glycosylation is heterogeneous. For characterization of the carbohydrate moieties, the protein was treated with neuraminidase and/or O-glycanase and analysed by gel electrophoresis; in addition, glycopeptides obtained by proteinase digestion and separated by h.p.l.c. were characterized by sequence analysis and m.s. Further information on the composition of the glycans was obtained by monosaccharide analysis. The results indicate that natural IFN-alpha 2 contains the disaccharide galactosyl-N-acetylgalactosamine (Gal-GalNAc) linked to Thr-106. In part of the molecules, this core carbohydrate carries (alpha-)N-acetylneuraminic acid, whereas a disaccharide, probably N-acetyl-lactosamine, is bound to Gal-GalNAc in another

  5. In situ growth of a C-terminal interferon-alpha conjugate of a phospholipid polymer that outperforms PEGASYS in cancer therapy.

    PubMed

    Hu, Jin; Wang, Guilin; Zhao, Wenguo; Gao, Weiping

    2016-09-10

    Conjugating therapeutic proteins and peptides to poly(ethylene glycol) (PEG) can improve their pharmacokinetics and therapeutic potential. However, PEGylation suffers from non-specific conjugation, low yield and immunogenicity. Herein we report a new and general methodology to synthesize a protein-polymer conjugate with site-specificity, high yield and activity, long circulation half-life and excellent therapeutic efficacy. A phospholipid polymer, poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), was grown solely from the C-terminus of interferon-alpha to form a site-specific (C-terminal) and stoichiometric (1:1) PMPC conjugate of interferon-alpha in high yield. Notably, the PMPC conjugate showed 194- and 158-fold increases in systemic exposure and tumor uptake as compared with interferon-alpha, respectively. The in vitro antiproliferative bioactivity of the PMPC conjugate was 8.7-fold higher than that of PEGylated interferon-alpha (PEGASYS). In a murine cancer model, the PMPC conjugate completely inhibited tumor growth and cured 75% mice, whereas at the same dose, no mice treated with interferon-alpha or PEGASYS survived. We believe that this new approach to synthesize C-terminal protein conjugates of PMPC may be applicable to a large subset of protein and peptide drugs, thereby providing a general platform for the development of next-generation protein therapeutics. PMID:27393654

  6. Modulation of epidermal growth factor receptors by human alpha interferon.

    PubMed Central

    Zoon, K C; Karasaki, Y; zur Nedden, D L; Hu, R Q; Arnheiter, H

    1986-01-01

    Treatment of Madin-Darby bovine kidney (MDBK) cells with human interferon (IFN)-alpha 2 at 37 degrees C results in a dose-dependent inhibition of cell growth and a reduction of the subsequent binding of 125I-labeled epidermal growth factor (EGF) at 4 degrees C. Human IFN-beta and -gamma, which exhibit little antiviral and antiproliferative activities on MDBK cells, have little effect on cell growth or the binding of 125I-labeled EGF to these cells. The binding of EGF is decreased after exposure to IFN-alpha for greater than 8 hr. Scatchard analyses of the EGF binding data indicate that a 20-hr exposure period results in a decrease in the apparent number of cell-surface EGF receptors and a reduction in the affinity of EGF for its receptor. The rate of internalization of EGF by MDBK cells does not appear to be affected by IFN treatment. PMID:3095830

  7. Modulation of epidermal growth factor receptors by human alpha interferon.

    PubMed

    Zoon, K C; Karasaki, Y; zur Nedden, D L; Hu, R Q; Arnheiter, H

    1986-11-01

    Treatment of Madin-Darby bovine kidney (MDBK) cells with human interferon (IFN)-alpha 2 at 37 degrees C results in a dose-dependent inhibition of cell growth and a reduction of the subsequent binding of 125I-labeled epidermal growth factor (EGF) at 4 degrees C. Human IFN-beta and -gamma, which exhibit little antiviral and antiproliferative activities on MDBK cells, have little effect on cell growth or the binding of 125I-labeled EGF to these cells. The binding of EGF is decreased after exposure to IFN-alpha for greater than 8 hr. Scatchard analyses of the EGF binding data indicate that a 20-hr exposure period results in a decrease in the apparent number of cell-surface EGF receptors and a reduction in the affinity of EGF for its receptor. The rate of internalization of EGF by MDBK cells does not appear to be affected by IFN treatment. PMID:3095830

  8. Type III interferon (IFN-lambda) antagonizes the antiviral activity of interferon-alpha in vitro.

    PubMed

    Bordi, L; Lalle, E; Lapa, D; Caglioti, C; Quartu, S; Capobianchi, M R; Castilletti, C

    2013-01-01

    Type III interferons (IFN-lambda) are the most recently discovered members of IFN family. Synergism between different IFN types is well established, but for type I and type III IFNs no conclusive evidence has been reported so far. Possible synergism/antagonism between IFN-alpha and IFN-lambda in the inhibition of virus replication (EMCV, WNV lineage 1 and 2, CHIKV and HSV-1), and in the activation of intracellular pathways of IFN response (MxA and 2'-5' OAS) was evaluated in different cell lines (Vero E6, A549 and Wish cells). The antiviral potency of IFN-lambda1 and -l2 was lower than that of IFN-alpha. When IFN-alpha and -lambda were used together, the Combination Index (CI) for virus inhibition was greater than 1 virtually for all virus/host cell systems, indicating antagonistic effect. Antagonism between IFN-alpha and -l was also observed for the induction of mRNA for both MxA and 2'-5'OAS. Elucidating the interplay between IFN-alpha and -lambda may help to better understand innate defence mechanisms against viral infections, including the molecular mechanisms underlying the influence of IL-28B polymorphisms in the response to HCV and other viral infections. PMID:24382181

  9. Polymorphism in the interferon-alpha gene family.

    PubMed Central

    Golovleva, I.; Kandefer-Szerszen, M.; Beckman, L.; Lundgren, E.

    1996-01-01

    A pronounced genetic polymorphism of the interferon type I gene family has been assumed on the basis of RFLP analysis of the genomic region as well as the large number of sequences published compared to the number of loci. However, IFNA2 is the only locus that has been carefully analyzed concerning gene frequency, and only naturally occurring rare alleles have been found. We have extended the studies on a variation of expressed sequences by studying the IFNA1, IFNA2, IFNA10, IFNA13, IFNA14, and IFNA17 genes. Genomic white-blood-cell DNA from a population sample of blood donors and from a family material were screened by single-nucleotide primer extension (allele-specific primer extension) of PCR fragments. Because of sequence similarities, in some cases "nested" PCR was used, and, when applicable, restriction analysis or control sequencing was performed. All individuals carried the interferon-alpha 1 and interferon-alpha 13 variants but not the LeIF D variant. At the IFNA2 and IFNA14 loci only one sequence variant was found, while in the IFNA10 and IFNA17 groups two alleles were detected in each group. The IFNA10 and IFNA17 alleles segregated in families and showed a close fit to the Hardy-Weinberg equilibrium. There was a significant linkage disequilibrium between IFNA10 and IFNA17 alleles. The fact that the extent of genetic polymorphism was lower than expected suggests that a majority of the previously described gene sequences represent nonpolymorphic rare mutants that may have arisen in tumor cell lines. Images Figure 1 Figure 2 Figure 3 PMID:8751858

  10. 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.

  11. 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...

  12. Palmitoyl derivatives of interferon alpha: potential for cutaneous delivery.

    PubMed

    Foldvari, M; Attah-Poku, S; Hu, J; Li, Q; Hughes, H; Babiuk, L A; Kruger, S

    1998-10-01

    Palmitoyl derivatives of interferon alpha2b (p-IFNalpha) were prepared by covalent attachment of the fatty acid to lysine residues in the protein through a reaction with N-hydroxysuccinimide palmitate ester. The p-IFNalpha was characterized by capillary electrophoresis (CE), mass spectrometry (MS), SDS-PAGE, and antiviral assay. Flow-through diffusion cells and human breast skins were used to measure cutaneous and percutaneous absorption. Formation of p-IFNalpha derivatives was demonstrated by CE to be dependent on reaction time and reagent: protein ratio. Electrospray MS of the crude p-IFNalpha mixture indicated three populations of IFNalpha derivatives with 10, 11, and 12 palmitoyl substitutions. The addition of palmitoyl residues to IFNalpha under the conditions described reduced the antiviral specific activity by 50%. However, the cutaneous absorption of p-IFNalpha was about 5-6 times greater than the parent protein. The amount of p-IFNalpha and IFN alpha in whole skin after 24 h of treatment was 2.106 +/- 1.216 microg/cm2 and 0.407 +/- 0.108 microg/cm2, respectively. Approximately two times higher flux was detected for p-IFNalpha compared to the nonfatty acylated IFNalpha. The total amount of drug diffused in 24 h was also approximately two times higher for the p-IFNalpha. The results indicate a potential for using fatty acylated derivatives of IFN alpha for dermal and transdermal delivery. PMID:9758677

  13. Development of myasthenia gravis after interferon alpha therapy.

    PubMed

    Gurtubay, I G; Morales, G; Aréchaga, O; Gállego, J

    1999-03-01

    Interferon (IFN) alpha is now used in the treatment of some malignant diseases and chronic viral hepatitis. There have been several reports of development of autoantibodies and autoimmune diseases or the deterioration of preexisting disorders in patients under treatment. We enclose a case of myasthenia gravis (MG) which developed after six weeks of treatment as fluctuating bilateral ptosis, intermittent diplopia, and mild weakness of limb and neck muscles. A test dose of edrophonium chloride was administered, resulting in improved muscle strength. Elevated anti acetylcholine receptor (AChR) antibody titer was found. Single fiber electromyography showed an increased jitter from extensor digitorum communis, frequently accompanied by transmission blocking. Repetitive electric 3 Hz stimulation of the abductor pollicis brevis muscle, revealed an abnormal decrement of 28% in compound motor action potential. Myasthenia gravis was diagnosed and the patient was given pyridostigmine, immunoglobulines and prednisone with benefit. Six months latter he developed an acute myasthenic crisis with severe respiratory failure and high anti AChR antibody titer. IFN-alpha can induce MG or simply manifests a preexisting subclinical disease, but otherwise its therapeutic efficacy in MG has been shown in experimental and clinical studies. Autoimmune mechanisms, as the release of different cytokines as IFN, by immunocompetent cells, may be involved in the pathogenesis of both MG and chronic active hepatitis. Autoantibody production against postsynaptic membrane structures by IFN-alpha could be the underlying pathophysiology. PMID:10207675

  14. Interferon-alpha-induced destructive thyroiditis followed by Graves' disease in a patient with chronic hepatitis C: a case report.

    PubMed

    Kim, Bu Kyung; Choi, Young Sik; Park, Yo Han; Lee, Sang Uk

    2011-12-01

    Interferon-induced thyroiditis (IIT) is a major clinical problem for patients receiving interferon-alpha (IFN-α) therapy. But, destructive thyroiditis followed by Graves' disease associated with IFN-α therapy is very rarely reported. Herein, we report a rare case of pegylated IFN-α (pegIFN-α) induced destructive thyroiditis followed by Graves' disease in a patient with HCV infection. A 31-yr-old woman suffered from chronic active hepatitis C and was treated with pegIFN-α and ribavirin for 12 months. Results of a thyroid function test and autoantibody levels were normal before IFN-α therapy was initiated. Destructive thyrotoxicosis appeared seven months after the initiation of IFN-α therapy, followed by Graves' thyrotoxicosis two months after the cessation of therapy. The diagnoses of destructive thyroiditis and Graves' disease were confirmed by the presence of TSH receptor antibodies in addition to Tc-99m scintigraphy findings. The patient's antithyroglobulin antibody titer increased gradually during IFN-α therapy and remained weakly positive after IFN-α therapy was discontinued. PMID:22148004

  15. A case of arthropathy and hypothyroidism during recombinant alpha-interferon therapy.

    PubMed

    Maccari, S; Bassi, C; Giovannini, A G; Plancher, A C

    1991-12-01

    Late side effects of alpha-interferon therapy include some autoimmune diseases, such as thyroiditis. We present the case of a patient with severe chronic active hepatitis and hepatitis-C-virus positivity, who during alpha-interferon therapy developed an autoimmune thyroiditis and at the same time arthropathy with some characteristics of rheumatoid arthritis (several articular stations simultaneously affected, involvement of the hand joints and morning stiffness). PMID:1666349

  16. Relationship between the hepatitis C viral load and the serum interferon concentration during the first week of peginterferon-alpha-2b-ribavirin combination therapy.

    PubMed

    François, Catherine; Descamps, Véronique; Brochot, Etienne; Bernard, Isabelle; Canva, Valérie; Mathurin, Philippe; Castelain, Sandrine; Duverlie, Gilles

    2010-10-01

    In chronic hepatitis C virus (HCV) infections, the current standard of care (combination therapy with pegylated alpha interferon (PEG-IFNalpha) and ribavirin) is only effective in around 50% of cases. The aim of the present study was to analyze the relationship between the HCV load and the PEG-IFN concentration during the first week of treatment. Fifteen treatment-naive patients with chronic hepatitis C infection (genotypes 1, 2, 3, and 4) underwent PEG-IFNα-2b/ribavirin combination therapy. Blood samples were collected before the first injection (T(0)) and then at different time points until the next injection a week later. The PEG-IFN concentration and the HCV load were assayed. The serum interferon concentration peaked 2 days after the first injection (mean value for the study population; T(max) = 40.9 hr; C(max) = 490 pg/ml) and a trough in viral load was seen at day 3. The PEG-IFNalpha-2b concentration decreased from day 2 to day 7, enabling a viral rebound in all patients. The change in viral load between day 0 and day 3 differed significantly according to whether the patients were responders at week 12 (Deltalog d(0)/d(3) = 2.729 +/- 1.419 log(10) IU/ml) or not (Deltalog d(0)/d(3) = 1.102 +/- 0.472 log(10) IU/ml). Our results emphasize the potential clinical importance of achieving viral decay immediately after initiation of interferon-ribavirin combination therapy. J. Med. Virol. 82:1640-1646, 2010. 2010 Wiley-Liss, Inc. PMID:20827759

  17. Interferon alpha 2b as maintenance therapy improves outcome in follicular lymphoma.

    PubMed

    Avilés, Agustin; Neri, Natividad; Huerta-Guzmán, Judith; Pérez, Felipe; Sotelo, León

    2004-11-01

    The role of interferon alpha as maintenance therapy in follicular lymphoma (FL) remains unsolved. We started a controlled clinical trial to assess if interferon alpha 2b could improve outcome, measured with event free survival (EFS) and overall survival (OS) in patients with FL in complete remission after chemotherapy based anthracyclines and adjuvant radiotherapy to sites of initial bulky disease. Three hundred and eighty four patients in complete response after 6 cycles of CEOP-Bleo (cyclophosphamide, epirubicin, vincristine, prednisone and bleomycin, at standard doses), and adjuvant radiotherapy when necessary, were randomized to received Interferon alpha 2b, three times a week for 1 year or no treatment (control group). Median follow up was 9.8 years (range 7.0-15 years); actuarial curves showed that EFS was 64% (95% confidence interval (CI) 56-71%) in patients treated with interferon that was statistically significant to patients in the control group: 35% (95% CI: 28-43%) (p<.01). OS was also statistically significant: 81% in patients treated with interferon (95% CI: 74-93%) and 57% (95% CI: 50-63%) in the control group (p<.001). Toxicity was mild, all patients received the planned dose of interferon on time. The use of aggressive chemotherapy and maintenance therapy with interferon alpha 2b in follicular lymphoma improved outcome; more than 60% of patients remain alive free of disease at longer follow-up. PMID:15512813

  18. Probable involvement of p11 with interferon alpha induced depression

    PubMed Central

    Guo, Jiqiang; Zhang, Wen; Zhang, Lili; Ding, Huaxia; Zhang, Jingjing; Song, Chen; Zhang, Yanfei; Xia, Namei; Li, Mingfang; Liang, Yinming; Hu, Xianzhang; Luan, Haojiang; Wang, Hui

    2016-01-01

    Depression is one of the major side effects of interferon alpha (IFN-α) treatment, but the molecular mechanism underlying IFN-α-induced depression remains unclear. Several studies have shown that the serotonin receptors 5-HTR1b and 5-HTR4 play key roles in the anti-depression effects associated with p11 (S100A10). We investigated the effects of IFN-α on the regulation of p11, 5-HTR1b and 5-HTR4 in mice and human neuroblastoma cells (SH-sy5y). We found that intraperitoneal injection with IFN-α in Balb/c mice resulted in an increased immobility in FST and TST, and potently lowered the protein levels of p11, 5-HTR1b and 5-HTR4 in the hippocampus or cingulate gyrus. IFN-α significantly down-regulated the protein levels of p11, 5-HTR1b and 5-HTR4 in SH-sy5y cells, in a time- and dose-dependent manner. Our study revealed that over-expression of p11 could prevent the IFN-α-induced down-regulation of 5-HTR1b and 5-HTR4. The results indicated that IFN-α treatment resulted in p11 down-regulation, which subsequently decreased 5-HTR1b and 5-HTR4 in vitro or in vivo. Our findings suggested that p11 might be a potential regulator on 5-HTR1b and 5-HTR4 as well as a predictor of or a therapeutic target for IFN-α-induced depression. PMID:26821757

  19. The effects of 5-fluorouracil and interferon-alpha on early healing of experimental intestinal anastomoses.

    PubMed Central

    de Waard, J. W.; Wobbes, T.; de Man, B. M.; van der Linden, C. J.; Hendriks, T.

    1996-01-01

    The continuing search for effective adjuvant therapy after resection of intestinal malignancies has prompted a growing interest in both immediate post-operative regional chemotherapy and the combination of 5-fluorouracil (5-FU) and interferon-alpha as drugs of choice. We have compared the effects of both compounds, alone and together, on early healing of intestinal anastomoses. Four groups (n = 26 each) of rats underwent resection and anastomosis of both ileum and colon: a control group and three groups receiving intraperitoneal 5-FU, interferon-alpha or both on the day of surgery and the next 2 days. Animals were killed 3 or 7 days (n = 10 each) after operation in order to measure anastomotic strength and hydroxyproline content. The remaining six animals in each group were used to study anastomotic collagen synthetic capacity at day 3. Three days after operation, ileal anastomotic bursting pressure was lowered by 37% in the 5-FU/interferon-alpha group (P = 0.0104). At day 7, anastomotic breaking strength was reduced significantly in ileum (P = 0.0221) and colon (P = 0.0054) of the 5-FU/interferon-alpha group and in colon of the interferon-alpha group (P = 0.0221). Collagen synthetic capacity was strongly suppressed by 5-FU but not by interferon-alpha. However, no differences in anastomotic hydroxyproline content were observed between groups at both days 3 and 7. Thus, post-operative use of interferon-alpha, in particular in combination with 5-FU, may be detrimental to anastomotic repair in the intestine. PMID:8795572

  20. CD3brightCD56+ T cells associate with pegylated interferon-alpha treatment nonresponse in chronic hepatitis B patients

    PubMed Central

    Guo, Chuang; Shen, Xiaokun; Fu, Binqing; Liu, Yanyan; Chen, Yongyan; Ni, Fang; Ye, Ying; Sun, Rui; Li, Jiabin; Tian, Zhigang; Wei, Haiming

    2016-01-01

    Chronic hepatitis B (CHB) infection is a serious and prevalent health concern worldwide, and the development of effective drugs and strategies to combat this disease is urgently needed. Currently, pegylated interferon-alpha (peg-IFNα) and nucleoside/nucleotide analogues (NA) are the most commonly prescribed treatments. However, sustained response rates in patients remain low, and the reasons are not well understood. Here, we observed that CHB patients preferentially harbored CD3brightCD56+ T cells, a newly identified CD56+ T cell population. Patients with this unique T cell population exhibited relatively poor responses to peg-IFNα treatment. CD3brightCD56+ T cells expressed remarkably high levels of the inhibitory molecule NKG2A as well as low levels of CD8. Even if patients were systematically treated with peg-IFNα, CD3brightCD56+ T cells remained in an inhibitory state throughout treatment and exhibited suppressed antiviral function. Furthermore, peg-IFNα treatment rapidly increased inhibitory TIM-3 expression on CD3brightCD56+ T cells, which negatively correlated with IFNγ production and might have led to their dysfunction. This study identified a novel CD3brightCD56+ T cell population preferentially shown in CHB patients, and indicated that the presence of CD3brightCD56+ T cells in CHB patients may be useful as a new indicator associated with poor therapeutic responses to peg-IFNα treatment. PMID:27174425

  1. CD3(bright)CD56(+) T cells associate with pegylated interferon-alpha treatment nonresponse in chronic hepatitis B patients.

    PubMed

    Guo, Chuang; Shen, Xiaokun; Fu, Binqing; Liu, Yanyan; Chen, Yongyan; Ni, Fang; Ye, Ying; Sun, Rui; Li, Jiabin; Tian, Zhigang; Wei, Haiming

    2016-01-01

    Chronic hepatitis B (CHB) infection is a serious and prevalent health concern worldwide, and the development of effective drugs and strategies to combat this disease is urgently needed. Currently, pegylated interferon-alpha (peg-IFNα) and nucleoside/nucleotide analogues (NA) are the most commonly prescribed treatments. However, sustained response rates in patients remain low, and the reasons are not well understood. Here, we observed that CHB patients preferentially harbored CD3(bright)CD56(+) T cells, a newly identified CD56(+) T cell population. Patients with this unique T cell population exhibited relatively poor responses to peg-IFNα treatment. CD3(bright)CD56(+) T cells expressed remarkably high levels of the inhibitory molecule NKG2A as well as low levels of CD8. Even if patients were systematically treated with peg-IFNα, CD3(bright)CD56(+) T cells remained in an inhibitory state throughout treatment and exhibited suppressed antiviral function. Furthermore, peg-IFNα treatment rapidly increased inhibitory TIM-3 expression on CD3(bright)CD56(+) T cells, which negatively correlated with IFNγ production and might have led to their dysfunction. This study identified a novel CD3(bright)CD56(+) T cell population preferentially shown in CHB patients, and indicated that the presence of CD3(bright)CD56(+) T cells in CHB patients may be useful as a new indicator associated with poor therapeutic responses to peg-IFNα treatment. PMID:27174425

  2. Predictors of psychopathological outcome during peg-interferon and ribavirin therapy in patients with chronic HCV-correlated hepatitis.

    PubMed

    Dell'Osso, Bernardo; Prati, Gianmaria; Palazzo, M Carlotta; Rumi, Maria Grazia; Cavallaro, Flaminia; Aghemo, Alessio; Colombo, Massimo; Altamura, A Carlo

    2013-01-01

    Peg-interferon (Peg-IFN) and ribavirin (RBV) therapy is reported to induce psychiatric symptoms and syndromes in 20% of patients treated for Hepatitis C Virus (HCV) infection. Present study was aimed to quantify the phenomenon and assess the influence of psychiatric counseling over antiviral completion rate and the use of psychometric tools, in terms of prediction of psychopathological outcome. Ninety-six HCV patients were assessed, before antiviral treatment, by means of the Sheehan Disability Scale (SDS), Mood Disorder Questionnaire (MDQ), Symptom Checklist-90, and Internal State Scale (ISS). Sociodemographic and clinical variables and completion rate were collected. Binary logistic regression was performed to evaluate whether scores were predictive of psychiatric visit, development of psychiatric disorders, and need for treatment. Ninety-five patients (99%) completed antiviral treatment; 27 subjects (29%) needed psychiatric visit: among them, mood disorder was diagnosed in 15 (16%) and were pharmacologically treated. Baseline SDS and MDQ higher scores were found to be predictive of psychiatric visit [odds ratio (OR)=1.258, P<0.001 and OR=1.425, P=0.05, respectively]. Furthermore, higher MDQ score (P=0.017) and ISS hostility scores (OR=1.048, P=0.014) at baseline predicted the subsequent development of mood episodes, while ISS activation correlated negatively (OR=0.948, P=0.009). Finally, the need for treatment was predicted by higher scores at the MDQ and ISS activation items (OR=2.467, P=0.030; OR=0.970, P=0.038). Present findings suggest that psychiatric counseling may be needed in almost 30% of HCV patients on antiviral treatment, with positive influence over the completion rate. Baseline higher scores at psychometric questionnaires-MDQ-in particular, predictors of psychopathological outcome during Peg-IFN and RBV therapy in patients with chronic HCV-correlated hepatitis reflecting individual functioning before starting antiviral therapy and positive history

  3. 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.

  4. Hyperinsulinaemia reduces the 24-h virological response to PEG-interferon therapy in patients with chronic hepatitis C and insulin resistance.

    PubMed

    Bortoletto, G; Scribano, L; Realdon, S; Marcolongo, M; Mirandola, S; Franceschini, L; Bonisegna, S; Noventa, F; Plebani, M; Martines, D; Alberti, A

    2010-07-01

    Insulin resistance (IR) reduces response to pegylated-interferon (PEG-IFN)/ribavirin in chronic hepatitis C (CHC), but the mechanisms are still undefined. We examined the relationship between baseline insulin levels, the main component affecting homeostasis model of assessment - insulin resistance (HOMA-IR) for assessment of IR in non-diabetic patients, and the 'acute' virological response to PEG-IFN measured 24 h after the first injection and taken as correlate of intracellular interferon signalling. In 62 patients treated with PEG-IFN/Ribavirin, serum insulin and HOMA-IR were assessed at baseline, while hepatitis C virus (HCV)-RNA was measured at baseline and 24 h, 1, 2, 4 and 12 weeks after treatment initiation. Sustained virological response was examined 24 weeks after therapy discontinuation. Mean baseline insulin was 11.52 +/- 8.51 U/L and mean HOMA-IR was 2.65 +/- 2.01 both being significantly higher with advanced liver fibrosis. Hepatitis C virus-RNA decay observed 24 h after the first injection of PEG-IFN was significantly lower (0.7 +/- 0.8 log) in patients with HOMA > or =3 compared with those with HOMA <3 (1.7 +/- 0.8, P = 0.001). A highly significant (r = -0.42) inverse correlation was observed between baseline insulin levels and the 24-h HCV-RNA decay. The difference in early viral kinetics between patients with HOMA > or =3 or <3 resulted in a significant difference in the percentage of patients achieving rapid (week 4) and sustained virological response. Multivariate analysis, inclusive of patient age, HCV genotype and fibrosis stage, identified baseline insulin levels as the main independent variable affecting the 24-h response to PEG-IFN. Hyperinsulinaemia reduces the cellular response to Pegylated-interferon in CHC with IR. Strategies to reduce insulin levels before initiation of treatment should be pursued to improve efficacy of anti-viral treatment. PMID:19878535

  5. Aplastic anemia and severe pancytopenia during treatment with peg-interferon, ribavirin and telaprevir for chronic hepatitis C

    PubMed Central

    Lens, Sabela; Calleja, Jose L; Campillo, Ana; Carrión, Jose A; Broquetas, Teresa; Perello, Christie; de la Revilla, Juan; Mariño, Zoe; Londoño, María-Carlota; Sánchez-Tapias, Jose M; Urbano-Ispizua, Álvaro; Forns, Xavier

    2015-01-01

    Telaprevir and Boceprevir are the first direct acting antivirals approved for chronic hepatitis C in combination with peg-interferon alfa and ribavirin. Pancytopenia due to myelotoxicity caused by these drugs may occur, but severe hematological abnormalities or aplastic anemia (AA) have not been described. We collected all cases of severe pancytopenia observed during triple therapy with telaprevir in four Spanish centers since approval of the drug in 2011. Among 142 cirrhotic patients receiving treatment, 7 cases of severe pancytopenia (5%) were identified and three were consistent with the diagnosis of AA. Mean age was 59 years, five patients had compensated cirrhosis and two patients had severe hepatitis C recurrence after liver transplantation. Severe pancytopenia was diagnosed a median of 10 wk after the initiation of therapy. Three patients had pre-treatment hematological abnormalities related to splenomegaly. In six patients, antiviral treatment was interrupted at the onset of hematological abnormalities. Two patients died due to septic complications and one patient due to acute alveolar hemorrhage. The remaining patients recovered. Severe pancytopenia and especially AA, are not rare during triple therapy with telaprevir in patients with advanced liver disease. Close monitoring is imperative in this setting to promptly detect serious hematological disorders and to prevent further complications. PMID:25954117

  6. Aplastic anemia and severe pancytopenia during treatment with peg-interferon, ribavirin and telaprevir for chronic hepatitis C.

    PubMed

    Lens, Sabela; Calleja, Jose L; Campillo, Ana; Carrión, Jose A; Broquetas, Teresa; Perello, Christie; de la Revilla, Juan; Mariño, Zoe; Londoño, María-Carlota; Sánchez-Tapias, Jose M; Urbano-Ispizua, Álvaro; Forns, Xavier

    2015-05-01

    Telaprevir and Boceprevir are the first direct acting antivirals approved for chronic hepatitis C in combination with peg-interferon alfa and ribavirin. Pancytopenia due to myelotoxicity caused by these drugs may occur, but severe hematological abnormalities or aplastic anemia (AA) have not been described. We collected all cases of severe pancytopenia observed during triple therapy with telaprevir in four Spanish centers since approval of the drug in 2011. Among 142 cirrhotic patients receiving treatment, 7 cases of severe pancytopenia (5%) were identified and three were consistent with the diagnosis of AA. Mean age was 59 years, five patients had compensated cirrhosis and two patients had severe hepatitis C recurrence after liver transplantation. Severe pancytopenia was diagnosed a median of 10 wk after the initiation of therapy. Three patients had pre-treatment hematological abnormalities related to splenomegaly. In six patients, antiviral treatment was interrupted at the onset of hematological abnormalities. Two patients died due to septic complications and one patient due to acute alveolar hemorrhage. The remaining patients recovered. Severe pancytopenia and especially AA, are not rare during triple therapy with telaprevir in patients with advanced liver disease. Close monitoring is imperative in this setting to promptly detect serious hematological disorders and to prevent further complications. PMID:25954117

  7. Patient education improves adherence to peg-interferon and ribavirin in chronic genotype 2 or 3 hepatitis C virus infection: A prospective, real-life, observational study

    PubMed Central

    Cacoub, Patrice; Ouzan, Denis; Melin, Pascal; Lang, Jean-Philippe; Rotily, Michel; Fontanges, Thierry; Varastet, Marina; Chousterman, Michel; Marcellin, Patrick

    2008-01-01

    AIM: To evaluate the impact of therapeutic education on adherence to antiviral treatment and sustained virological response (SVR) in a real-life setting in genotype 2/3 hepatitis C, as there are few adherence data in genotype 2/3 infection, even from randomized trials. METHODS: This prospective survey included genotype 2/3 patients who received peg-interferon alfa-2b and ribavirin. There was no intervention. Adherence was self-reported over the past 4 wk (peg-interferon) or 7 d (ribavirin). Adherence to bitherapy was defined as adherence to the two drugs for ≥ 20 wk. SVR was defined as undetectable RNA ≥ 12wk after the end of treatment. RESULTS: 370/674 patients received education during the first 3 mo of treatment. After 6 mo, adherence to bitherapy was higher in educated patients (61% vs 47%, P = 0.01). Adherence to peg-interferon was 78% vs 69% (P = 0.06). Adherence to ribavirin was 70% vs 56% (P = 0.006). The SVR (77% vs 70%, P = 0.05) and relapse (10% vs 16%, P = 0.09) rates tended to be improved. After adjustment for baseline differences, education improved adherence [Odds ratio (OR) 1.58, P = 0.04] but not the SVR (OR 1.54, P = 0.06). CONCLUSION: In genotype 2/3 patients, therapeutic education helped maintain real-life adherence to bitherapy. PMID:18985810

  8. Coinhibition of viral interferon induction by Benzo(. alpha. )pyrene in association with occupation-related particles

    SciTech Connect

    Hahon, N. West Virginia Univ., Morgantown ); Booth, J.A. ); Flowers, L. )

    1990-06-01

    Benzo({alpha})pyrene (B(a)P) in combination with coal, asbestos, silicate, or metal particles was studied for its inhibitory effects on interferon-{alpha}/{beta} induction by influenza virus in rhesus monkey kidney (LLC-MK{sub 2}) cell monolayers. B(a)P per se had no adverse effect on the induction process. However, when cell cultures were pretreated with B(a)P that was bioactivated by rat liver S9 homogenate, from 52 to 65% inhibition of interferon induction occurred. Significantly greater depression (coinhibition) of viral interferon induction (>83%) resulted when bioactivated B(a)P was incorporated with coal particles representative of coal rank (anthracite, bituminous, lignite, peat). Coinhibition affected by bioactivated B(a)P was coal rank-independent but any interferon inhibitory activity affected by coal particles per se was coal rank-independent. When metals (aluminum, aluminum oxide, ferric oxide, nickel, or chromium) or asbestos fibers were individually mixed with bioactivated B(a)P, coinhibition of cellular interferon synthesis also resulted which was significantly greater than that manifested by bioactivated B(a)P or particles per se. Coinhibition of interferon induction by silicates and the bioactivated hydrocarbon was not in evidence although some silicates alone partially inhibited the induction process. Viral interferon induction was inhibited in a dose-response manner by B(a)P ({+-}S9) in combination with selected particles.

  9. A multiphase model of the dynamics of HBV infection in HBeAg-negative patients during pegylated interferon-alpha2a, lamivudine and combination therapy.

    PubMed

    Colombatto, Piero; Civitano, Luigi; Bizzarri, Ranieri; Oliveri, Filippo; Choudhury, Somesh; Gieschke, Ronald; Bonino, Ferruccio; Brunetto, Maurizia R

    2006-01-01

    Using a multiphase bio-mathematical model, we studied the dynamics of hepatitis B virus (HBV) infection in 72 HBeAg-negative patients who received 48 weeks of either lamivudine (3TC; 25 patients); pegylated interferon-alpha2a (peg-IFN-alpha2a) 180 mg weekly plus 3TC (23 patients), or peg-IFN-alpha2a 180 mg weekly plus placebo (24 patients). During the first month of therapy most of the 3TC -/+ peg-IFN-alpha2a treated patients showed a multiphase decay of viral load: during the first two phases, where we hypothesized a direct inhibition of virus production, the mean viral production per infected cell was reduced by 2.22 log10 and 2.36 log10, respectively. At variance, peg-IFN-alpha2a treated patients had a biphasic profile: the first phase HBV DNA decline was slower than that observed in 3TC patients (mean HBV DNA t(1/2) = 1.6 +/- 1.1 days and 9.5 +/- 3.0 h, respectively) and the direct antiviral effect reduced virus production by 1.14 log10. From day 14 onwards (third or second phase according to multi- or biphasic patterns), HBV DNA declined mainly because of the infected hepatocyte clearance that slowed down in approximately 50% of the patients from day 35, possibly because of a negative feedback on the immune system activity. Computing the number of infected cells at the end of therapy we found that peg-IFN-alpha2a and 3TC monotherapy determined a similar reduction of infected hepatocytes (mean: -3.3 log10), whereas there was a greater reduction in combination therapy patients (-5.0 versus -3.3 log10, P = 0.039). In conclusion, peg-IFN-alpha2a, in spite of having direct antiviral activity lower than that of 3TC, achieved a comparable reduction of infected hepatocytes, possibly because of a higher infected cell clearance rate. PMID:16640101

  10. Severe osteoporosis due to systemic mast cell disease: successful treatment with interferon alpha-2B.

    PubMed

    Lehmann, T; Beyeler, C; Lämmle, B; Hunziker, T; Vock, P; Olah, A J; Dahinden, C; Gerber, N J

    1996-09-01

    We describe a 33-year old man suffering from severe vertebral osteoporosis and urticaria pigmentosa due to systemic mast cell disease (SMCD). Because i.v. clodronate therapy could not prevent further vertebral fractures, an additional treatment with interferon alpha-2b was initiated. During 24 months of treatment, our patient had no further pain episodes, no new vertebral fractures were discovered, trabecular bone mineral density (BMD) increased significantly and urticarial symptoms improved. Nevertheless, the extent of skin lesions remained unchanged. On histological examination, a remarkable decrease of mast cells was observed in the bone marrow, but not in the skin. Five months after discontinuation of interferon alpha-2b, trabecular BMD decreased and urticarial symptoms deteriorated. These findings illustrate a beneficial effect of interferon alpha-2b on SMCD-induced osteoporosis as well as urticarial symptoms, and raise the question whether this treatment may have a diverse impact on mast cell population in different tissues. PMID:8810675

  11. Celiac disease manifested during the treatment of chronic hepatitis C by pegylated alpha interferon and ribavirin.

    PubMed

    Gombosova, L; Jarcuska, P; Benova, B; Benicky, M; Lazurova, I

    2011-01-01

    Authors report a case of patient suffering from haemophilia A and hepatitis C virus infection acquired probably after blood transfusions and substitution factors application. He was treated with pegylated interferon alpha and ribavirin, with the development of malabsorption symptoms during the therapy. Celiac disease was established by histological, histochemical and serological examinations. oth, interferon alpha and ribavirin treatment as well as virus of hepatitis C may trigger coeliac disease in genetically predisposed individuals. The immunological mechanism of celiac disease include balance disruption between Th1 and Th2 immunological response with Th1 predominance. Only few similar cases have been published in the professional literature to date. Development of celiac disease during interferon alpha therapy with haemophilia A was not published until now (Fig. 3, Ref. 13). PMID:21692415

  12. [Alpha interferon induced hyperthyroidism: a case report and review of the literature].

    PubMed

    Maiga, I; Valdes-Socin, H; Thiry, A; Delwaide, J; Sidibe, A T; Beckers, A

    2015-01-01

    Treatment with alpha interferon in hepatitis C triggers a thyroid autoimmunity in a variable percentage of cases (2-8%). This complication raises some questions about its screening, the possibility to continue anti-viral therapy and thyroid treatment. Alpha interferon has an immunomodulatory effect on the thyroid, but also an inhibitory effect on thyroid hormone synthesis. This explains the occurrence of cases of thyroid dysfunction, which often remain undetected because of their latency. Factors predicting thyroid dysfunction with interferon use are: female sex, history of thyroid disease and previous autoimmunity. Several clinical aspects are encountered including hypothyroidism (the most frequent depending on the series) and hyperthyroidism related to Graves' disease. For their detection, a cooperation between general practionners, gastroenterologists and endocrinologists is mandatory thyroid function tests are requested before, during and after treatment,with alpha interferon. Therapeutic aspects of thyroid disorders range from simple monitoring to symptomatic treatment, such as thyroxine prescription in the presence of hypothyroidism. Antithyroid drugs radioactive iodine or thyroid surgery are used in cases of severe or persistent Graves' disease induced by alpha interferon. PMID:26376567

  13. Pharmacodynamics of PEG-IFN alpha-2a in HIV/HCV co-infected patients: Implications for treatment outcomes

    PubMed Central

    Dahari, Harel; Affonso de Araujo, Evaldo S.; Haagmans, Bart L.; Layden, Thomas J.; Cotler, Scott J.; Barone, Antonio A.; Neumann, Avidan U.

    2010-01-01

    Background & Aims The pharmacokinetics and pharmacodynamics of pegylated-interferon-α-2a (PEG-IFN) have not been described in HCV/HIV co-infected patients. We sought to estimate the pharmacokinetics and pharmacodynamics of PEG-IFN and determine whether these parameters predict treatment outcome. Methods Twenty-six HCV/human immunodeficiency virus (HIV)-co-infected patients were treated with a 48-week regimen of PEG-IFN (180 µg/week) plus ribavirin (11 mg/kg/day). HCV-RNA and PEG-IFN concentrations were obtained from samples collected until week 12. A modeling framework that includes pharmacokinetic and pharmacodynamic parameters was developed. Results Five patients discontinued treatment. Seven patients achieved a sustained virological response (SVR). PEG-IFN concentrations at day 8 were similar to steady-state levels (p = 0.15) and overall pharmacokinetic parameters were similar in SVRs and non-SVRs. The maximum PEG-IFN effectiveness during the first PEG-IFN dose and the HCV-infected cell loss rate (δ), was significantly higher in SVRs compared to non-SVRs (median 95% vs 86% [p = 0.013], 0.27 vs 0.11 day−1 [p = 0.006], respectively). Patients infected with HCV genotype-1 had a significantly lower average first-week PEG-IFN effectiveness (median 70% vs. 88% [p = 0.043]), however, 4- to 12-week PEG-IFN effectiveness was not significantly different compared to those with genotype-3 (p = 0.114). Genotype-1 had a significantly lower δ compared to genotype-3 (median 0.14 vs. 0.23 day−1 [p = 0.021]). The PEG-IFN concentration that decreased HCV production by 50% (EC50) was lower in genotype-3 compared to genotype-1 (median 1.3 vs. 3.4 [p = 0.034]). Conclusions Both the HCV infected cell loss rate (δ) and the maximum effectiveness of the first dose of PEG-IFN-α-2a distinguished HIV co-infected patients and were highly predictive of SVR. Further studies are needed to validate these viral kinetic parameters as early on-treatment prognosticators of response in

  14. Creation of transgenic Brassica napus L. plants expressing human alpha 2b interferon gene.

    PubMed

    Sakhno, L O; Kvasko, O Y; Olevinska, Z M; Spivak, M Y; Kuchuk, M V

    2012-01-01

    Spring rapeseed transgenic lines expressing human interferon alpha 2b were created by Agrobacterium-mediated transformation of aseptic plant leaf explants. The maximum antiviral activity of the leaf extracts reached 4500 IU/g fresh weight. It was determined that the antioxidant activity and the activity of an enzyme of plant antioxidant system--superoxide dismutase (SOD)--in the leaf tissues of transgenic plants increased compared to controls. There were no correlations between the interferon and antioxidant activities, as well as between SOD and interferon activities. Using the obtained transgenic rapeseed plants with high interferon and antioxidant activities as a feed additive for animals might have preventive effect on their body, increasing resistance to infections of various origins. PMID:23285745

  15. Cloning and expression of canine interferon-alpha genes in Escherichia coli.

    PubMed

    Taira, Osamu; Watanugi, Itsuki; Hagiwara, Yuko; Takahashi, Masaki; Arai, Setsuo; Sato, Hisaaki; Maehara, Nobutoshi

    2005-10-01

    We cloned five new subtypes of cDNA encoding canine interferon-alpha (CaIFN-alpha) from a canine epithelial cell line. CaIFN-alphas were divided into two groups by amino acid sequences and a molecular phylogenic tree. Two subtypes of them were expressed in Escherichia coli, and IFN proteins were purified. Recombinant CaIFN-alphas were highly species-specific and showed antiviral activity against Vesicular stomatitis New Jersey virus and canine adenovirus-1 , but not against canine herpesvirus-1. PMID:16276065

  16. Expression of biologically active human interferon alpha 2 in aloe vera

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have developed a system for transgenic expression of proteins in Aloe Vera. Using this approach we have generated plants expressing the human gene interferon alpha 2, IFNa2. IFNa2 is a small secreted cytokine that plays a vital role in regulating the body’s immune response to viral infections a...

  17. Blockade of interferon Beta, but not interferon alpha, signaling controls persistent viral infection.

    PubMed

    Ng, Cherie T; Sullivan, Brian M; Teijaro, John R; Lee, Andrew M; Welch, Megan; Rice, Stephanie; Sheehan, Kathleen C F; Schreiber, Robert D; Oldstone, Michael B A

    2015-05-13

    Although type I interferon (IFN-I) is thought to be beneficial against microbial infections, persistent viral infections are characterized by high interferon signatures suggesting that IFN-I signaling may promote disease pathogenesis. During persistent lymphocytic choriomeningitis virus (LCMV) infection, IFNα and IFNβ are highly induced early after infection, and blocking IFN-I receptor (IFNAR) signaling promotes virus clearance. We assessed the specific roles of IFNβ versus IFNα in controlling LCMV infection. While blockade of IFNβ alone does not alter early viral dissemination, it is important in determining lymphoid structure, lymphocyte migration, and anti-viral T cell responses that lead to accelerated virus clearance, approximating what occurs during attenuation of IFNAR signaling. Comparatively, blockade of IFNα was not associated with improved viral control, but with early dissemination of virus. Thus, despite their use of the same receptor, IFNβ and IFNα have unique and distinguishable biologic functions, with IFNβ being mainly responsible for promoting viral persistence. PMID:25974304

  18. A species of human alpha interferon that lacks the ability to boost human natural killer activity.

    PubMed Central

    Ortaldo, J R; Herberman, R B; Harvey, C; Osheroff, P; Pan, Y C; Kelder, B; Pestka, S

    1984-01-01

    Most species of recombinant leukocyte interferons (IFN-alpha A, -alpha B, -alpha C, -alpha D, -alpha F, -alpha I, and -alpha K) were capable of boosting human natural killer (NK) activity after a 2-hr treatment of cells at a concentration of 1-80 units/ml. In contrast, recombinant human IFN-alpha J was found to be incapable of augmenting NK activity after exposure of cells for 2 hr to concentrations as high as 10,000 units/ml. This inability of IFN-alpha J to boost NK activity was not complete because, after exposure of cells to a high concentration of IFN-alpha J (10,000 units/ml) for 18 hr, boosting of cytolysis was observed. IFN-alpha J appeared to interact with receptors for IFN on NK cells since it was found to interfere with the boosting of NK activity by other species of IFN-alpha. In contrast to its deficient ability to augment NK activity, IFN-alpha J has potent antiviral and antiproliferative activities. Such extensive dissociation of these biological activities has not been observed previously with any other natural or recombinant IFN species. Thus, this IFN species may be useful for evaluating the relative importance of various biological activities on the therapeutic effects of IFN, for understanding structure-function relationships, and for determining the biochemical pathways related to the various biological effects of IFN. PMID:6589637

  19. [Interferon-alpha and liver fibrosis in patients with chronic damage due to hepatitis C virus].

    PubMed

    Gonzalez-Huezo, María Sarai; Gallegos-Orozco, Juan Fernando

    2003-01-01

    The present review focuses on the published information published regarding the effects of interferon alpha therapy on liver fibrosis in patients with chronic liver damage secondary to hepatitis C infection. Data reviewed included results of the in vitro effects of interferon on hepatic cell line cultures with regards to indirect markers of fibrosis, activation of hepatic stellate cells and oxidative stress response. In the clinical arena, there is current clear evidence of a favorable histological outcome in patients with sustained viral response to interferon therapy. For this reason, the current review focuses more on the histological outcomes regarding liver fibrosis in patients who have not attained viral response to therapy (non-responders) or who already have biopsy defined cirrhosis. Data in these patients were analyzed according to the results of objective testing of fibrosis through the assessment of liver biopsy and its change during time, specially because the morbidity and mortality of this disease is directly related to the complications of liver cirrhosis and not necessarily to the persistence of the hepatitis C virus. Lastly, it is concluded that the process of liver fibrosis/cirrhosis is a dynamic one and that there is some evidence to support the usefulness of interferon alpha therapy as a means to halt or retard the progression of hepatic fibrosis. The result of current clinical trials in which interferon therapy is being used to modify the progression of fibrosis in non-responders or cirrhotic patients is eagerly awaited. PMID:14702938

  20. Macroscale production and analysis of crystalline interferon alpha-2B in microgravity on STS-52

    NASA Astrophysics Data System (ADS)

    Reichert, Paul; Nagabhushan, Tattanahalli L.; Long, Marianna M.; Bugg, Charles E.; DeLucas, Lawrence J.

    1996-03-01

    The development and production of a zinc-interferon alpha-2b crystalline suspension on STS-52 has accelerated our ability to prepare novel high quality pharmaceutical preparations. Crystalline suspensions of protein therapeutics have applications in drug delivery, formulation, and manufacturing. These applications require crystalline suspensions of relatively small particles (<100 microns) of uniform size and shape. Previously, a crystalline form of interferon alpha-2b was identified from microscale crystallization methods with utility in pharmaceutical applications from microscale crystallization methods. Conditions for macroscale crystallization were established by adapting a microscale vapor diffusion method to a macroscale temperature induction method. A series of earth based pilot experiments established conditions to reproducibly crystallize zinc interferon alpha-2b in high yield and under ``cleanroom'' conditions. These conditions were maintained in microgravity. Greater than 95% of the available protein crystallized in both the ground and flight experiments. The samples were analyzed using a battery of physical, biochemical, and biological characterization methods. The results demonstrated that sample processing, polysulfone bottle confinement, and the conditions used for crystallization did not have a negative effect on protein integrity. Redissolved crystals from the flight and ground experiments showed full biological activity in a cytopathic effect inhibition assay as compared to an interferon control standard. Morphometric analysis comparing the overall length and width of the derived crystals showed a 2.4 fold increase in the length and width of the space grown crystals as compared to earth grown crystals. Subcutaneous injections of space grown crystalline preparation was compared to a non-crystalline interferon preparation in a primate pharmacokinetic study. The crystalline interferon preparation had a measured serum half-life of 12 hours as compared

  1. Efficacy of low-dose intermittent interferon-alpha monotherapy in patients infected with hepatitis C virus genotype 1b who were predicted or failed to respond to pegylated interferon plus ribavirin combination therapy.

    PubMed

    Akuta, Norio; Suzuki, Fumitaka; Kawamura, Yusuke; Yatsuji, Hiromi; Sezaki, Hitomi; Suzuki, Yoshiyuki; Hosaka, Tetsuya; Kobayashi, Masahiro; Kobayashi, Mariko; Arase, Yasuji; Ikeda, Kenji; Kumada, Hiromitsu

    2008-08-01

    The efficacy of interferon (IFN) monotherapy for non-responders to pegylated interferon (PEG-IFN) plus ribavirin (RBV) combination therapy is still unclear. To evaluate the impact of IFN monotherapy on biochemical response, 200 consecutive patients infected with HCV genotype 1b, who received low-dose intermittent IFN-alpha monotherapy, were investigated. A median IFN dose per day of 3 million units was administered during a median period of 74 weeks. As a whole, the ALT normalization rates were 50.5, 65.9, 58.4, and 61.7% at 4, 12, 24, and 48 weeks, respectively. In 40 patients, who had abnormal AFP levels at the start of treatment, 52.5% achieved normalization of AFP within 48 weeks. Multivariate analysis identified indocyanine green retention rate at 15 min as the parameter that influenced significantly and independently ALT normalization. ALT normalization rates of patients who were predicted to be poor responders to PEG-IFN plus RBV combination therapy (but not substitutions of amino acid 70 and/or 91 in the HCV core region, female sex, and lower levels of low-density lipoprotein cholesterol) were similar to others. Furthermore, the ALT normalization rates in non-responders to combination therapy were 29.2, 60.9, 60.0, and 40.0% at 4, 12, 24, and 48 weeks, respectively. The results suggest that low-dose intermittent IFN monotherapy is an efficacious therapeutic regimen for patients unsuitable for PEG-IFN plus RBV, including non-responders, because it can lead to ALT normalization and thus a reduced risk of hepatocarcinogenesis. PMID:18551610

  2. Epstein Barr virus/complement C3d receptor is an interferon alpha receptor.

    PubMed

    Delcayre, A X; Salas, F; Mathur, S; Kovats, K; Lotz, M; Lernhardt, W

    1991-04-01

    Interferon alpha contains a sequence motif similar to the complement receptor type two (CR2/CD21) binding site on complement fragment C3d. Antibodies against a peptide with the CR2 binding sequence on C3d react with a peptide carrying the IFN alpha CR2 binding motif (residues 92-99) and with recombinant IFN alpha. The IFN alpha-derived peptide, as well as recombinant IFN alpha, inhibits C3bi/C3d interaction with CR2 on the Burkitt lymphoma Raji. The direct interaction of IFN alpha and CR2 is inhibited by polyclonal anti-IFN alpha, anti-CR2 and anti-C3d peptide antibodies as well as by C3bi/C3d, EBV coat protein gp350/220 and IFN but not by IFN gamma. [125I]IFN alpha binding to Raji cells is inhibited by polyclonal anti-IFN alpha and anti-CR2 antibodies, by peptides with the CR2 binding motif and partially by C3bi/C3d. Monoclonal anti-CR2 antibody HB5, but not OKB-7, blocks IFN alpha binding to Raji cells. CR2 or CR2-like molecules may therefore be the major IFN alpha receptors on B lymphocytes. PMID:1849076

  3. Immunomodulatory effects of alpha interferon and thymostimulin in patients with neoplasias.

    PubMed Central

    Munno, I; Marinaro, M; Gesario, A; Cannuscio, B; Michel, Y; Paulling, E

    1995-01-01

    In this report, we have evaluated the immunological effects following administration of alpha interferon (IFN-alpha) in combination with thymostimulin (TP-1), as well as of IFN-alpha and TP-1 alone in patients with neoplasias who underwent surgery and were subsequently treated with conventional chemotherapy. Data suggest that the combination of IFN-alpha and TP-1 is the most effective in the up-regulation of some immune parameters such as the CD4(+)-CD8+ cell-dependent antibacterial activity. Since this immune function plays an important role in the host protection against different targets such as invading microorganisms and/or neoplastic cells, the administration of TP-1-IFN-alpha is advisable for patients with neoplasias under chemotherapy. PMID:7583935

  4. Rapid response to 2'-deoxycoformycin in advanced hairy cell leukemia after failure of interferons alpha and gamma.

    PubMed

    Lembersky, B C; Ratain, M J; Westbrook, C; Golomb, H M

    1988-01-01

    A patient with advanced hairy cell leukemia initially had a short-lived minor response to interferon alpha therapy and failed to respond to interferon gamma. Subsequent treatment with 2'-deoxycoformycin (dCF) administered biweekly for 12 wk resulted in a complete hematological remission which has continued for 16 months without additional therapy. PMID:3128105

  5. Increased binding of circulating systemic lupus erythematosus autoantibodies to recombinant interferon alpha 2b.

    PubMed

    Khan, Wahid Ali; Qureshi, Javed Anwer

    2015-12-01

    Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by various types of immunological abnormalities including circulating and tissue-fixed autoantibodies reactive with autoantigens. The mechanism that can explain the production of these antibodies is unclear. Here we address the binding specificity of SLE autoantibodies with recombinant alpha interferon 2b (hrIFN α-2b), commercially available interferon (IFN α-2b), and the gene (cIFN α-2b) encoding this interferon. hrIFN α-2b showed higher binding with naturally occurring SLE autoantibodies as compared to IFN α-2b (p < 0.05) or cIFN α-2b gene (p < 0.001) as assessed by direct binding, inhibition ELISA, and quantitative precipitin titration. The relative affinity of SLE autoantibodies for hrIFN α-2b, IFN α-2b, and cIFN α-2b gene was in the order of 1.13 × 10(-7) , 1.38 × 10(-6) , and 1.22 × 10(-6) , respectively. hrIFN α-2b is shown to have unique epitopes that would explain the possible antigenic role of hrIFN α-2b in the generation of SLE autoantibodies. Anti-hrIFN α-2b antibodies have been shown to represent an alternative immunological probe for the estimation of interferon alpha 2b in the serum of SLE patients. PMID:26547367

  6. Recurrent Classical Type of Kaposi's Sarcoma Treated by Interferon-alpha

    PubMed Central

    Kang, Min Ju

    2008-01-01

    Kaposi's sarcoma (KS) is a lympho-angioproliferative disease, with four variants; one of which is classical KS (CKS). Classical KS is clinically characterized by single or multiple pea-sized bluish-red macules on the distal portions of the lower extremities. A 60-year-old man presented with an asymptomatic, solitary patch on the left sole. He had been successfully treated for the classical type of Kaposi sarcoma on the right sole with interferon-alpha 3 years before. The patient was treated with six million units of interferon-alpha three times per week for 6 months. The lesion showed complete resolution and there has been no report of recurrence for 1 year after treatment. PMID:27303184

  7. [Hyper-IgE syndrome treated with interferon alpha 2 beta. Report of a case].

    PubMed

    Segura Mendez, N H; del Rivero Hernández, L; Mejía Ortega, J; Ubaldo Ortiz Vázquez, J; Varela Delgado, A L; Espínola Reyna, G; Rico, G

    2000-01-01

    The hyper IgE syndrome is characterized by recurrent abscess on the skin, and airways and itching dermatitis. The data acquired in the lab is hypergammaglobulinemy, eosinophil in blood, tissue, sputum, with fagocitos, and quimiotaxis defect. Since 1972 it has been reported 150 cases in the world without no geographic difference and 2:1 relation with the masculine gender. The therapeutic ways are even controversial. The therapy with interferon alpha 2 beta is the alternative treatment so diminish the dermis inflammation as the seric IgE reduction. This case shows a patient with the classic clinic data and seric IgE levels who didn't present response to the habitual therapy, because of this. He was the switch to the interferon alpha 2 beta. Later on the therapy it wasesented clinical changes over the symptomatology with reduction in the over seric IgE. PMID:11558395

  8. Pharmacokinetic and pharmacodynamic comparison of two "pegylated" interferon alpha-2 formulations in healthy male volunteers: a randomized, crossover, double-blind study

    PubMed Central

    2010-01-01

    Background Interferon (IFN) alpha conjugation to polyethylene glycol (PEG) results in a better pharmacokinetic profile and efficacy. The aim of this study was to compare the pharmacokinetic, pharmacodynamic and safety properties of a new, locally developed, 40-kDa PEG-IFN alpha-2b preparation with a reference, commercially available PEG-IFN alpha-2a in healthy male volunteers. Methods A randomized, crossover, double-blind study with a 3-weeks washout period, was done. A single 180 micrograms PEG-IFN alpha-2 dose was administered subcutaneously in both groups. Sixteen apparently healthy male subjects were included. Serum PEG-IFN concentration was measured during 336 hours by an enzyme immunoassay (EIA). Other clinical and laboratory variables were used as pharmacodynamic and safety criteria. Results The pharmacokinetic comparison by EIA yielded a high similitude between the formulations. In spite of a high subject variability, the parameters' mean were very close (in all cases p > 0.05): AUC: 53623 vs. 44311 pg.h/mL; Cmax: 333 vs. 271 pg/mL; Tmax: 54 vs. 55 h; half-life (t1/2): 72.4 vs. 64.8 h; terminal elimination rate (lambda): 0.011 vs. 0.014 h-1; mean residence time (MRT): 135 vs. 123 h for reference and study preparations, respectively. There were no significant differences with respect to the pharmacodynamic variables either: serum neopterin and beta-2 microglobulin levels, stimulation of 2'5' oligoadenylate synthetase expression, and serum IFN antiviral activity. A strong Spearman's rank order correlation (p < 0.01) between the pharmacokinetic and pharmacodynamic concentration-time curves was observed. Both products caused similar leukocyte counts diminution and had similar safety profiles. The most frequent adverse reactions were leukopenia, fever, thrombocytopenia, transaminases increase and asthenia, mostly mild. Conclusions Both formulations are fully comparable from the pharmacokinetic, pharmacodynamic, and safety profiles. Efficacy trials can be carried

  9. Continuous infusion of 5-fluorouracil with alpha 2b interferon for advanced colorectal carcinoma.

    PubMed Central

    Ferguson, J. E.; Hulse, P.; Lorigan, P.; Jayson, G.; Scarffe, J. H.

    1995-01-01

    Thirty patients with symptomatic colorectal carcinoma were commenced on treatment with 5-fluorouracil (2.5 g week-1) administered by continuous intravenous infusion and alpha 2b interferon (3 x 10(6) U s.c. three times a week). Six out of 30 patients (20%) achieved a partial response. Three patients (10%) had stable disease and 21 patients (70%) progressed on treatment. Twenty patients (67%) completed ten or more weeks of treatment. In nine patients, treatment was withdrawn after 2-9 weeks because of disease progression or death. One patient's treatment was interrupted by emergency surgery. The median survival for all patients was 210 days (7 months). The principal side-effects were oral mucositis (12/30 patients), nausea (8/30 patients) and transient diarrhoea (4/30 patients), and initial constitutional symptoms due to alpha 2b interferon. The combination of low-dose continuous infusional 5-fluorouracil and low-dose alpha 2b interferon is well tolerated but has no obvious advantage over alternative infusional regimens using 5-fluorouracil as a single agent. PMID:7599051

  10. Extracellular matrix interacts with interferon {alpha} protein: Retention and display of cytotoxicity

    SciTech Connect

    Yoshida, Kimiko; Kondoh, Atsushi; Narumi, Kenta; Yoshida, Teruhiko; Aoki, Kazunori

    2008-11-14

    We have been investigating the efficacy of an intratumoral interferon (IFN)-{alpha} gene transfer against solid cancers, and found that when the gene is transduced into the subcutaneous tumors, IFN-{alpha} concentration is markedly increased in the injected tumor but not in the serum. To explain this effective confinement of IFN-{alpha} to target tissues, we hypothesized that the extracellular matrix in the tumors interacts with IFN-{alpha}. In this study, a solid-phase-binding assay and immunoprecipitation demonstrated that the IFN-{alpha} binds directly to matrix proteins. Immunohistochemical staining showed a co-localization of IFN-{alpha} with pericellular fibronectin. In addition, matrix-bound IFN-{alpha} protein transduced intracellular signaling and potentiated its cytotoxic activity, suggesting that the retention of IFN-{alpha} protein on extracellular matrix is likely to play a role in its in vivo biological activity. The data suggest a therapeutic advantage of the intratumoral IFN-{alpha} gene transfer over the conventional parenteral therapy both in the safety and efficacy.

  11. Analgesic effect of interferon-alpha via mu opioid receptor in the rat.

    PubMed

    Jiang, C L; Son, L X; Lu, C L; You, Z D; Wang, Y X; Sun, L Y; Cui, R Y; Liu, X Y

    2000-03-01

    Using the tail-flick induced by electro-stimulation as a pain marker, it was found that pain threshold (PT) was significantly increased after injecting interferon-alpha (IFN alpha) into the lateral ventricle of rats. This effect was dosage-dependent and abolished by monoclonal antibody (McAb) to IFN alpha. Naloxone could inhibit the analgesic effect of IFN alpha, suggesting that the analgesic effect of IFN alpha be related to the opioid receptors. Beta-funaltrexamine (beta-FNA), the mu specific receptor antagonist could completely block the analgesic effect of IFN alpha. The selective delta-opioid receptor antagonist, ICI174,864 and the kappa-opioid receptor antagonist, nor-BNI both failed to prevent the analgesic effect of IFN alpha. IFN alpha could significantly inhibit the production of the cAMP stimulated by forskolin in SK-N-SH cells expressing the mu-opioid receptor, not in NG108-15 cells expressing the delta-opioid receptor uniformly. The results obtained provide further evidence for opioid activity of IFN alpha and suggest that this effect is mediated by central opioid receptors of the mu subtype. The evidence is consistent with the hypothesis that multiple actions of cytokines, such as immunoregulatory and neuroregulatory effects, might be mediated by distinct domains of cytokines interacting with different receptors. PMID:10676852

  12. Zinc supplementation prevents the increase of transaminase in chronic hepatitis C patients during combination therapy with pegylated interferon alpha-2b and ribavirin.

    PubMed

    Murakami, Yasuko; Koyabu, Tomoko; Kawashima, Aiko; Kakibuchi, Naoko; Kawakami, Takayo; Takaguchi, Kouichi; Kita, Keiji; Okita, Misako

    2007-06-01

    We investigated the effects of zinc supplementation on clinical observations in chronic hepatitis C patients receiving pegylated interferon (PEG-IFN) alpha-2b plus ribavirin combination therapy. Patients were randomly allocated to receive 150 mg polaprezinc (zinc group, n=11) or no supplement (control group, n=12) daily in addition to PEG-IFN alpha-2b plus ribavirin therapy and 300 mg vitamin E and 600 mg vitamin C supplementation daily for 48 wk. Among the patients who continued treatment, the serum alanine aminotransferase (ALT) level at 12 wk in the zinc group was significantly lower than that in the control group. All patients in the zinc group (9/9) and 67% (8/12) of the control patients at 24 wk, and all patients in the zinc group (7/7) and 60% (6/10) of the control patients at 48 wk showed a decrease in serum ALT levels to within the normal range (7-44 U/L). HCV RNA disappeared in all patients (7/7) in the zinc group and in 8 of 10 control patients at 48 wk. Polaprezinc supplementation decreased plasma thiobarbituric acid reactive substances and prevented the decrease of polyunsaturated fatty acids of erythrocyte membrane phospholipids. No significant differences were observed in the dosage of medicines or other clinical data during the treatment. These observations indicate that polaprezinc supplementation may have induced some antioxidative functions in the liver which resulted in reduced hepatocyte injury during PEG-IFN alpha-2b plus ribavirin therapy. PMID:17874825

  13. Sensitive radioimmunoassay for detection of antibodies to recombinant human interferon-alpha A

    SciTech Connect

    Palleroni, A.V.; Trown, P.W.

    1986-12-01

    A radioimmunoassay (RIA) for the detection of antibodies to recombinant human leukocyte interferon A (rHuIFN-alpha A) in human serum has been developed and validated against the standard antiviral neutralization bioassay (ANB). The assay measures the binding of /sup 125/I-labeled rHuIFN-alpha A to immunoglobulins in serum. Aliquots of patients' sera are incubated with /sup 125/I-rHuIFN-alpha A and the complexes formed between antibodies in the sera and the /sup 125/I-rHuIFN-alpha A are precipitated with goat anti-human IgG serum. The radioactivity in the immune precipitate is a measure of the quantity of antibody (if present) in the serum. The sensitivity of this RIA is 5 ng of IgG/ml of serum.

  14. Congenital Dyserythropoietic Anemia Type 1: Report of One Patient and Analysis of Previously Reported Patients Treated with Interferon Alpha.

    PubMed

    Salihoglu, Ayse; Elverdi, Tugrul; Eskazan, Ahmet Emre; Eyice, Deniz; Bavunoglu, Isil; Ar, Muhlis Cem; Ongoren, Seniz; Guzel, Elif; Baslar, Zafer; Tunckale, Aydin; Tuzuner, Nukhet; Soysal, Teoman

    2016-06-01

    Congenital dyserythropoietic anemias are a rare group of inherited anemias characterized by ineffective erythropoiesis and distinct morphological abnormalities in the erythroblasts. Interferon alpha has been shown to be effective in type 1 congenital dyserythropoietic anemia but the optimal duration of therapy is undefined. We present here a 32-years-old female patient diagnosed with type 1 congenital dyserythropoietic anemia precipitated by pregnancy and treated successfully with a short course of interferon alpha resulting in a durable response. A literature search including PubMed database on previously published articles regarding congenital dyserythropoietic anemia type 1 patients treated with interferon is conducted. PMID:27408411

  15. Experimental study of transplacental passage of alpha interferon by two assay techniques.

    PubMed Central

    Waysbort, A; Giroux, M; Mansat, V; Teixeira, M; Dumas, J C; Puel, J

    1993-01-01

    Two methods of assaying alpha interferon (IFN-alpha) were compared during an experiment aimed at determining whether IFN-alpha crosses the human placenta. Human placentas, collected after delivery following a normal pregnancy to term, were catheterized on both sides: fetal and maternal. The IFN-alpha was introduced in known amounts in the maternal circulation and was assayed in the efferent fetal fluid. The following two detection methods were used: radioimmunoassay by competition with [125I]IFN-alpha and assay with a biological system in which IFN-alpha protected Madin-Darby bovine kidney cells from destruction by vesicular stomatitis virus. The results obtained by the two methods were in perfect agreement for the efferent fetal fluid samples. They showed the absence of placental transfer of IFN-alpha. The biological method was found to be more sensitive than radioimmunoassay for low IFN-alpha titers (< 10 IU/ml) but was less reproducible, probably owing to the use of twofold dilutions. The specificities of the two methods were similar and their practicalities were equivalent; the biological method, however, was less costly. The study illustrates the complementarity of the two methods, which were based on different principles. The agreement obtained between the two methods provides a clear confirmation of the experimental results. PMID:8328774

  16. Interferon-alpha stimulates production of interleukin-10 in activated CD4+ T cells and monocytes.

    PubMed

    Aman, M J; Tretter, T; Eisenbeis, I; Bug, G; Decker, T; Aulitzky, W E; Tilg, H; Huber, C; Peschel, C

    1996-06-01

    In the present study, we investigated the effect of interferon-alpha (IFN-alpha) on the expression of interleukin-10 (IL-10) mRNA and protein synthesis in human monocytes and CD4+ T cells. In mononuclear cells, IFN-alpha induced expression of IL-10 mRNA and further enhanced lipopolysaccharide (LPS)-stimulated IL-10 expression. In purified monocytes, a strong expression of IL-10 mRNA induced by LPS was not further enhanced by IFN-alpha. In highly purified CD4+ T cells, IFN-alpha upregulated IL-10 mRNA upon activation with phytohemagglutinin and phorbol myristate acetate. In purified monocytes, an effect of IFN-alpha on IL-10 protein synthesis was dependent on costimulation with LPS. Maximal stimulation of IL-10 protein by IFN-alpha was seen after prolonged incubation periods of 48 to 96 hours, whereas IFN-gamma reduced IL-10 production in the early incubation period. Similar effects of IFN-alpha were observed in CD4+ T cells activated with CD3 and CD28 monoclonal antibodies. Addition of IFN-alpha caused an increase of IL-10 in culture supernatants of activated T-helper cells of more than 100% after 96 hours of incubation. In contrast, other cytokines, including IFN-gamma and IL-4, had no influence on IL-10 secretion stimulated by CD3 and CD28 in CD4+ T cells. In serum samples of IFN-alpha-treated individuals, we failed to detect an influence of cytokine treatment on IL-10 serum levels, confirming the requirement of additional activating signals for IFN-alpha-mediated effects on IL-10 synthesis. In conclusion, IFN-alpha enhances the late induction of IL-10, which physiologically occurs upon stimulation of monocytes and T cells. Biologically, this effect might enhance the negative-feedback mechanism ascribed to IL-10, which limits inflammatory reactions. PMID:8639843

  17. [Expression of the human interferon alpha F gene in the obligate methylotroph Methylobacillus flagellatum KT and Pseudomonas putida].

    PubMed

    Chistoserdov, A Iu; Eremashvili, M R; Mashko, S V; Lapidus, A L; Skvortsova, M A

    1987-08-01

    The expression of human leucocyte interferon alpha F gene in plasmid pLM-IFN alpha F-273 is controlled by a hybrid tac (trp-lac) promoter. A structural gene for interferon alpha F is a component of the hybrid operon lacZ'-IFN alpha F-TcR, that contains an E. coli trp-operon intercystronic region. Plasmid pLM IFN alpha F-273--directed interferon synthesis allows to obtain about 10(7) IU/l. This plasmid was cloned in broad-host-range vector plasmid pAYC31. The hybrid bi-repliconed plasmid containing interferon gene as well as its single-repliconed deletion derivatives obtained by the in vivo recombination, were introduced into obligate methylotroph Methylobacillus flagellatum KT and Pseudomonas putida PpG6. Methylotrophic strain and Pseudomonas were able to transcribe the interferon gene from E. coli tac promoter, the yield of interferon being 2-4-fold higher as compared with the one in the initial host. PMID:3119998

  18. [Treatment of advanced renal cell carcinoma with interferon alpha and OK-432 (streptococcal preparation)].

    PubMed

    Shinoda, M; Naide, Y

    1992-11-01

    A total of 12 patients with advanced renal cell carcinoma received interferon alpha (3 million units intramuscularly 6 times weekly) and OK-432 (5 KE (Klinische Einheit) intramuscularly twice weekly). Metastatic lesions appeared before operation in six patients and after operation in six patients. Among them 5 patients had received interferon therapy and this combination therapy was started after the judgment of progressive disease for interferon therapy. Eleven pulmonary and 5 bone metastases were evaluable. The median duration of the combination therapy was 89.3 weeks. There were 4 partial responses and no complete responses among the 12 patients, giving a response rate of 33.3%. The median duration of response was 25 months, with a range of 6 to 54 months. Responses were seen predominantly in patients in whom metastases appeared after operation (3 of 4 responders). However, regarding the individual organs, two complete and 2 partial responses were observed among 11 pulmonary metastases and 2 partial responses among 5 bone metastases. The survival period after discovery of the metastasis was 10 to 67 months and the 5-year survival rate was 70.5%. Almost all patients had fever and induration at the injection site. Other side effects included leukopenia, anorexia, and depression. This combination therapy is thought to be effective against bone or other organs metastasis resistant to interferon alone. PMID:1485585

  19. [Treatment of advanced renal cell carcinoma with a combination of interferon alpha and gamma].

    PubMed

    Naito, S; Yasumasu, T; Kumazawa, J; Hiratsuka, Y; Sakamoto, K; Iguchi, A; Masaki, Z; Hasui, Y; Osada, Y; Kurozumi, T

    1995-08-01

    A total of 29 patients with advanced renal cell carcinoma entered a pilot study of combination therapy with interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma). IFN-alpha (HLBI: 3 x 10(6) IU, BALL 1:5 x 10(6) IU, IFN-alpha-2a: 9 x 10(6) IU or IFN-alpha-2b: 6 x 10(6) IU) was given intramuscularly every day and IFN-gamma (IFN-gamma-1a: 3 x 10(6) JRU) was given intravenously by drip infusion 3 times a week (every 2-3 days). The treatment was continued for 3 months as the induction therapy, and then the tumor response was evaluated. Of the 22 evaluable patients, 4 achieved a partial response (PR), 10 showed no change (NC), and in 8 the disease had progressed (PD) during the therapy. Thus, the overall response rate was 18.2% [95% confidence interval (CI) 2.1-34.3%]. A favorable response tended to be obtained in patients with good performance status or small pulmonary metastases, or in those who had no prior therapy with IFN-alpha, who received this treatment immediately subsequent to radical nephrectomy, or who received IFN-gamma as much as possible according to this regimen. Toxicity was evaluated in 28 patients: fever, general fatigue, anorexia, leukocytopenia and impaired liver function were frequently noted, and 3 patients were withdrawn from the study because of such adverse effects. In patients who had a PR or NC, the same dosage of IFN-alpha was continued to be given intramuscularly 2-3 times a week (every 2-4 days) as the maintenance therapy.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7474618

  20. Cytokine Response Associated with Hepatitis C Virus Clearance in HIV Coinfected Patients Initiating Peg Interferon-α Based Therapy

    PubMed Central

    Nguyen, Truong Tam; Niloofar, Reihani; Rubbo, Pierre-Alain; Nils, Kuster; Bollore, Karine; Ducos, Jacques; Pageaux, Georges-Philippe; Reynes, Jacques; Van de Perre, Philippe; Tuaillon, Edouard

    2016-01-01

    Background Treatment of hepatitis C virus (HCV) infection based on peginterferon-α (pegIFNα) and ribavirin induces important changes in cytokine release and T cell activation. Objective Immune response to pegIFNα-ribavirin therapy was explored in patients coinfected by HCV and HIV. Methods Concentrations of 25 cytokines and CD8+ T cell activation were monitored in HCV/HIV coinfected patients classified as sustained virological responders (SVR, n=19) and non-responders (NR, n=11). Results High pretreatment concentrations of IP-10 (CXCL-10) and MCP-1 (CCL-2) were associated with a poor anti-HCV response. PegIFNα-ribavirin therapy increased CD8+ T cell activation and induced significant changes in levels of eleven cytokines related to both Th1 and Th2 responses in SVR (IL-1β, IL-1RA, IL-4, IL-5, IL-6, IL-7, IL-12p40/70, IL-13, IP-10, eotaxin, MCP-1) but of only six cytokines in NR (IL-1β, IL-2, IL-5, IL-12p40/70, IL-13, eotaxin). The highest rise in MIP-1β and MCP-1 levels was observed four weeks after anti-HCV treatment initiation in SVR compared to NR (p=0.002 and p=0.03, respectively), whereas a decrease in IL-8 concentration was associated with treatment failure (p= 0.052). Conclusions Higher and broader cytokine responses to pegIFNα-ribavirin therapy were observed in SVR patients compared to NR. Changes in IL-8, MIP-1β, and MCP-1 serum concentrations may be associated with efficacy of pegIFNα- and ribavirin-based therapies in patients coinfected by HCV and HIV. PMID:26740864

  1. Behavior of a cloned murine interferon alpha/beta receptor expressed in homospecific or heterospecific background.

    PubMed Central

    Uzé, G; Lutfalla, G; Bandu, M T; Proudhon, D; Mogensen, K E

    1992-01-01

    A murine interferon (IFN) alpha/beta receptor was cloned from the IFN-sensitive L1210 cell line on the basis of its homology with the human receptor. A combination of methods that includes the screening of random-primed and oligo(dT)-primed cDNA libraries and polymerase chain reactions with a single-side specificity was used. At the amino acid level, the murine IFN-alpha/beta shows 46% identity with its human counterpart. Both human WISH cells presenting a low sensitivity to mouse IFN and a murine L1210 mutant subline that does not express the receptor have been stably transfected with the murine IFN-alpha/beta receptor. Whereas transfected human cells became sensitive to a limited number of mouse IFN-alpha/beta subtypes, the transfected murine L1210 mutant was found to be fully complemented and became sensitive to all mouse IFN-alpha/beta subtypes tested, including those that were not active on transfected human cells. These results strongly suggest that the receptor described here is implicated in the mediation of the activities of all murine IFN-alpha/beta subtypes. Images PMID:1533935

  2. Effects of interferon-gamma and tumor necrosis factor-alpha on macrophage enzyme levels

    NASA Technical Reports Server (NTRS)

    Pierangeli, Silvia S.; Sonnenfeld, Gerald

    1989-01-01

    Murine peritoneal macrophages were treated with interferon-gamma (IFN-gamma) or tumor necrosis factor-alpha (TNF). Measurements of changes in acid phosphatase and beta-glucuronidase levels were made as an indication of activation by cytokine treatment. IFN-gamma or TNF-gamma treatment resulted in a significant increase in the activities of both enzymes measured in the cell lysates. This increase was observable after 6 h of incubation, but reached its maximum level after 24 h of incubation. The effect of the treatment of the cell with both cytokines together was additive. No synergistic effect of addition of both cytokines on the enzyme levels was observed.

  3. [Clinical study of recombinant interferon alpha-2 (Sch 30500) in advanced gynecological cancers].

    PubMed

    Kasamatsu, T; Ohmi, K; Takeuchi, S; Takamizawa, H; Matsuzawa, M; Kawana, T; Ueda, K; Kubo, H; Tsumuji, Y; Kawashima, Y

    1985-08-01

    Recombinant interferon alpha-2 (Sch 30500) was administered to 29 patients with advanced gynecological cancers (14 patients with cancer of the cervix, 8 with ovarian cancer, 4 with uterine sarcoma, 2 with endometrial cancer and 1 with unclassified cancer). No antitumor effects (CR and PR) were noted in 23 evaluable patients. Side effects observed were fever, tachycardia, diarrhea, chills, general fatigue, anorexia, nausea and vomiting. In some patients, leukopenia, decrease of hemoglobin and elevation of SGOT and SGPT were observed. No production of antibody for Sch 30500 was noted. PMID:3896157

  4. Rapid progression to cardiac tamponade in Erdheim-Chester disease despite treatment with interferon alpha.

    PubMed

    Nakhleh, Afif; Slobodin, Gleb; Elias, Nizar; Bejar, Jacob; Odeh, Majed

    2016-07-01

    Erdheim-Chester disease (ECD) is a rare form of non-Langerhans histiocytosis with heterogeneous clinical manifestations. The most common presentation is bone pains typically involving the long bones. Approximately 75% of the patients develop extraskeletal involvement. Cardiac involvement is seen in up to 45% of the patients, and although, pericardial involvement is the most common cardiac pathology of this rare disease, cardiac tamponade due to ECD has been very rarely reported. We describe a case of a patient found to have ECD with multi-organ involvement and small pericardial effusion, which progressed to cardiac tamponade despite treatment with interferon alpha. PMID:24754271

  5. Late onset autoimmune thrombocytopenia associated with pegylated interferon-alpha-2b plus ribavirin treatment for chronic hepatitis C.

    PubMed

    Elefsiniotis, Ioannis S; Pantazis, Konstantinos D; Fotos, Nikolaos V; Moulakakis, Antonios; Mavrogiannis, Christos

    2006-03-01

    Interferon-induced, immune-mediated, thrombocytopenia is a rare event. In this report the case is described of development of severe, reversible, autoimmune thrombocytopenia in a patient with chronic hepatitis C virus infection, 6 months after the discontinuation of pegylated interferon-alpha-2b plus ribavirin treatment. Physicians must be aware that autoimmune thrombocytopenia can occur even after the end of treatment, as a late onset complication, especially when using the pegylated forms of interferons, which have longer half-lives and prolonged activity. PMID:16638114

  6. Modulation of alpha-interferon's antiviral and clinical effects by aspirin, acetaminophen, and prednisone in healthy volunteers.

    PubMed

    Hendrix, C W; Petty, B G; Woods, A; Kuwahara, S K; Witter, F R; Soo, W; Griffin, D E; Lietman, P S

    1995-10-01

    The magnitude and duration of the antiviral and clinical effect of alpha-interferon was measured in healthy volunteers. A single 3 million unit intramuscular dose of interferon was given either alone (controls) or after 72 h of concomitant medications. These medications included either aspirin (650 mg every 4 h), acetaminophen (650 mg every 4 h), or prednisone (40 mg per day). Peripheral blood mononuclear cells were assayed for resistance to vesicular stomatitis virus infection and induction of 2'-5'-oligoadenylate synthetase activity as evidence of interferon's antiviral effect. Co-administration of acetaminophen increased both antiviral parameters by more than 70% (P < 0.05) and reduced symptoms after interferon dosing, compared to controls. Aspirin and prednisone did not demonstrate any significant differences from controls in antiviral effect. As a group, acetaminophen, aspirin, and prednisone reduced the clinical symptoms by 47% compared to controls (P = 0.03) after interferon dosing, although individual drug comparisons failed to reach statistical significance. Independent of treatment group, the changes in antiviral markers after interferon dosing correlated closely with each other (r = 0.72, P < 0.001), but neither correlated with symptoms or fever (r < 0.30, P > 0.05). Acetaminophen enhances the antiviral effects of a single intramuscular dose of alpha-interferon, considering the parameters measured in these healthy volunteers. PMID:8585766

  7. In vitro and in vivo studies of the Interferon-alpha action on distinct Orthobunyavirus.

    PubMed

    Livonesi, Márcia Cristina; de Sousa, Ricardo Luiz Moro; Badra, Soraya Jabur; Figueiredo, Luiz Tadeu Moraes

    2007-08-01

    Oropouche, Caraparu, Guama, Guaroa and Tacaiuma viruses (Orthobunyavirus genus) cause human febrile illnesses and/or encephalitis. To achieve a therapeutical agent to prevent and/or treat these diseases we evaluated the antiviral action of Interferon-alpha (IFN-alpha) on these orthobunyaviruses. In vitro results showed that all the studied orthobunyaviruses are susceptible to antiviral action of IFN-alpha, but this susceptibility is limited and dependent on both concentration of drug and treatment period. In vivo results demonstrated that IFN-alpha present antiviral action on Oropouche and Guaroa viruses when used as a prophylactic treatment. Moreover, a treatment initiated 3h after infection prevented the death of Guaroa virus infected-mice. Additionally, mortality of mice was related to the migration and replication of viruses in their brains. Our results suggest that IFN-alpha could be potentially useful in the prevention of diseases caused by Oropouche virus and in the prevention and/or treatment of diseases caused by Guaroa virus. PMID:17368573

  8. Alpha interferon in T helper phenotype chronic lymphocytic leukemia: a report of three cases.

    PubMed

    Cuneo, A; Lanza, F; Spanedda, R; Tomasi, P; Ferrari, L; Castoldi, G L

    1988-01-01

    Three patients affected by T helper chronic lymphocytic leukemia were treated with low dose interferon alpha-2b (3 MU/m2 3 times weekly). The disease presented different pathologic expressions with diffuse skin lesions in one patient, a mild clinical course and a prolymphocytic variant with aggressive features, respectively, in the other two cases. A consistent response was observed within 3-6 weeks; by that time a reduction of blood and marrow lymphocytosis in the three patients and a regression of the cutaneous lesions were documented. Therefore, it should be emphasized that the use of alpha IFN, whose effectiveness on cutaneous T cell lymphomas has been already demonstrated, may represent an active agent in the treatment of leukemic T helper phenotype chronic lymphocytic proliferations. PMID:2972175

  9. [Phase II studies of interferon alpha-2 Sch 30500 in advanced gastrointestinal carcinoma].

    PubMed

    Furue, H

    1985-08-01

    Eighteen patients with advanced metastatic gastrointestinal cancer (stomach cancer 7, liver cancer 9, pancreas cancer 2) were treated with human recombinant interferon alpha-2 at doses of 3.0 X 10(6)-10.0 X 10(6) IU/body i.m. daily or every second day, 30 X 10(6) IU/body for five consecutive days every four weeks, or 30 X 10(6) IU/body once weekly. No tumor response was demonstrated in any of our cases. Among fifteen evaluable cases, nine had stabilization of evaluable disease at four weeks, but six showed progressive disease. On the other hand, fever, chills, fatigue, anorexia, nausea and vomiting were pronounced. In two cases, CNS toxicities developed. In some instances, leukopenia, thrombocytopenia, decrease of hemoglobin content and elevation of transaminase were observed. According to these findings, single use of recombinant interferon alpha-2 at the dose schedule outlined above does not seem to be of use for the treatment of advanced gastrointestinal cancer. PMID:3896154

  10. [Human recombinant leukocyte interferon alpha-2-A in 22 cases of metastatic malignant melanoma].

    PubMed

    Maral, J; Steinberg, M; Weil, M; Chleq, C; Khayat, D; Banzet, P; Jacquillat, C

    1987-06-01

    Twenty-two patients with metastatic malignant melanoma received either 36 X 10(6) U (15 patients) or 18 X 10(6) U (7 patients) of human recombinant interferon alpha-2-A daily for 3 months by the intramuscular route, with progressive increase of dosage. This was followed in responders by a maintenance treatment consisting of 3 intramuscular injections per week in the same doses as those received at the end of the induction treatment. Out of 18 patients assessable for effectiveness, 1 had complete remission (7 months +) and 3 had partial response (52,61 and 82 days respectively), an overall improvement rate of 22%. The main side-effects observed were: pseudoinfluenza syndrome (100%), fatigue (100%), somnolence (95%), anorexia (90%) and haematological disorders. Dosage reduction was necessary in 13 of the 15 patients receiving 36 MU. This study shows that human recombinant interferon alpha-2-A has antitumoral activity in metastatic malignant melanoma. Other studies, notably with therapeutic combinations, are needed to determine the optimal dosage regimen of the drug and to increase its effectiveness. PMID:2955323

  11. Efficacy and safety of pegylated interferon-alpha2b plus ribavirin for the treatment of chronic hepatitis C in HIV-infected patients.

    PubMed

    Santin, Miguel; Shaw, Evelyn; Garcia, M Jose; Delejido, Antonio; de Castro, Eduardo Rodriguez; Rota, Rosa; Altés, Jordi; Baguena, Francisco; Valero, Silvia; Sala, Montserrat; Casanova, Aurora

    2006-04-01

    Low response rates and concerns about safety have limited the implementation of treatment for chronic hepatitis C (CHC) in patients with HIV infection. The efficacy and safety of pegylated interferon (peg-IFN) plus ribavirin in HIV-infected patients with CHC were evaluated in a prospective, open-label, multicenter study. Sixty patients with persistently high transaminases, positive HCV-RNA, CD4 count > or = 300 cells/microl, and HIVRNA <10,000 copies/ml were included. Patients were given peg-IFN 80-150 microg/week plus ribavirin 800-1200 mg/day. Treatment was scheduled for 24 weeks for genotypes 2/3 and 48 weeks for genotypes 1/4. In an intent- to-treat analysis, 16 (26.7%) patients achieved a sustained virological response (SVR). Twenty patients (33.3%) discontinued treatment prematurely, but only in 10 (16.6%) was discontinuation due to adverse events. Negative predictive values for SVR on the basis of HCV-RNA decline between baseline and week 4 were 100% for 1- and 2-log10 fall, and positive predictive values were 40% and 58.3% for 1- and 2-log10 fall, respectively. CD4 fell by a median of 216 cells during treatment, but no HIV-associated complications occurred. In conclusion, treatment with peg-IFN alpha-2b plus ribavirin is safe and clears RNA-HCV in about one-quarter of HIV-infected patients with CHC. Efforts should be focused on optimizing management of side effects and counseling to improve adherence and to keep patients on treatment. Assessment of HCV-RNA at week 4 may help guide early therapeutic decision making. PMID:16623633

  12. Phorbol esters potentiate the induction of class I HLA expression by interferon. alpha

    SciTech Connect

    Erusalimsky, J.D.; Kefford, R.F.; Gilmore, D.J.; Milstein, C. )

    1989-03-01

    The authors have studied the effect of phorbol esters on the induction of class I histocompatibility antigen (HLA) expression by interferons (IFNs) in the T-cell line MOLT-4 and in the MOLT-4 mutant YHHH. Addition of IFN-{alpha} to phorbol 12,13-dibutyrate-pretreated MOLT-4 cells causes a >20-fold increase in the expression of class I HLA, as compared to a 4- to 7-fold IFN-{alpha}-induced increase in control cells. Pretreatment with phorbol 12,13-dibutyrate does not alter the class I HLA response to IFN-{gamma} or the responses of other IFN-induced genes. This effect of phorbol 12,13-dibutyrate reproduces in MOLT-4 cells the phenotype of the mutant YHHH, which also displays a selective enhanced class I HLA response to IFN-{alpha}. Pretreatment of YHHH with phorbol 12,13-dibutyrate does not affect any of the responses induced by IFN. These findings suggest the existence of a phorbol ester-sensitive factor, inducible in MOLT-4 and constitutively expressed or modified in YHHH, which operates in the pathway of induction of class I HLA by IFN-{alpha} but not in the pathway used by IFN-{gamma}.

  13. [Phase I study of human lymphoblastoid alpha-interferon on malignant tumor].

    PubMed

    Furue, H

    1986-04-01

    A phase I study with human lymphoblastoid alpha-interferon (IFN-alpha) was conducted in 31 patients with malignant tumors. IFN-alpha was administered by intravenous drip infusion, intramuscular injection or local injection. In each patient, the dose was increased in 6 steps from 3 X 10(6) IU/body up to 54 X 10(6) IU/body for the purpose of investigating the safety, optimal regimen, pharmacokinetics and antitumor effect. The following findings were obtained: 1) Fever as a side effect was most frequently (in about 80%) found. However, the temperature did not exceed 40 degrees C in most cases and, on the next day, spontaneously fell to normal. 2) The dose-limiting factors (DLF) may include the subjective symptoms of anorexia, general fatigue and nausea/vomiting and the objective symptom of pancytopenia. 3) The maximum tolerated dose (MTD) was estimated to be between 36 X 10(6) and 54 X 10(6) IU/body per dose. 4) As for the route of administration, the intramuscular one was considered most suitable on the basis of the plasma concentration profile of INF-alpha. It was therefore concluded that the drug may be further submitted to a phase II study which is to be conducted with due consideration of its safety. PMID:3963861

  14. Release of biologically functional interferon-alpha from a nanochannel delivery system.

    PubMed

    Lesinski, Gregory B; Sharma, Sadhana; Varker, Kimberly A; Sinha, Piyush; Ferrari, Mauro; Carson, William E

    2005-03-01

    Metastatic melanoma lesions often are unresectable due to their size and/or location near critical structures. These lesions represent a significant challenge for the oncologist, because radiation therapy and chemotherapy are infrequently successful in halting tumor growth. Of primary concern is the fact that these lesions are usually painful and present a cosmetic dilemma. We hypothesized that the development of a silicon-based nano-device capable of delivering antitumor compounds (e.g. immune modulators), locally, at a constant rate, to the tumor microenvironment could avoid the toxicity of systemic administration and the inconvenience of frequent clinic visits for local injections. Because of its diminutive size, such a device could be implanted using a minimally invasive procedure in close proximity to unresectable melanoma lesions. The current report uses interferon alpha-2b (IFN-alpha) as a model antitumor agent, since it is commonly used in the treatment of malignant melanoma and metastatic renal cell carcinoma. In this system, IFN-alpha is delivered directly to the tumor microenvironment by a novel nanochannel delivery system (nDS) that is capable of zero order release of small molecules. We have demonstrated that the IFN-alpha released from the nDS is functionally active on both host immune cells and a human melanoma cell line in vitro. This drug delivery platform could be used to develop alternative strategies for the treatment of unresectable tumors. PMID:15834523

  15. An Observational, Multicenter, Cohort Study Evaluating the Antiviral Efficacy and Safety in Korean Patients With Chronic Hepatitis B Receiving Pegylated Interferon-alpha 2a (Pegasys): TRACES Study.

    PubMed

    Chon, Young Eun; Kim, Dong Joon; Kim, Sang Gyune; Kim, In Hee; Bae, Si Hyun; Hwang, Seong Gyu; Heo, Jeong; Jang, Jeong Won; Lee, Byung Seok; Kim, Hyung Joon; Jun, Dae Won; Kim, Kang Mo; Chung, Woo Jin; Choi, Moon Seok; Jang, Jae Young; Yim, Hyung Joon; Tak, Won Young; Yoon, Ki Tae; Park, Jun Yong; Han, Kwang-Hyub; Suk, Ki Tae; Lee, Hyun Woong; Jang, Byoung Kuk; Ahn, Sang Hoon

    2016-04-01

    Currently, limited data are available regarding the efficacy and safety of pegylated interferon alpha-2a (PEG-IFN α-2a) in Korean patients with chronic hepatitis B (CHB), in whom hepatitis B virus (HBV) genotype C is the most common type.We collected data from 439 patients (HBeAg positive, n = 349; HBeAg negative, n = 90) with CHB who were treated with PEG-IFN α-2a as a first-line therapy from 18 institutions. Treatment responses at the end of treatment (ET) and at 6 months posttreatment (PT6) were compared between the patients who were treated for 24 weeks versus 48 weeks, and adverse events (AEs) were evaluated.In HBeAg-positive patients, those who received PEG-IFN α-2a for 48 weeks showed significantly higher HBV DNA suppression (HBV DNA < 2000 IU/mL) than those who were treated for 24 weeks (48 weeks vs 24 weeks; at ET, 44.4% vs 36.7%, P = 0.035; at PT6, 35.9% vs 13.3%, P = 0.035). The HBeAg seroconversion rate at ET was 18.1% in 48-week treatment group, which is significantly higher than the 2.2% (P < 0.001) that was seen in 24-week treatment group. This finding also continued at PT6 (29.0% vs 10.0%, P < 0.001). Following 48 weeks of treatment in HBeAg-negative patients, HBV DNA suppression at ET was higher than in HBeAg-positive patients (87.8% vs 44.4%). AEs were typical of those associated with PEG-IFN α-2a.In naïve Korean HBeAg-positive CHB patients treated with PEG-IFN α-2a, higher rates of HBV DNA suppression and HBeAg seroconversion were achieved in the 48-week treatment group than in the 24-week treatment group without additional risk of AEs. PMID:27057828

  16. Treatment of metastatic renal cell carcinoma with a combination of human lymphoblastoid interferon-alpha and cimetidine.

    PubMed

    Kotake, T; Kinouchi, T; Saiki, S; Kuroda, M; Miki, T; Kiyohara, H; Usami, M

    1991-02-01

    Human lymphoblastoid interferon-alpha was administered intramuscularly at a dose of 5 x 10(6) units/day to 20 metastatic renal cell carcinoma patients. For potentiating the antitumor effect of interferon, cimetidine was also given to them orally at a dose of 800 mg/day. The combination therapy obtained a complete response in three patients (15%) and a partial response in three (15%). Nine patients (45%) had stable disease and five (25%), progressive disease. All six patients who responded to the combination therapy had been nephrectomized and had pulmonary metastases. Two of them also had metastases to other sites (mediastinal lymph nodes and bone). The pulmonary metastases were significantly more receptive to interferon therapy than those at the other sites. The average times before a response was obtained were 2.2 months for a minor response, 2.7 months for a partial response and 3.0 months for a complete response, and the average duration of response was 26 months. The six patients who responded survived for a significantly longer period than the 14 non-responding patients treated with interferon in combination with cimetidine. The major toxicities encountered were fever, fatigue and anorexia due to interferon, and the combination therapy was well tolerated except in three patients. The results suggest that interferon-alpha and cimetidine combination therapy may be of use in the management of patients with metastatic renal cell carcinoma. PMID:2067120

  17. Retinal complications with elevated circulating plasma C5a associated with interferon-alpha therapy for chronic active hepatitis C.

    PubMed

    Sugano, S; Yanagimoto, M; Suzuki, T; Sato, M; Onmura, H; Aizawa, H; Makino, H

    1994-11-01

    Retinal hemorrhage is a complication of interferon therapy of unknown pathogenesis. We report two chronic active hepatitis C patients who developed retinal hemorrhage and/or cotton wool patches during interferon-alpha therapy 4 and 12 wk after beginning treatment. At the time of the hemorrhage, plasma-activated complement 5, a known potent intravascular aggregator of granulocytes, increased to 54 ng/ml in one patient and to 29 ng/ml in the other patient. When the hemorrhage resolved, it decreased to under 5 ng/ml. Our cases suggest that complement activation occurs in patients treated with interferon-alpha and that activation of complement 5 can lead to retinal capillary infarction and retinal hemorrhage. High levels of activated complement 5 may predict retinal artery infarction or perhaps microvascular emboli in the other organs. PMID:7942735

  18. Separate and combined effects of recombinant interleukin-1 alpha and gamma interferon on antibacterial resistance.

    PubMed Central

    Kurtz, R S; Young, K M; Czuprynski, C J

    1989-01-01

    Our laboratory has previously reported that administration of murine recombinant interleukin 1 alpha (rIL-1 alpha) substantially enhanced the resistance of mice to Listeria monocytogenes infection. Other investigators have reported that gamma interferon (IFN-gamma) plays a pivotal role in antilisteria resistance. In the present study, we have defined doses of human rIL-1 alpha that enhanced the antilisteria resistance of mice. We then addressed the possibility that combined immunotherapy with rIL-1 alpha and recombinant IFN-gamma (rIFN-gamma) might result in an additive or synergistic enhancement of antibacterial resistance. Simultaneous administration of rIL-1 alpha and rIFN-gamma enhanced antilisteria resistance (at 3 days after infection) to a greater extent than did either cytokine alone, although the results did not imply a synergistic action between the two cytokines. Experiments which examined the effects of the timing of cytokine administration indicated that maximal protection was observed when rIL-1 alpha and rIFN-gamma were administered together concomitantly with the L. monocytogenes challenge. When we compared the separate and combined protective effects of rIL-1 alpha and rIFN-gamma throughout the course of a primary L. monocytogenes infection, we observed an additive effect of the two cytokines only at 3 days after challenge, the time at which the peak bacterial burden occurs in the spleens and livers of infected mice. Histopathological comparisons of livers and spleens from cytokine-treated and control listeria-infected mice verified that cytokine treatment reduced the severity of tissue damage in cytokine-treated listeria-infected mice. In an attempt to provide a potential mechanism for the protective effects of rIL-1 alpha and rIFN-gamma administration, we compared levels of colony-stimulating activity in sera from cytokine-treated and control listeria-infected mice. The highest levels of colony-stimulating activity were detected in sera from

  19. Pegylated interferon alpha-2b as adjuvant treatment of Stage III malignant melanoma: an evidence-based review

    PubMed Central

    Okuyama, Sonia; Gonzalez, Rene; Lewis, Karl D

    2010-01-01

    Introduction: Stage III melanoma, also referred to as regional metastatic melanoma, has five-year survival rates ranging between 40% and 78%. In order to reduce the likelihood of recurrence in this high-risk population, patients undergo resection of primary tumors and all involved nodal basins. Systemic therapy is being pursued in an effort to improve outcome data, but the best strategy has yet to be defined. Interferon alpha-2b remains to date the most promising approach available. Toxicities and intensive intravenous administration, unfortunately, are major concerns. An alternative is the use of interferon in its pegylated subcutaneous form. The aim of this research was to review the evidence for the use of pegylated interferon alpha-2b in Stage III malignant melanoma. Evidence review: ECOG 1684 was the pivotal trial that first demonstrated a statistically significant benefit in relapse-free and overall survival for adjuvant interferon alpha-2b in high-risk melanoma. Other larger studies, such as ECOG 1690, confirmed a relapse-free survival benefit but did not achieve statistical significance for overall survival. The first study of the pegylated form of interferon alpha-2b in Stage III melanoma, EORTC 18991, is reviewed here. This trial showed a statistically significant improvement in relapse-free survival but not overall survival. Encouraging data of potential equivalent efficacy, easier administration, and fewer Grade 3 and 4 adverse reactions compared with high-dose intravenous interferon raises the question of its potential role in Stage III melanoma in the adjuvant setting. PMID:21042541

  20. Interleukin-2 and interferon-alpha-2a outpatient therapy for metastatic renal cell carcinoma.

    PubMed

    Lipton, A; Harvey, H; Givant, E; Hopper, K; Lawler, J; Matthews, Y; Hirsh, M; Zeffren, J

    1993-02-01

    The combination of interleukin-2 (IL-2) and interferon-alpha-2a (IFN-alpha-2a) has synergistic bioactivity in numerous preclinical model systems. Thirty-nine patients with metastatic renal cell cancer were treated with continuous intravenous infusion IL-2 for 4-5 days plus intramuscular IFN-alpha-2a 2-3 days a week for 4 consecutive weeks. A 2- to 4-week rest period was permitted after each 4 weeks of treatment. Thirty-one of the 39 patients were assessable for response determination. Response rate (six complete+seven partial remissions) was 33.3% for all patients, or 41.9% when the analysis was restricted to the 31 evaluable patients. Three patients were unable to tolerate treatment due to anorexia, weight loss, and severe fatigue. This therapy was relatively well tolerated in the outpatient setting in the other patients despite fever, chills, fatigue, anorexia, and weight loss. There was no correlation of response with site of metastases or bulk of disease. PMID:8318497

  1. Expression of biologically active human interferon alpha 2 in Aloe vera.

    PubMed

    Lowther, William; Lorick, Kevin; Lawrence, Susan D; Yeow, Wen-Shuz

    2012-12-01

    Methods necessary for the successful transformation and regeneration of Aloe vera were developed and used to express the human protein, interferon alpha 2 (IFNα2). IFNα2 is a secreted cytokine that plays a vital role in regulating the cellular response to viral infection. Transgenic plants were regenerated from callus cultures initiated from zygotic embryos. Expression of the IFNA2 transgene in transformed plants was confirmed by RT-PCR and IFNα2 protein was detected by immunoblot analysis. Human A549 cells treated with transgenic aloe extracts for 6 h induced expression of the interferon stimulated gene 54, indicating activation of the IFN signaling pathway. The biological activity of the aloe produced IFNα2 was assessed using an antiviral assay with A549 cells treated with extracts from both the rind and pulp fractions of the shoot and subsequently infected with the lytic encephalomyocarditis virus. The highest level of activity attributable to recombinant IFNα2 was determined to be 625 IU/mg of total soluble protein (TSP) in the rind and 2,108 IU/mg TSP in the pulp. Two daughter plants that vegetatively budded during the course of this study were also confirmed to express IFNα2. These results confirm that Aloe vera is capable of expressing a human protein with biological activity, and that a secreted protein targeting the apoplast can be detected in the pulp fraction of the plant. PMID:22528466

  2. A Computational Model of Inhibition of HIV-1 by Interferon-Alpha

    PubMed Central

    Browne, Edward P.; Letham, Benjamin; Rudin, Cynthia

    2016-01-01

    Type 1 interferons such as interferon-alpha (IFNα) inhibit replication of Human immunodeficiency virus (HIV-1) by upregulating the expression of genes that interfere with specific steps in the viral life cycle. This pathway thus represents a potential target for immune-based therapies that can alter the dynamics of host-virus interactions to benefit the host. To obtain a deeper mechanistic understanding of how IFNα impacts spreading HIV-1 infection, we modeled the interaction of HIV-1 with CD4 T cells and IFNα as a dynamical system. This model was then tested using experimental data from a cell culture model of spreading HIV-1 infection. We found that a model in which IFNα induces reversible cellular states that block both early and late stages of HIV-1 infection, combined with a saturating rate of conversion to these states, was able to successfully fit the experimental dataset. Sensitivity analysis showed that the potency of inhibition by IFNα was particularly dependent on specific network parameters and rate constants. This model will be useful for designing new therapies targeting the IFNα network in HIV-1-infected individuals, as well as potentially serving as a template for understanding the interaction of IFNα with other viruses. PMID:27010978

  3. A Computational Model of Inhibition of HIV-1 by Interferon-Alpha.

    PubMed

    Browne, Edward P; Letham, Benjamin; Rudin, Cynthia

    2016-01-01

    Type 1 interferons such as interferon-alpha (IFNα) inhibit replication of Human immunodeficiency virus (HIV-1) by upregulating the expression of genes that interfere with specific steps in the viral life cycle. This pathway thus represents a potential target for immune-based therapies that can alter the dynamics of host-virus interactions to benefit the host. To obtain a deeper mechanistic understanding of how IFNα impacts spreading HIV-1 infection, we modeled the interaction of HIV-1 with CD4 T cells and IFNα as a dynamical system. This model was then tested using experimental data from a cell culture model of spreading HIV-1 infection. We found that a model in which IFNα induces reversible cellular states that block both early and late stages of HIV-1 infection, combined with a saturating rate of conversion to these states, was able to successfully fit the experimental dataset. Sensitivity analysis showed that the potency of inhibition by IFNα was particularly dependent on specific network parameters and rate constants. This model will be useful for designing new therapies targeting the IFNα network in HIV-1-infected individuals, as well as potentially serving as a template for understanding the interaction of IFNα with other viruses. PMID:27010978

  4. Dexamethasone, all trans retinoic acid and interferon alpha 2a in patients with refractory multiple myeloma.

    PubMed

    Avilés, A; Rosas, A; Huerta-Guzmán, J; Talavera, A; Cleto, S

    1999-02-01

    Few effective regimen are available for patients with refractory multiple myeloma (RMM). Generally, responses are scarce and disease free survival is very short. We developed a new therapeutic option in these patients using dexamethasone (40 mg/m2, i.v., daily, days 1 to 4), all-trans retinoic acid (45 mg/m2, po, daily, days 5 to 14) and interferon alpha 2a (9.0 MU, daily, subcutaneously, days 5 to 14). The treatment was administered every 21 days for 6 cycles. In a pilot study, 12 patients, heavily treated with chemotherapy and radiotherapy and in some cases with interferon, were allocated to receive the afore mentioned treatment. Response was observed in 10 patients (83%). With a median follow-up of 36.1 months (range 27 to 41), seven patients remain alive and disease-free without any treatment. Two patients were failures and have died due to tumor progression. Toxicity was mild and all patients received treatment according to the planned doses of drugs. The use of biological modifiers in combination with dexamethasone offer a safe and effective therapeutic option in patients with refractory multiple myeloma. More studies are warranted to define the role of this type of treatment. PMID:10850283

  5. [Therapy of thrombocytosis in myeloproliferative syndromes using recombinant interferon-alpha-2a].

    PubMed

    Tichelli, A; Gratwohl, A; Delacrétaz, F; Dazzi, H; Stebler, C; Wernli, M; Holdener, E E; Nissen, C; Speck, B

    1989-09-30

    In a prospective open study 16 consecutive patients with a myeloproliferative syndrome and thrombocytosis were treated with interferon (IFN) alpha-2a. 4 patients had polycythemia vera, 4 essential thrombocythemia, 3 myeloid metaplasia and 5 chronic granulocytic leukemia. Platelet counts decreased in all treated patients within 2 to 12 weeks from a median value of 1010 x 10(9)/l to 350 x 10(9)/l. No primary or secondary resistance was observed. The initial dose of IFN was 9 m U per day. After correction of the thrombocytosis, it was progressively reduced to a minimum dose of 3 m U per week. Despite the good platelet response to IFN, leukocytosis persisted in 3 patients and polycythemia in a further 3. Side effects and poor compliance required discontinuation of therapy in 6 patients. Special attention is focused on the follow-up in 6 patients who have been treated for more than 15 months. PMID:2799342

  6. Treatment with interferon-alpha delays disease in swine infected with a highly virulent CSFV strain.

    PubMed

    Fernandez-Sainz, I; Ramanathan, P; O'Donnell, V; Diaz-San Segundo, F; Velazquez-Salinas, L; Sturza, D F; Zhu, J; de los Santos, T; Borca, M V

    2015-09-01

    Interferon-alpha (IFNα) can effectively inhibit or abort a viral infection within the host. It has been reported that IFN induction and production is hindered during classical swine fever virus (CSFV) infection. Most of those studies have been performed in vitro, making it difficult to elucidate the actual role of IFNs during CSFV infection in swine. Here, we report the effect of IFNα treatment (delivered by a replication defective recombinant human adenovirus type 5, Ad5) in swine experimentally infected with highly virulent CSFV strain Brescia. Treatment with two different subtypes of IFNα delayed the appearance of CSF-related clinical signs and virus replication although it did not prevent lethal disease. This is the first report describing the effect of IFNα treatment during CSFV infection in swine. PMID:26004252

  7. Lack of effect of interferon alpha 2a upon fluorouracil pharmacokinetics.

    PubMed Central

    Seymour, M. T.; Patel, N.; Johnston, A.; Joel, S. P.; Slevin, M. L.

    1994-01-01

    The disposition of 5-fluorouracil (FUra) was studied in 19 colorectal cancer patients during treatment with FUra and high-dose leucovorin (LV) with or without interferon alpha 2a (IFN-alpha). All received LV 200 mg m-2 over 2 h, then FUra 400 mg m-2 over 5 min then FUra 400 mg m-2 over 22 h, repeated on day 2, on a 14 day cycle. Nine patients also received IFN-alpha 6 MU every 48 h, starting at least 2 weeks before the study. Series of 14 blood samples were assayed for FUra by reversed-phase high-performance liquid chromatography (HPLC). Minimum Akaike information criterion estimation was used to determine the simplest effective pharmacokinetic model. This consisted of a single compartment with first-order (linear) and Michaelis-Menten (non-linear) components to drug elimination. This model gave r2 > 0.98 in 19/20 data sets. With the Michaelis constant (KM) set at 15 microM, values were derived for the volume of distribution (Vd), the maximum rate of non-linear elimination (Vmax) and the first-order elimination rate constant (K1.e). Mean (+/- s.d.) values in control (no IFN-alpha) patients were: Vd 10.4 (+/- 1.9) l m-2, Vmax 182 (+/- 59) mumol l-1 h-1 and k1.e 4.35 (+/- 0.58) h-1. No significant differences were detected in patients receiving IFN-alpha, in whom the equivalent mean values were Vd 10.0 (+/- 0.9) l m-2, Vmax 141 (+/- 27) mumol l-1 h-1 and k1.e 3.96 (+/- 0.5) h-1. Mean trapezoidal AUC0-22 h was similar in the two groups (control patients 116 microM h, IFN-alpha patients 125 microM h). No significant correlations with renal or hepatic function were detected. These results, while not inconsistent with previous reports of a reduced rate of FUra elimination at higher IFN-alpha doses, suggest that any clinical effect of this moderate dose of IFN-alpha on FUra toxicity or activity is due to modulation at target cells, not to pharmacokinetic interaction. PMID:7917928

  8. Inhibition of Epstein-Barr virus-mediated capping of CD21/CR2 by alpha interferon (IFN-alpha): immediate antiviral activity of IFN-alpha during the early phase of infection.

    PubMed Central

    Delcayre, A X; Lotz, M; Lernhardt, W

    1993-01-01

    Early events of human B-lymphocyte infection by Epstein-Barr virus involve the virus binding to CD21, capping, and subsequent internalization of the virus-receptor complex. We show here that alpha interferon (IFN-alpha) inhibits the capping of Epstein-Barr virus-CD21 complexes. Synthetic peptides with the CD21 binding motif of IFN-alpha mimic IFN-alpha activity, suggesting that this effect may be mediated by IFN-alpha-CD21 interaction. Our findings demonstrate a novel and immediate mechanism of IFN-alpha action. PMID:8386282

  9. The induction and characterization of natural porcine interferons alpha and beta.

    PubMed Central

    Weingartl, H M; Derbyshire, J B

    1990-01-01

    The purpose of this study was to define optimum conditions for the production of high concentrations of natural porcine interferon (POIFN)-alpha and POIFN-beta, and to characterize the IFNs which were produced. The inducers used were Newcastle disease virus (NDV), polyinosinic:polycytidylic acid (poly IC), poly IC complexed with diethylaminoethyl dextran (poly IC-DEAEdx) and poly IC complexed with poly-L-lysine and carboxymethylcellulose. The highest yields of POIFN-alpha were obtained from porcine peripheral blood leukocyte (PBL) cultures induced with NDV. The concentrations of both cells and virus were critical for high yields of IFN, which were also enhanced by priming. Poly IC was found to be a relatively poor IFN inducer in PBL, in which low yields were obtained only after priming or in response to poly IC-DEAEdx. POIFN-beta was prepared by induction of the PK-15 cell line with poly IC or poly IC-DEAEdx. The highest yields were obtained from cultures induced 24 h after seeding, although when poly IC-DEAEdx or superinduction was used, the age of the cells was less critical. Priming had little effect on the yields of POIFN-beta. PK-15 cells induced with NDV gave relatively low yields of IFN. Both POIFN-alpha and POIFN-beta were classified as type I IFN on the basis of their resistance or susceptibility to pH 2.0, ultracentrifugation, 56 degrees C and trypsin treatment. Disulphide bonds essential for antiviral activity were demonstrated in both types of IFN by reduction with 2-beta-mercaptoethanol, and anionic exchange chromatography after treatment with dithiothreitol indicated a second disulphide bond in POIFN-alpha which was not essential for antiviral activity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2379114

  10. Peyronie's disease: intralesional treatment with interferon alpha-2A and evaluation of the results by magnetic resonance imaging.

    PubMed

    Polat, O; Gül, O; Ozbey, I; Ozdikici, M; Bayraktar, Y

    1997-01-01

    In this clinical study, to determine the therapeutic efficacy of interferon (IFN) treatment for Peyronie's disease, we applied interferon alpha-2A (IFN alpha-2A) intralesionally in the treatment of Peyronie plaques in 15 patients and results were evaluated by magnetic resonance imaging (MRI). Patients whose plaque sizes were 0.5 and 1 cm responded better to the treatment. There was about a 90% lessening in the sizes of the plaques of 1.5 cm, 83.3% of 2 cm, as the ones which were 0.5 cm and 1 cm disappeared completely after treatment. As a conclusion, the treatment of Peyronie's disease with IFN alpha-2A is effective and side effects are minimum. PMID:9406006

  11. Psychosocial assessment and monitoring in the new era of non-interferon-alpha hepatitis C virus treatments

    PubMed Central

    Rowan, Paul J; Bhulani, Nizar

    2015-01-01

    Chronic hepatitis C virus (HCV) is a global concern. With the 2014 Food and Drug Administration approvals of two direct-acting antiviral (DAA) regimens, ledipasvir/sofosbuvir regimen and the ombitasvir/paritaprevir/ritonavir and dasabuvir regimen, we may now be in the era of all-pill regimens for HCV. Until this development, interferon-alpha along with Ribavirin has remained part of the standard of care for HCV patients. That regimen necessitates psychosocial assessment of factors affecting treatment eligibility, including interferon-alpha-related depressive symptoms, confounding psychiatric conditions, and social aspects such as homelessness affecting treatment eligibility. These factors have delayed as much as 70% of otherwise eligible candidates from interferon-based treatment, and have required treating physicians to monitor psychiatric as well as medical side effects throughout treatment. All-pill DAA regimens with the efficaciousness that would preclude reliance upon interferon-alpha or ribavirin have been anticipated for years. Efficacy studies for these recently approved DAA regimens provide evidence to assess the degree that psychosocial assessment and monitoring will be required. With shorter treatment timelines, greatly reduced side effect profiles, and easier regimens, psychosocial contraindications are greatly reduced. However, current or recent psychiatric comorbidity, and drug-drug interactions with psychiatric drugs, will require some level of clinical attention. Evidence from these efficacy studies tentatively demonstrate that the era of needing significant psychosocial assessment and monitoring may be at an end, as long as a manageable handful of clinical issues are managed. PMID:26380046

  12. Psychosocial assessment and monitoring in the new era of non-interferon-alpha hepatitis C virus treatments.

    PubMed

    Rowan, Paul J; Bhulani, Nizar

    2015-09-01

    Chronic hepatitis C virus (HCV) is a global concern. With the 2014 Food and Drug Administration approvals of two direct-acting antiviral (DAA) regimens, ledipasvir/sofosbuvir regimen and the ombitasvir/paritaprevir/ritonavir and dasabuvir regimen, we may now be in the era of all-pill regimens for HCV. Until this development, interferon-alpha along with Ribavirin has remained part of the standard of care for HCV patients. That regimen necessitates psychosocial assessment of factors affecting treatment eligibility, including interferon-alpha-related depressive symptoms, confounding psychiatric conditions, and social aspects such as homelessness affecting treatment eligibility. These factors have delayed as much as 70% of otherwise eligible candidates from interferon-based treatment, and have required treating physicians to monitor psychiatric as well as medical side effects throughout treatment. All-pill DAA regimens with the efficaciousness that would preclude reliance upon interferon-alpha or ribavirin have been anticipated for years. Efficacy studies for these recently approved DAA regimens provide evidence to assess the degree that psychosocial assessment and monitoring will be required. With shorter treatment timelines, greatly reduced side effect profiles, and easier regimens, psychosocial contraindications are greatly reduced. However, current or recent psychiatric comorbidity, and drug-drug interactions with psychiatric drugs, will require some level of clinical attention. Evidence from these efficacy studies tentatively demonstrate that the era of needing significant psychosocial assessment and monitoring may be at an end, as long as a manageable handful of clinical issues are managed. PMID:26380046

  13. Low dose alpha interferon therapy can be effective in chronic active hepatitis C. Results of a multicentre, randomised trial.

    PubMed Central

    Sánchez-Tapias, J M; Forns, X; Ampurdanés, S; Titó, L; Planas, R; Viver, J M; Acero, D; Torres, M; Mas, P; Morillas, R; Forné, M; Espinós, J; Llovet, J M; Costa, J; Olmedo, E; López-Labrador, F X; Jiménez de Anta, M T; Rodés, J

    1996-01-01

    BACKGROUND--There is some controversy concerning the efficacy of low dose alpha interferon therapy in chronic hepatitis C. AIMS--To evaluate the effectiveness of treatment with low doses of alpha interferon in chronic hepatitis C. PATIENTS--One hundred and forty one patients with anti-HCV positive chronic active hepatitis C from six hospitals were enrolled in the study. METHODS--Patients were randomised to treatment with 5 MU (group A) or 1.5 MU (group B) injections. The dose was reduced in responders from group A or increased in non-responders from group B to maintain treatment with the minimal effective dose. Patients were treated for 48 weeks and followed up for 24 additional weeks with no treatment. Normalisation of alanine aminotransferase (ALT) was used to evaluate response. RESULTS--A sustained response was seen in eight patients from group A (12%) and in 15 (21%) from group B. This difference was not statistically significant. Increasing the dose of interferon led to sustained response in only five of 58 patients (9%) from group B who did not respond to 1.5 MU injections. In contrast, 15 of 21 patients (71%) in whom ALT remained normal with 1.5 MU injections developed a sustained response. By multivariate analysis sustained response seemed associated with young age and was more frequent in patients with genotype 3 HCV infection. Sustained response was preceded by a rapid normalisation of ALT and was inversely related to the amount of alpha interferon necessary to maintain ALT at low values during treatment. CONCLUSIONS--Some patients with chronic hepatitis C are very sensitive to alpha interferon and can be successfully treated with low doses. Treatment with higher doses may be effective in a minority of patients who do not respond to low doses. PMID:8707096

  14. Raised levels of tumour necrosis factor-alpha and neopterin, but not interferon-alpha, in serum of HIV-1-infected patients from Ethiopia.

    PubMed Central

    Ayehunie, S; Sonnerborg, A; Yemane-Berhan, T; Zewdie, D W; Britton, S; Strannegard, O

    1993-01-01

    Serum levels of tumour necrosis factor-alpha (TNF-alpha), neopterin and interferon-alpha (IFN-alpha) were determined by immunoradiometric assays in 60 HIV-1+ and 20 HIV-1- subjects from Ethiopia. Swedish samples were used as reference material. The Ethiopian HIV-1+ subjects were found to have significantly increased TNF-alpha and neopterin, but not IFN-alpha levels. Increased levels of TNF-alpha and neopterin were frequently found in Ethiopian asymptomatic subjects (37% and 47%), and the concentration increased in patients with AIDS (83% and 90% respectively). The levels of the two substances and the proportion of patients with higher TNF-alpha values were lower in the corresponding Swedish subjects. The proportion of sera with raised levels of IFN-alpha was very low (asymptomatic 4%, and AIDS 7%) in Ethiopian subjects. These results suggest a very early increase in the TNF-alpha production and activation of the cellular immune response, and a low level of IFN-alpha synthesis in the natural course of HIV infection in Ethiopia. The aberrations may contribute to a rapid progress of immunodeficiency and cachexia often seen in Ethiopian patients. PMID:8419084

  15. Weight-based dosing of pegylated interferon-alpha in chronic hepatitis C: just a marketing 'gag'?

    PubMed

    Ferenci, P

    2003-09-01

    Today medical-scientific data are diluted by the marketing strategies of the biomedical industry making it difficult for practising physicians to decide what is correct or wrong. One typical example is the use of pegylated interferons for treatment of chronic hepatititis C. In this report the arguments pro and contra weight-based dosing are critically discussed. The factors contributing to success or failure to eradicate the virus are manifold, and include the sensitivity of the virus to interferon, viral genotype, age, gender stage of fibrosis, presence or absense of steatosis. Weight by itself plays just a minor role. The impact of weight-based dosing in general is overestimated and certainly not needed when 40 kD branched PEG-IFNalpha2a with a restricted volume of distribution is used. Whether weight-based dosing of 12 kD linear PEG-IFNalpha2b provides any benefit over a flat dose of the drug remains to be studied. PMID:14563179

  16. Leishmania donovani amastigotes impair gamma interferon-induced STAT1alpha nuclear translocation by blocking the interaction between STAT1alpha and importin-alpha5.

    PubMed

    Matte, Christine; Descoteaux, Albert

    2010-09-01

    The protozoan parasite Leishmania donovani, the etiological agent of visceral leishmaniasis, is renowned for its capacity to sabotage macrophage functions and signaling pathways stimulated by activators such as gamma interferon (IFN-gamma). Our knowledge of the strategies utilized by L. donovani to impair macrophage responsiveness to IFN-gamma remains fragmentary. In the present study, we investigated the impact of an infection by the amastigote stage of L. donovani on IFN-gamma responses and signaling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in mouse bone marrow-derived macrophages. The levels of IFN-gamma-induced expression of major histocompatibility complex class II and inducible nitric oxide synthase (iNOS) were strongly reduced in L. donovani amastigote-infected macrophages. As the expression of those genes is mediated by the transcription factors STAT1alpha and IFN regulatory factor 1 (IRF-1), we investigated their activation in amastigote-infected macrophages treated with IFN-gamma. We found that whereas STAT1alpha protein levels and the levels of phosphorylation on Tyr701 and Ser727 were normal, IRF-1 expression was inhibited in infected macrophages. This inhibition of IRF-1 expression correlated with a defective nuclear translocation of STAT1alpha, and further analyses revealed that the IFN-gamma-induced STAT1alpha association with the nuclear transport adaptor importin-alpha5 was compromised in L. donovani amastigote-infected macrophages. Taken together, our results provide evidence for a novel mechanism used by L. donovani amastigotes to interfere with IFN-gamma-activated macrophage functions and provide a better understanding of the strategies deployed by this parasite to ensure its intracellular survival. PMID:20566692

  17. Pharmacokinetic characteristics, pharmacodynamic effect and in vivo antiviral efficacy of liver-targeted interferon alpha.

    PubMed

    Rycroft, Daniel; Sosabowski, Jane; Coulstock, Edward; Davies, Marie; Morrey, John; Friel, Sarah; Kelly, Fiona; Hamatake, Robert; Ovečka, Milan; Prince, Rob; Goodall, Laura; Sepp, Armin; Walker, Adam

    2015-01-01

    Interferon alpha (IFNα) is used for the treatment of hepatitis B virus infection, and whilst efficacious, it is associated with multiple adverse events caused by systemic exposure to interferon. We therefore hypothesise that targeting IFN directly to the intended site of action in the liver would reduce exposure in blood and peripheral tissue and hence improve the safety and tolerability of IFNα therapy. Furthermore we investigated whether directing IFN to the reservoir of infection in the liver may improve antiviral efficacy by increasing local concentration in target organs and tissues. Our previous results show that the mIFNα2 fused to an ASGPR specific liver targeting antibody, DOM26h-196-61, results in a fusion protein which retains the activity of both fusion partners when measured in vitro. In vivo targeting of the liver by mIFNα2-DOM26h-196-61, hereafter referred to as targeted mIFNα2, was observed in microSPECT imaging studies in mice. In this study we show by pharmacokinetic analysis that antibody mediated liver-targeting results in increased uptake and exposure of targeted mIFNα2 in target tissues, and correspondingly reduced uptake and exposure in systemic circulation, clearance organs and non-target tissues. We also show that cytokine activity and antiviral activity of liver-targeted IFN is observed in vivo, but that, contrary to expectations, liver-targeting of mIFNα2 using ASGPR specific dAbs actually leads to a reduced pharmacodynamic effect in target organs and lower antiviral activity in vivo when compared to non-targeted mIFNα2-dAb fusions. PMID:25689509

  18. Pharmacokinetic Characteristics, Pharmacodynamic Effect and In Vivo Antiviral Efficacy of Liver-Targeted Interferon Alpha

    PubMed Central

    Rycroft, Daniel; Sosabowski, Jane; Coulstock, Edward; Davies, Marie; Morrey, John; Friel, Sarah; Kelly, Fiona; Hamatake, Robert; Ovečka, Milan; Prince, Rob; Goodall, Laura; Sepp, Armin; Walker, Adam

    2015-01-01

    Interferon alpha (IFNα) is used for the treatment of hepatitis B virus infection, and whilst efficacious, it is associated with multiple adverse events caused by systemic exposure to interferon. We therefore hypothesise that targeting IFN directly to the intended site of action in the liver would reduce exposure in blood and peripheral tissue and hence improve the safety and tolerability of IFNα therapy. Furthermore we investigated whether directing IFN to the reservoir of infection in the liver may improve antiviral efficacy by increasing local concentration in target organs and tissues. Our previous results show that the mIFNα2 fused to an ASGPR specific liver targeting antibody, DOM26h-196-61, results in a fusion protein which retains the activity of both fusion partners when measured in vitro. In vivo targeting of the liver by mIFNα2-DOM26h-196-61, hereafter referred to as targeted mIFNα2, was observed in microSPECT imaging studies in mice. In this study we show by pharmacokinetic analysis that antibody mediated liver-targeting results in increased uptake and exposure of targeted mIFNα2 in target tissues, and correspondingly reduced uptake and exposure in systemic circulation, clearance organs and non-target tissues. We also show that cytokine activity and antiviral activity of liver-targeted IFN is observed in vivo, but that, contrary to expectations, liver-targeting of mIFNα2 using ASGPR specific dAbs actually leads to a reduced pharmacodynamic effect in target organs and lower antiviral activity in vivo when compared to non-targeted mIFNα2-dAb fusions. PMID:25689509

  19. Selective production of interferon-alpha subtypes by cultured peripheral blood mononuclear cells and lymphoblastoid cell lines.

    PubMed Central

    Greenway, A L; Overall, M L; Sattayasai, N; Rowley, M J; Hertzog, P J; McMullen, G L; Cheetham, B F; Marzuki, S

    1992-01-01

    The biological significance of the existence of multiple interferon-alpha (IFN-alpha) subtypes is unknown but may represent a finely tuned mechanism whereby different subtypes are produced in response to different stimuli. To investigate the expression of individual IFN-alpha subtypes, polyclonal antipeptide antisera designed to react with all IFN-alpha subtypes, or with a particular subtype, IFN-alpha 2 or IFN-alpha 4, have been produced. In this study we demonstrate the utility of these antisera for the detection, using indirect immunofluorescence staining, of intracellular IFN-alpha produced by human peripheral blood mononuclear cells (PBMC) and lymphoblastoid cells. Secreted IFN-alpha was also investigated by bioassay and a sandwich radioimmunoassay (RIA), using two monoclonal antibodies (mAb) and specific for IFN-alpha 4. The PBMC were shown to produce IFN reactive with all three polyclonal antisera, after stimulation with Sendai virus. The lymphoblastoid cells also produced IFN, including IFN-alpha 2, but IFN-alpha 4 was not detected either intracellularly, by immunofluorescence, or in the medium, by sandwich RIA. The immunofluorescence studies also demonstrate that in the absence of viral stimulation IFN-alpha is found in the cytoplasm of PBMC and lymphoblastoid cells but not secreted in detectable levels. The finding that two lymphoblastoid cell lines do not produce the subtype IFN-alpha 4 raises important questions as to whether other cell lines and cell types produce IFN-alpha subtypes selectively, and whether individual IFN-alpha subtypes have different roles in human physiology and pathology. Images Figure 1 Figure 2 Figure 3 PMID:1537595

  20. Interferon-gamma and tumor necrosis factor-alpha exert their antirickettsial effect via induction of synthesis of nitric oxide.

    PubMed Central

    Feng, H. M.; Walker, D. H.

    1993-01-01

    How the host defenses control rickettsiae in the cytosol of nonphagocytic host cells, where they are not exposed to antibodies or phagocytes, has posed a difficult question. Rickettsia conorii infection of a mouse fibroblast cell line was inhibited in a dose-dependent manner by nitrogen oxide synthesized by eukaryotic host cells stimulated by interferon-gamma or tumor necrosis factor-alpha. L-arginine was the source of the nitric oxide as demonstrated by competitive inhibition by NG-monomethyl-L-arginine. Nitric oxide synthesis required host cell protein synthesis and had an approximately 48-hour lag phase following cytokine stimulation. At low doses of interferon-gamma and tumor necrosis factor-alpha, which had no detectable response as single agents, dramatic synergistic nitric oxide synthesis and antirickettsial effects were observed. PMID:8213997

  1. [A case of subacute sclerosing panencephalitis treated with intraventricular interferon--the side effects of interferon-alpha to the central nervous system].

    PubMed

    Hayashi, Y; Taku, K; Nitta, E; Nakajima, T; Fukuhara, N

    1994-01-01

    A patient with subacute sclerosing panencephalitis (SSPE) was treated with an intraventricular alpha interferon (IFN-alpha) through an Ommaya reservoir. A 17-year-old boy, who had a history of measles exposure at age 1, showed forgetfulness, difficulties in calculation, reading and writing. Two months later he developed generalized convulsions and myoclonic spasms. He was admitted to the National Saigata Hospital in May 20, 1992. On admission, anti-measles antibody titer in the CSF was 1:16 by complement-fixation method. His EEG revealed a periodic synchronous discharge. Therefore, the diagnosis of SSPE was confirmed. An Ommaya reservoir was implanted on July 7, 1992, and an intraventricular administration of INF-alpha was begun after two weeks. The dose of INF-alpha was gradually increased from 1.0 x 10(6) IU/m2 to 2.0 x 10(6) IU/m2 twice a week. Fever, vomiting and anorexia were developed when the INF-alpha injection was first started. When he received a total dose of 8.0 x 10(6) IU, he became bed ridden for remarkable lethargy. The lethargy was continued for about 10 days despite the therapy was interrupted, and then he gradually became alert. The frequency of myoclonus became more frequent and mentality got worse, so the treatment with INF-alpha was tried again in decreasing the dose to 1.0 x 10(6) IU/m2 twice a week. However, be became drowsy again after he received a total of 7.5 x 10(6) IU. With intramuscular or intravenous administrations of the high doses of INF-alpha (> or = 1.0 x 10(7) IU), significant neurological abnormalities were reported to occur.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8156718

  2. Interferon alpha and rapamycin inhibit the growth of carcinoid and medullary thyroid cancer in vitro.

    PubMed

    Motylewska, Ewelina; Lawnicka, Hanna; Kowalewicz-Kulbat, Magdalena; Sicinska, Paulina; Niedziela, Agata; Melen-Mucha, Gabriela; Stepien, Henryk

    2014-08-01

    Neuroendocrine tumors (NETs) are highly vascularized neoplasms characterized by rising incidence. Moreover, the neuroendocrine cells were shown to express vascular endothelial growth factor (VEGF) and VEGF receptors. Therefore, angiomodulators could be potentially a new group of drugs enhancing still unsatisfactory effectiveness of NET therapy. The aim of this study was to assess the direct influence of angiomodulators: VEGF and five endogenous and exogenous antiangiogenic compounds (endostatin, interferon alpha [IFNα], rapamycin, JV1-36, semaxinib [SU5416]) on the growth of two NET cell lines: lung carcinoid H727 cell line and medullary thyroid cancer TT cell line in vitro. IFNα and rapamycin induced the inhibitory effect on H727 and TT cell viability and proliferation, increasing apoptosis and arresting the cell cycle. Also semaxinib (10(-5)M) inhibited proliferation of both cell lines. VEGF and endostatin did not influence the growth of H727 and TT cells. The inhibitory effect of IFNα, rapamycin and semaxinib on carcinoid and medullary thyroid cancer growth was revealed in our in vitro study, although some other antiangiogenic agents did not directly influence H727 and TT cell growth. Thus, IFNα and mTOR inhibitors as multidirectionally acting drugs with antiangiogenic effect could be potentially efficient in treatment of neuroendocrine tumors and are worth further studies. PMID:24948064

  3. Neuropsychiatric Side-Effects of Interferon-Alpha Treatment: Pathophysiology and Therapeutic Options

    PubMed Central

    ZAHIU, Carmen Denise Mihaela; RIMBAS, Mihai

    2014-01-01

    Interferon alpha (IFN-α) is the approved standard of care for chronic hepatitis C and B. Unfortunately, it has neuropsychiatric side-effects that have a major impact upon the quality of life and the drug adherence. The mechanism of IFN-α-induced behavioral changes is complex, involving interactions between the immune system, the endocrine system, the monoaminergic systems and the opioid receptors. Recent studies support the neurodegeneration hypothesis as a possible mechanism of IFN-α-induced depressive behavior. Although a meta-analysis showed that antidepressant pretreatment effectively reduces the incidence and severity of depressive symptoms, irrespective of pre-existing psychiatric disorders, it is not approved for prophylactic use. The "on demand" treatment strategy is justified as the majority of patients have only mild depressive symptoms. Patients with risk factors for depression undergoing IFN-α therapy need to be regularly screened and followed-up by a psychiatric specialist. Further studies should be conducted to show which therapy is the most appropriate to reduce the neuropsychiatric symptoms that are related to the use of IFN-α and to investigate the clinical significance of IFN-α-induced neurodegeneration. PMID:25705266

  4. Liver-Specific Alpha 2 Interferon Gene Expression Results in Protection from Induced Hepatitis

    PubMed Central

    Aurisicchio, Luigi; Delmastro, Paola; Salucci, Valentina; Paz, Odalys Gonzalez; Rovere, Patrizia; Ciliberto, Gennaro; La Monica, Nicola; Palombo, Fabio

    2000-01-01

    The current therapy for hepatitis B and C is based on systemic administration of recombinant human alpha interferon (r-hIFN-α). However, systemic delivery of r-hIFN-α is associated with severe side effects, but more importantly, it is effective in only a small percentage of patients. In an effort to maximize IFN-α antiviral efficacy, we have explored the therapeutic potential of murine IFN-α2 (mIFNα2) selectively expressed in the liver. To this end, we have developed a helper-dependent adenovirus vector (HD) containing the mIFN-α2 gene under the control of the liver-specific transthyretin promoter (HD-IFN). Comparison with a first-generation adenovirus carrying the same mIFN-α2 expression cassette indicates that at certain HD-IFN doses, induction of antiviral genes can be achieved in the absence of detectable circulating mIFN-α2. Challenge of injected mice with mouse hepatitis virus type 3 showed that HD-IFN provides high liver protection. Moreover, liver protection was also observed in acute nonviral liver inflammation hepatitis induced by concanavalin A at 1 month postinfection. These results hold promise for the development of a gene therapy treatment for chronic viral hepatitis based on liver-restricted expression of IFN-α2. PMID:10775620

  5. Lack of Reproductive Toxicity in Adult Male Rats Exposed to Interferon-Alpha.

    PubMed

    Rosa, Josiane de Lima; Cavariani, Marilia Martins; Borges, Cibele dos Santos; Leite, Gabriel Adan Araújo; Anselmo-Franci, Janete Aparecida; Kempinas, Wilma De Grava

    2015-01-01

    Interferon-alpha (IFN- α), a type I IFN, is a protein with antiviral, antiproliferative, and immunoregulatory activities, widely used in the treatment of several types of cancers as well as hepatitis B and C. Decrease of libido and erectile dysfunction are commonly reported by male patients during treatment of chronic hepatitis C with IFN- α . However, IFN therapy-associated underlying factors attributed to sexual dysfunction are still not well defined. Currently, there are few studies investigating the effects of IFN on male reproductive system functions. Given that, the aim of the present investigation was to examine effects of subchronic exposure to IFN- α (5 × 10(4) U/kg and 10 × 10(4) U/kg, 30 d) on serum hormones, sperm parameters, fertility, and testicular and epididymal hystopathology and morphometry in adult male Wistar rats. None of the evaluated parameters was markedly altered by IFN- α . Thus, our results suggest that exposure to IFN- α , in this experimental design, did not adversely affect sperm quality and fertile capacity of male rats. PMID:26488366

  6. A case of chronic neutrophilic leukemia successfully treated with pegylated interferon alpha-2a.

    PubMed

    Yassin, Mohamed A; Kohla, Samah; Al-Sabbagh, Ahmed; Soliman, Ashraf T; Yousif, Anil; Moustafa, Afraa; Battah, Afaf Al; Nashwan, Abdulqadir; Al-Dewik, Nader

    2015-01-01

    Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) that represents a diagnostic dilemma for both clinicians and pathologists. Because this disease entity is very rare, and because its diagnosis is by exclusion, it is important for clinical hematologists and hematopathologists to be familiar with CNL when approaching patients with MPNs and persistent neutrophilia. A woman in her 40s who was incidentally found to have leukocytosis was referred to the hematology service at the National Center for Cancer Care and Research for evaluation. Complete blood count revealed hyperleukocytosis with predominant neutrophilia. Peripheral blood and flow cytometry did not show any evidence of lymphoproliferative disorder or myeloblasts. Bone marrow aspirate and biopsy revealed a hypercellular marrow with myeloid hyperplasia. Cytogenetics revealed normal karyotype. Tests for both Janus kinase mutation JAK2 V617F and rearrangement of the genes BCR-ABL1, platelet-derived growth factor receptor-α (PDGFRα), PDGFRβ, and fibroblast growth factor receptor-1 (FGFR1) were negative. Thereafter, the diagnosis of CNL was reached. She was treated with pegylated interferon alpha-2a, with very good hematological response. To the best of our knowledge, this is the first case of CNL reported among the Arab population. PMID:25983565

  7. A Case of Chronic Neutrophilic Leukemia Successfully Treated with Pegylated Interferon Alpha-2a

    PubMed Central

    Yassin, Mohamed A; Kohla, Samah; Al-Sabbagh, Ahmed; Soliman, Ashraf T; Yousif, Anil; Moustafa, Afraa; Battah, Afaf Al; Nashwan, Abdulqadir; Al-Dewik, Nader

    2015-01-01

    Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN) that represents a diagnostic dilemma for both clinicians and pathologists. Because this disease entity is very rare, and because its diagnosis is by exclusion, it is important for clinical hematologists and hematopathologists to be familiar with CNL when approaching patients with MPNs and persistent neutrophilia. A woman in her 40s who was incidentally found to have leukocytosis was referred to the hematology service at the National Center for Cancer Care and Research for evaluation. Complete blood count revealed hyperleukocytosis with predominant neutrophilia. Peripheral blood and flow cytometry did not show any evidence of lymphoproliferative disorder or myeloblasts. Bone marrow aspirate and biopsy revealed a hypercellular marrow with myeloid hyperplasia. Cytogenetics revealed normal karyotype. Tests for both Janus kinase mutation JAK2 V617F and rearrangement of the genes BCR-ABL1, platelet-derived growth factor receptor-α (PDGFRα), PDGFRβ, and fibroblast growth factor receptor-1 (FGFR1) were negative. Thereafter, the diagnosis of CNL was reached. She was treated with pegylated interferon alpha-2a, with very good hematological response. To the best of our knowledge, this is the first case of CNL reported among the Arab population. PMID:25983565

  8. Interferon alpha antagonizes STAT3 and SOCS3 signaling triggered by hepatitis C virus.

    PubMed

    Zhao, Lan-Juan; He, Sheng-Fei; Wang, Wen; Ren, Hao; Qi, Zhong-Tian

    2016-04-01

    We aimed to investigate regulation of signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling 3 (SOCS3) by interferon alpha (IFN-α) and to analyze the relationship between STAT3 and SOCS3 during hepatitis C virus (HCV) infection. Changes in STAT3 and SOCS3 were analyzed at both mRNA and protein levels in human hepatoma cells infected with HCV (J6/JFH1). At 72h of HCV infection, STAT3 expression was decreased with sustained phosphorylation, and IFN-α increased such decrease and phosphorylation. HCV increased SOCS3 expression, while IFN-α impaired such increase, indicating different regulation of STAT3 and SOCS3 by IFN-α. IFN-α-induced expression and phosphorylation of upstream kinases of the JAK/STAT pathway, Tyk2 and Jak1, were suppressed by HCV. Moreover, knockdown of STAT3 by RNA interference led to decreases in HCV RNA replication and viral protein expression, without affecting either the expression of Tyk2 and Jak1 or the SOCS3 induction in response to IFN-α. These results show that IFN-α antagonizes STAT3 and SOCS3 signaling triggered by HCV and that STAT3 regulation correlates inversely with SOCS3 induction by IFN-α, which may be important in better understanding the complex interplay between IFN-α and signal molecules during HCV infection. PMID:26945996

  9. In-vitro antiviral efficacy of ribavirin and interferon-alpha against canine distemper virus

    PubMed Central

    Carvalho, Otávio V.; Saraiva, Giuliana L.; Ferreira, Caroline G.T.; Felix, Daniele M.; Fietto, Juliana L.R.; Bressan, Gustavo C.; Almeida, Márcia R.; Silva Júnior, Abelardo

    2014-01-01

    Canine distemper is a highly contagious disease with high incidence and lethality in the canine population. The objective of this study was to evaluate the efficacy of antiviral action with ribavirin (RBV), interferon-alpha (IFNα), and combinations of RBV and IFNα against canine distemper virus (CDV). Vero cells inoculated with CDV were treated with RBV, IFNα, and combinations of these drugs. The efficacy to inhibit viral replication was evaluated by adding the compounds at different times to determine which step of the viral replicative process was affected. Both drugs were effective against CDV in vitro. The IFNα was the most active compound, with an average IC50 (50% inhibitory concentration) value lower than the IC50 of the RBV. Ribavirin (RBV) was more selective than IFNα, however, and neither drug showed extracellular antiviral activity. The combination of RBV and IFNα exhibited antiviral activity for the intra- and extracellular stages of the replicative cycle of CDV, although the intracellular viral inhibition was higher. Both RBV and IFNα showed high antiviral efficacy against CDV, and furthermore, RBV + IFNα combinations have shown greater interference range in viral infectivity. These compounds could potentially be used to treat clinical disease associated with CDV infection. PMID:25355997

  10. Combined therapy with danazol, pegilated interferon, and ribavirin improves thrombocytopenia and liver injury in rats with fibrosis.

    PubMed

    Alvarez, Guillermo Cabrera; Madrid-Marina, Vicente; Jimenez-Mendez, Ricardo; Buitimea, Angel Leon; Román, Margarita Bahena; Cortez-Gomez, Rudyard; Esparza, Jorge Reyes; Rodríguez-Fragoso, Lourdes

    2007-01-01

    The aim of this study was to investigate the effects of combinations of pegilated-interferon (PEG-IFN), ribavirin, and danazol on thrombocytopenia and liver injury in rats with fibrosis. Male adult Wistar rats were treated with either mineral oil, danazol (0.83 mg/kg per day), PEG-interferon alpha-2a (PEG-IFN, 0.3 microg/ week) + ribavirin (12 mg/kg per day), PEG-IFN + ribavirin + danazol, CCl(4) (4 g/kg for eight weeks), CCl(4) + PEG-IFN + ribavirin, or CCl(4) + PEG-IFN + ribavirin+ danazol. The following assays were conducted: hematology, clinical chemistry, liver function, liver fibrosis, lymphocyte cytokine mRNA expression, and bone-marrow DNA content. Platelet counts were low in sham-treated animals and animals treated with PEG- IFN + ribavirin (30% and 25% respectively; P < 0.05). PEG-IFN + ribavirin + danazol reduced platelet counts of fibrotic animals by only 9% (P < 0.05). PEG- IFN + ribavirin reduced hepatic collagen content by 50%, whereas danazol + PEG-IFN + ribavirin reduced hepatic collagen content by 60% (P < 0.05). PEG-IFN + ribavirin reduced the total bilirubin concentration by 27%, alanine amino transferase (ALT) activity by 75% and gamma-glutamyl transpeptidase (gamma-GTP) activity by 74% (P < 0.05). In contrast, danazol + PEG-IFN + ribavirin reduced total bilirubin levels by 61%, alkaline phosphatase activity by 45%, ALT activity by 76%, and gamma-GTP activity by 74% (P < 0.05). The only treatment that increased interleukin 10 (IL-10) mRNA in fibrotic rats was PEG-IFN + ribavirin. However, danazol + PEG-IFN + ribavirin reduced the expression of IL-6, IL-10, tumor necrosis factor alpha and transforming growth factor ss. Bone-marrow DNA content was not altered by any treatment. In conclusion, PEG-IFN + ribavirin + danazol could be a new therapeutic option for patients with liver injury, fibrosis, and thrombocytopenia. PMID:18007553

  11. CD20-targeted tetrameric interferon-alpha, a novel and potent immunocytokine for the therapy of B-cell lymphomas.

    PubMed

    Rossi, Edmund A; Goldenberg, David M; Cardillo, Thomas M; Stein, Rhona; Chang, Chien-Hsing

    2009-10-29

    Interferon-alpha (IFN-alpha) has direct inhibitory effects on some tumors and is a potent stimulator of both the innate and adaptive immune systems. A tumor-targeting antibody-IFN-alpha conjugate (mAb-IFN-alpha) could kill by direct actions of the monoclonal antibody (mAb) and IFN-alpha on tumor cells and also potentiate a tumor-directed immune response. The modular Dock-and-Lock method (DNL) was used to generate 20-2b, the first immunocytokine having 4 cytokine (IFN-alpha2b) groups that are fused to the humanized anti-CD20 mAb, veltuzumab. Additional mAb-IFN-alpha constructs, each retaining potent IFN-alpha2b biologic activity, also were produced by DNL. The 20-2b shows enhanced antibody-dependent cellular cytotoxicity compared with veltuzumab but lacks complement-dependent cytotoxicity. The 20-2b inhibits in vitro proliferation of lymphoma cells and depletes them from whole human blood more potently than the combination of veltuzumab and a nontargeting, irrelevant, mAb-IFN-alpha. The 20-2b demonstrated superior therapeutic efficacy compared with veltuzumab or nontargeting mAb-IFN-alpha in 3 human lymphoma xenograft models, even though mouse immune cells respond poorly to human IFN-alpha2b. Targeting IFN-alpha with an anti-CD20 mAb makes the immunocytokine more potent than either agent alone. These findings suggest that 20-2b merits clinical evaluation as a new candidate antilymphoma therapeutic. PMID:19710501

  12. Interleukin 10 inhibits macrophage microbicidal activity by blocking the endogenous production of tumor necrosis factor alpha required as a costimulatory factor for interferon gamma-induced activation.

    PubMed Central

    Oswald, I P; Wynn, T A; Sher, A; James, S L

    1992-01-01

    Interleukin 10 (IL-10) inhibits interferon gamma-induced macrophage activation for cytotoxicity against larvae of the human parasite Schistosoma mansoni by suppressing production of the toxic effector molecule nitric oxide (NO). In this study, the mechanism of IL-10 action was identified as inhibition of endogenous tumor necrosis factor alpha (TNF-alpha) production by interferon gamma-activated macrophages. TNF-alpha appears to serve as a cofactor for interferon gamma-mediated activation, since both schistosomulum killing and NO production were inhibited by anti-TNF-alpha antibody, whereas TNF-alpha alone was unable to stimulate these macrophage functions. IL-10 blocked TNF-alpha production by interferon gamma-treated macrophages at the levels of both protein and mRNA synthesis. Addition of exogenous TNF-alpha reversed IL-10-mediated suppression of macrophage cytotoxic activity as well as NO production. Likewise, addition of a macrophage-triggering agent (bacterial lipopolysaccharide or muramyl dipeptide), which induced the production of TNF-alpha, also reversed the suppressive effect of IL-10 on cytotoxic function. In contrast to IL-10, two other cytokines, IL-4 and transforming growth factor beta, which also inhibit macrophage activation for schistosomulum killing and NO production, did not substantially suppress endogenous TNF-alpha production. These results, therefore, describe a separate pathway by which macrophage microbicidal function is inhibited by the down-regulatory cytokine IL-10. Images PMID:1528880

  13. Antitumor potential of a synthetic interferon-alpha/PLGF-2 positive charge peptide hybrid molecule in pancreatic cancer cells

    PubMed Central

    Yin, Hongmei; Chen, Naifei; Guo, Rui; Wang, Hong; Li, Wei; Wang, Guanjun; Cui, Jiuwei; Jin, Haofan; Hu, Ji-Fan

    2015-01-01

    Pancreatic cancer is the most aggressive malignant disease, ranking as the fourth leading cause of cancer-related death among men and women in the United States. Interferon alpha (IFNα) has been used to treat pancreatic cancer, but its clinical application has been significantly hindered due to the low antitumor activity. We used a “cDNA in-frame fragment library” screening approach to identify short peptides that potentiate the antitumor activity of interferons. A short positively charged peptide derived from the C-terminus of placental growth factor-2 (PLGF-2) was selected to enhance the activity of IFNα. For this, we constructed a synthetic interferon hybrid molecule (SIFα) by fusing the positively charged PLGF-2 peptide to the C-terminus of the human IFNα. Using human pancreatic cell lines (ASPC and CFPAC1) as a model system, we found that SIFα exhibited a significantly higher activity than did the wild-type IFNα in inhibiting the tumor cell growth. The enhanced activity of the synthetic SIFα was associated with the activation of interferon pathway target genes and the increased binding of cell membrane receptor. This study demonstrates the potential of a synthetic SIFα as a novel antitumor agent. PMID:26584517

  14. Acute Changes in Striatal Microstructure Predict the Development of Interferon-Alpha Induced Fatigue

    PubMed Central

    Dowell, Nicholas G.; Cooper, Ella A.; Tibble, Jeremy; Voon, Valerie; Critchley, Hugo D.; Cercignani, Mara; Harrison, Neil A.

    2016-01-01

    Background Interferon-alpha (IFN-α) is a key mediator of antiviral immune responses used clinically for hepatitis C treatment. Though effective, IFN-α induces marked behavioral changes that, when severe, can appear indistinguishable from major depression. Curiously, fatigue and motivational impairment evolve rapidly, suggesting acute engagement of immune-brain communicatory pathways, yet mood impairments typically emerge later, after weeks of treatment. Whether this reflects prolonged modulation of motivational processes underpinning fatigue or separate neurobiological mechanisms is currently unclear. Methods Here, we used quantitative magnetization transfer (qMT) imaging, an advanced microstructural neuroimaging technique sensitive to effects of inflammation, in a prospective study design to measure acute brain changes to IFN-α and relate these to later development of discrete behavioral changes. Twenty-three patients initiating IFN-α treatment for hepatitis C underwent qMT imaging and blood sampling at baseline and 4 hours after their first IFN-α injection. Comprehensive behavioral and psychological assessments were completed at both scanning sessions and at treatment weeks 4, 8, 12, and 24. Results IFN-α injection stimulated an acute inflammatory cytokine response and evoked fatigue that peaked between 4 and 12 weeks, preceding mood change by 4 weeks. In the brain, IFN-α induced an acute change in striatal microstructure that additionally predicted development of fatigue but not mood symptoms. Conclusions Our findings highlight qMT as an in vivo biomarker of central effects of peripheral inflammation. We demonstrate exquisite sensitivity of the striatum to IFN-α, implicate striatal perturbation in IFN-α-induced fatigue, and dissociate this from mechanisms underlying IFN-α-induced mood symptoms, providing empirical support for distinct neural substrates mediating actions on motivation and mood. PMID:26169252

  15. Minocycline treatment ameliorates interferon-alpha- induced neurogenic defects and depression-like behaviors in mice

    PubMed Central

    Zheng, Lian-Shun; Kaneko, Naoko; Sawamoto, Kazunobu

    2015-01-01

    Interferon-alpha (IFN-α) is a proinflammatory cytokine that is widely used for the treatment of chronic viral hepatitis and malignancy, because of its immune-activating, antiviral, and antiproliferative properties. However, long-term IFN-α treatment frequently causes depression, which limits its clinical utility. The precise molecular and cellular mechanisms of IFN-α-induced depression are not currently understood. Neural stem cells (NSCs) in the hippocampus continuously generate new neurons, and some evidence suggests that decreased neurogenesis plays a role in the neuropathology of depression. We previously reported that IFN-α treatment suppressed hippocampal neurogenesis and induced depression-like behaviors via its receptors in the brain in adult mice. However, it is unclear how systemic IFN-α administration induces IFN-α signaling in the hippocampus. In this study, we analyzed the role of microglia, immune cells in the brain, in mediating the IFN-α-induced neurogenic defects and depressive behaviors. In vitro studies demonstrated that IFN-α treatment induced the secretion of endogenous IFN-α from microglia, which suppressed NSC proliferation. In vivo treatment of adult mice with IFN-α for 5 weeks increased the production of proinflammatory cytokines, including IFN-α, and reduced neurogenesis in the hippocampus. Both effects were prevented by simultaneous treatment with minocycline, an inhibitor of microglial activation. Furthermore, minocycline treatment significantly suppressed IFN-α-induced depressive behaviors in mice. These results suggest that microglial activation plays a critical role in the development of IFN-α-induced depression, and that minocycline is a promising drug for the treatment of IFN-α-induced depression in patients, especially those who are low responders to conventional antidepressant treatments. PMID:25674053

  16. Disturbance of Tumor Necrosis Factor Alpha-Mediated Beta Interferon Signaling in Cervical Carcinoma Cells

    PubMed Central

    Bachmann, Anastasia; Hanke, Brigitte; Zawatzky, Rainer; Soto, Ubaldo; van Riggelen, Jan; zur Hausen, Harald; Rösl, Frank

    2002-01-01

    In the present study we show that malignant human papillomavirus (HPV)-positive cells lost their ability to synthesize endogenous beta interferon (IFN-β) upon tumor necrosis factor alpha (TNF-α) treatment. IFN-β transcription, however, was reinducible in nonmalignant HPV-positive cells, which was confirmed in functional protection assays against encephalomyocarditis virus or vesicular stomatitis virus infections. Addition of neutralizing antibodies against IFN-β blocked the antiviral effect, excluding the possibility that other IFN types were involved. Conversely, both malignant and immortalized cells could be protected against viral cytolysis when either IFN-β, IFN-α, or IFN-γ was added exogenously. This indicates that only the cross talk between TNF-α and the IFN-β pathways, and not IFN-α/β and IFN-γ signaling in general, is perturbed in cervical carcinoma cells. Notably, full virus protection was restricted exclusively to nonmalignant cells, indicating that the antiviral effect correlates with the growth-inhibitory and virus-suppressive properties of TNF-α. The IFN-regulatory factors IRF-1 and p48 (ISGF3γ) emerged as key regulatory molecules in the differential IFN-β response, since their transcription was either absent or only inefficiently enhanced in tumorigenic cells upon treatment with TNF-α. Inducibility of both genes, however, became reestablished in cervical carcinoma cells, which were complemented to nontumorigenicity after somatic cell hybridization. Complementation was paralleled by the entire reconstitution of cytokine-mediated IFN-β expression and the ability of TNF-α to exert an antiviral state. In contrast, under conditions where tumor suppression was not accomplished upon somatic cell hybridization, neither expression of IRF-1, p48, and IFN-β nor antiviral activity could be restored. PMID:11739693

  17. Influence of Interferon-Alpha Combined with Chemo (Radio) Therapy on Immunological Parameters in Pancreatic Adenocarcinoma

    PubMed Central

    Karakhanova, Svetlana; Mosl, Beate; Harig, Sabine; von Ahn, Katharina; Fritz, Jasmin; Schmidt, Jan; Jäger, Dirk; Werner, Jens; Bazhin, Alexandr V.

    2014-01-01

    Prognosis of patients with carcinoma of the exocrine pancreas is particularly poor. A combination of chemotherapy with immunotherapy could be an option for treatment of pancreatic cancer. The aim of this study was to perform an immunomonitoring of 17 patients with pancreatic cancer from the CapRI-2 study, and tumor-bearing mice treated with combination of chemo (radio) therapies with interferon-2α. Low doses of interferon-2α led to a decrease in total leukocyte and an increase in monocyte counts. Furthermore, we observed a positive effect of interferon-2α therapy on the dendritic cells and NK (natural killer) cell activation immediately after the first injection. In addition, we recorded an increased amount of interferon-γ and IL-10 in the serum following the interferon-2α therapy. These data clearly demonstrate that pancreatic carcinoma patients also show an immunomodulatory response to interferon-2α therapy. Analysis of immunosuppressive cells in the Panc02 orthotopic mouse model of pancreatic cancer revealed an accumulation of the myeloid-derived suppressor cells in spleens and tumors of the mice treated with interferon-2α and 5-fluorouracil. The direct effect of the drugs on myeloid-derived suppressor cells was also registered in vitro. These data expose the importance of immunosuppressive mechanisms induced by combined chemo-immunotherapy. PMID:24608924

  18. Influence of interferon-alpha combined with chemo (radio) therapy on immunological parameters in pancreatic adenocarcinoma.

    PubMed

    Karakhanova, Svetlana; Mosl, Beate; Harig, Sabine; von Ahn, Katharina; Fritz, Jasmin; Schmidt, Jan; Jäger, Dirk; Werner, Jens; Bazhin, Alexandr V

    2014-01-01

    Prognosis of patients with carcinoma of the exocrine pancreas is particularly poor. A combination of chemotherapy with immunotherapy could be an option for treatment of pancreatic cancer. The aim of this study was to perform an immunomonitoring of 17 patients with pancreatic cancer from the CapRI-2 study, and tumor-bearing mice treated with combination of chemo (radio) therapies with interferon-2α. Low doses of interferon-2α led to a decrease in total leukocyte and an increase in monocyte counts. Furthermore, we observed a positive effect of interferon-2α therapy on the dendritic cells and NK (natural killer) cell activation immediately after the first injection. In addition, we recorded an increased amount of interferon-γ and IL-10 in the serum following the interferon-2α therapy. These data clearly demonstrate that pancreatic carcinoma patients also show an immunomodulatory response to interferon-2α therapy. Analysis of immunosuppressive cells in the Panc02 orthotopic mouse model of pancreatic cancer revealed an accumulation of the myeloid-derived suppressor cells in spleens and tumors of the mice treated with interferon-2α and 5-fluorouracil. The direct effect of the drugs on myeloid-derived suppressor cells was also registered in vitro. These data expose the importance of immunosuppressive mechanisms induced by combined chemo-immunotherapy. PMID:24608924

  19. The effect of interferon-{alpha} on the expression of cytochrome P450 3A4 in human hepatoma cells

    SciTech Connect

    Flaman, Anathea S.; Gravel, Caroline; Hashem, Anwar M.; Tocchi, Monika; Li Xuguang

    2011-06-01

    Interferon {alpha} (IFN{alpha}) is used to treat malignancies and chronic viral infections. It has been found to decrease the rate of drug metabolism by acting on cytochrome P450 enzymes, but no studies have investigated the consequences of IFN{alpha} treatment on the CYP3A4 isoform, responsible for the metabolism of a majority of drugs. In this study, we have examined the effect of IFN{alpha} on CYP3A4 catalytic activity and expression in human hepatoma cells. We found that IFN{alpha} inhibits CYP3A4 activity and rapidly down-regulates the expression of CYP3A4, independent of de novo protein synthesis. Pharmacologic inhibitors and a dominant-negative mutant expression plasmid were used to dissect the molecular pathway required for CYP3A4 suppression, revealing roles for Jak1 and Stat1 and eliminating the involvement of the p38 mitogen-activated and extracellular regulated kinases. Treatment of hepatoma cells with IFN{alpha} did not affect the nuclear localization or relative abundance of Sp1 and Sp3 transcription factors, suggesting that the suppression of CYP3A4 by IFN{alpha} does not result from inhibitory Sp3 out-competing Sp1. To our knowledge, this is the first report that IFN{alpha} down-regulates CYP3A4 expression largely through the JAK-STAT pathway. Since IFN{alpha} suppresses CYP3A4 expression, caution is warranted when IFN{alpha} is administered in combination with CYP3A4 substrates to avoid the occurrence of adverse drug interactions.

  20. Limited proteolysis of human leukocyte interferon-. cap alpha. 2 and localization of the monoclonal antibody-binding antigenic determinant

    SciTech Connect

    Kostrov, S.V.; Chernovskaya, T.V.; Khodova, O.M.; Borukhov, S.I.; Ryzhavskaya, A.S.; Izotova, L.S.; Strongin, A.Ya.

    1986-05-20

    Large peptide fragments of human leukocyte interferon-..cap alpha..2 (INF-..cap alpha..2) were produced by limited proteolysis with trypsin, pepsin, thermolysin, and Bacillus amyloliquefaciens serine proteinase, and the ability of the fragments to react with murine monoclonal antibodies NK2, directed toward INF-..cap alpha..2, was studied by the immunoblotting technique. The region of the sequence 110-149 is the most sensitive to proteinase attack and evidently is exposed on the surface of the INF-..cap alpha..2 molecule. The INF-..cap alpha..2 fragments 1-139, 1-147, and 1-149 react with antibodies, whereas the fragments 1-109 and 1-112 do not bind NK2 antibodies. A comparison of the primary structure of the families of human leukocyte and murine leukocyte INF in the region of the sequence 110-139 and an analysis of the ability of human INF differing in amino acid sequence to interact with NK2 antibodies suggested that the antigenic determinant that binds monoclonal antibodies NK2 is the sequence Glu/sub 114/-Asp/sub 115/-Ser/sub 116/-He/sub 117/ of the INF-..cap alpha..2 molecule.

  1. Calcineurin inhibitor tacrolimus does not interfere with the suppression of hepatitis C virus infection by interferon-alpha.

    PubMed

    Pan, Qiuwei; Metselaar, Herold J; de Ruiter, Petra; Kwekkeboom, Jaap; Tilanus, Hugo W; Janssen, Harry L A; van der Laan, Luc J W

    2010-04-01

    Immunosuppression considerably affects hepatitis C virus (HCV) recurrence and the outcome of antiviral treatment after liver transplantation. Recent findings have suggested that the calcineurin inhibitor tacrolimus (Tac), unlike cyclosporine A (CsA), interferes with the antiviral activity of interferon-alpha (IFN-alpha) in vitro. The aim of this study was to more extensively investigate the effects of calcineurin inhibitors on IFN-alpha signaling and antiviral activity in subgenomic and infectious HCV models. Treatment with Tac and CsA did not affect Huh7 cell proliferation at doses of 10 to 500 ng/mL; however, it completely inhibited T cell proliferation. In contrast to previous reports, Tac had no effect on IFN-alpha-stimulated reporter gene expression, even at the dose of 5 microg/mL. Furthermore, in Huh7 subgenomic HCV replicon cells, treatment with Tac had no significant effect on the suppression of viral replication by IFN-alpha. In the infectious HCV model, treatment with IFN-alpha effectively inhibited both viral RNA replication and de novo production of virus particles, and neither was attenuated at any concentration of Tac. CsA had no significant effect on IFN-alpha-stimulated reporter gene expression; however, as shown previously, a combination of CsA (at 500 ng/mL and higher) and IFN-alpha resulted in enhanced inhibition of viral replication in both the subgenomic and infectious HCV models. In conclusion, our study shows no evidence that Tac or CsA interferes with IFN-alpha-mediated inhibition of HCV replication and virion production in vitro. Therefore, no further mechanistic arguments have been found to break the clinical controversy about the choice of calcineurin inhibitors during posttransplantation antiviral therapy. PMID:20373462

  2. Dose-response studies of interferon-alpha 2b on liver fibrosis and cholestasis induced by biliary obstruction in rats.

    PubMed

    Muriel, P; Castro, V

    1997-04-01

    Interferons have been utilized widely in chronic liver diseases for their antiviral properties. In addition, there is evidence for their antifibrogenic actions. In this work we studied effects of various doses of interferon-alpha 2b on experimental liver fibrosis and cholestasis induced in the rat by biliary obstruction. Collagen was measured as hepatic hydroxyproline content. Cholestasis was determined by serum alkaline phosphatase and gamma-glutamyltranspeptidase activities and by bilirubin content. Glycogen was measured in the liver. Interestingly, the best effects (antifibrotic and anticholestatic) were observed in the group receiving the lowest dose of interferon. These results suggest that interferon-alpha 2b may be used at low doses, thereby decreasing side effects and costs. PMID:9211563

  3. Interferon-alpha 2b increases fibrolysis in fibrotic livers from bile duct ligated rats: possible participation of the plasminogen activator.

    PubMed

    Rodríguez-Fragoso, L; González, M P; Muriel, P

    1995-12-01

    Interferons are known to prevent liver collagen by an antifibrogenic mechanism that involves mRNA procollagen regulation. The aim of the present work was to determine whether interferon could also decrease collagen by increasing its degradation. Fibrosis was induced in male Wistar rats by double ligation and section of the common bile duct. Interferon-alpha 2b (100,000 IU/rat s.c.) was administered to bile duct ligated rats daily after surgery for 4 weeks. Interferon increased the capacity of the liver to degrade type I and III collagens and matrigel. In addition, the plasminogen activator activity also increased. Since plasminogens are thought to be key participants in the balance of proteolytic activities that regulate extracellular matrix degradation, their elevation may also provide another antifibrotic (proteolytic) mechanism of action of interferon. PMID:8966190

  4. Fabrication of polymer-platinum(II) complex nanomicelle from mPEG-g-alpha,beta-poly [(N-amino acidyl)-DL-aspartamide] and cis-dichlorodiammine platinum(II) and its cytotoxicity.

    PubMed

    Wang, Chengyun; Gong, Yanbao; Fan, Naiqian; Liu, Shunying; Luo, Shufang; Yu, Jiahui; Huang, Jin

    2009-04-01

    The aim of research is to develop and optimize delivery system for cis-dichlorodiammine platinum(II) (CDDP) based on polymer-metal complex nanomicelles with controllable particle size in order to achieve the passive tumor targeting. In particular, graft copolymers, mPEG-g-alpha,beta-poly [(N-amino acidyl)-DL-aspartamide] (mPEG-g-PAAsp) were synthesized by the ring-opening reaction of polysuccinimide with mPEG-NH(2) (M(w): 2000 and 5000 Da), and then with l-aspartic acid and l-glutamic acid, respectively. mPEG-g-PAAsp-CDDP complex nanomicelles were fabricated from mPEG-g-PAAsp and CDDP. The formation of mPEG-g-PAAsp-CDDP nanomicelles was confirmed by fluorescence spectrophotoscopy, electrical conductivity and particle size measurements. It was found that all the nanomicelles showed spherical shapes with clear core-shell structures and narrow size distributions. Their sizes ranged from 80 to 160 nm, suggesting of their passive targeting potential to tumor tissue. With the increase of the molecular weight of mPEG, the sizes of mPEG-g-PAAsp-CDDP micelles showed a tendency to increase. mPEG-g-PAAsp-CDDP nanomicelles showed linear gradual drug release profiles in 40 h, suggestion of their sustained drug release behaviors. Compared with CDDP, mPEG-g-PAAsp-CDDP micelles showed essential decreased cytotoxicity to Bel-7402 cell line. PMID:19150231

  5. [Antiviral activity of extracts of transgenic cichory and lettuce plants with the human interferon alpha-2b gene].

    PubMed

    Matveeva, N A; Kudriavets, Iu I; Likhova, A A; Shakhovskiĭ, A M; Bezdenezhnykh, N A; Kvasko, E Iu

    2012-01-01

    Biological activity of protein extracts from transgenic plants of chicory Cichorium intybus L. and lettuce Lactuca sativa L. with human interferon alpha2b gene was investigated against vesicular stomatitis virus. It was shown that the extracts from the hairy roots of chicory and lettuce transformed by A. rhizogenes possess the antiviral activity 1620...5400 IU/g weight, and the extracts from leaves of the plants transformed by A. tumefaciens--till 9375 IU/g weight. Dependence of plant extract biological activity on the transformation vector was shown. PMID:23342646

  6. VEGF Secretion is Inhibited by Interferon-Alpha in Several Melanoma Cell Lines

    PubMed Central

    Raig, Ene T.; Jones, Natalie B.; Varker, Kimberly A.; Benniger, Kristen; Go, Michael R.; Biber, Jennifer L.; Lesinski, Gregory B.

    2008-01-01

    Interferon-alpha (IFN-α) is employed in the treatment of malignant melanoma; however, it mediates regression of disease in only 10–15% of patients. Currently, its mechanism of action is uncharacterized. Low-dose IFN-α exerts anti-angiogenic effects when used in the treatment of life-threatening hemangiomas of infancy, suggesting anti-angiogenesis as a mechanism of action. IFN-α may exert its anti-tumor effect in the setting of advanced malignancy by inhibiting the secretion of vascular endothelial growth factor (VEGF), a pro-angiogenic substance. We hypothesized that IFN-α would decrease the release of VEGF by melanoma tumors. We studied the effect of IFN-α on VEGF production in nine human melanoma cell lines. We also examined VEGF levels in 49 patients with advanced malignancies who received low-dose IFN-α and interleukin-12 (IL-12) on an NCI-sponsored phase I trial. Human melanoma cell lines produced varying amounts of VEGF in vitro (60–1500 pg/mL at 48 h). Certain melanoma cell lines such as 18105 MEL secreted low levels of VEGF (152 pg/mL) after 48 h of culture, whereas other lines secreted very high levels (FO-1 3,802 pg/mL). Treatment of melanoma cells with IFN-α (2000 U/mL) decreased VEGF secretion by 40–60% in VEGF-high cell lines; however, this effect was not demonstrated in VEGF-low cell lines. In cancer patients, pretreatment VEGF plasma levels varied from 471 to 4200 pg/mL. A decrease in VEGF plasma levels after treatment directly correlated with the number of treatment cycles administered (Pearson correlation, p = 0.04). In summary, IFN-α inhibits VEGF secretion by melanoma cell lines in vitro and may have similar actions in malignancies that respond to IFN-α treatment. PMID:18771339

  7. Leishmania major: differential resistance to infection in C57BL/6 (high interferon-alpha/beta) and congenic B6.C-H-28c (low interferon-alpha/beta) mice.

    PubMed

    Shankar, A H; Morin, P; Titus, R G

    1996-11-01

    In murine cutaneous leishmaniasis caused by Leishmania major (Lm), resistance often associates with the outgrowth of Lm-specific Th1 cells. Parasites are eliminated by Th1-mediated activation of infected macrophages (M phi) which destroy Lm by producing toxic nitrogen and oxygen radicals. The cytokine IFN-alpha activates microbicidal functions of M phis and facilitates outgrowth of Th1 cells. Therefore, we compared the course of infection with Lm in resistant C57BL/6 mice, bearing the If-1h high expression allele for IFN-alpha/beta, with the congenic B6.C-H-28c mouse, bearing the If-1I low expression allele from the Lm-susceptible BALB/c strain. We observed that B6.C-H-28c animals developed up to 70% larger footpad lesions and harbored up to 1000-fold more parasites than C57BL/6 mice. Furthermore, peak Lm-specific IFN-gamma production in the B6.C-H-28c animals was lower and delayed by approximately 2 weeks, whereas IL-4 production was higher and persisted approximately 2 weeks longer. Since these results suggested that IFN-alpha/beta plays a protective role in mice infected with Lm, we determined whether infusing B6.C-H-28c mice with IFN-alpha would influence the course of infection with Lm. Unfortunately, the mice developed severe peritoneal hemorrhaging in response to injection with IFN-alpha. Therefore, we examined the ability of IFN-alpha to activate M phis to destroy Lm in vitro. We observed that rIFN-alpha could synergize with subactivating doses of LPS to activate both C57BL/6 and BALB/c peritoneal M phis to produce NO and to kill intracellular Lm. Taken as a whole, these results suggest that type I interferons may play a protective role in cutaneous leishmaniasis. PMID:8932763

  8. Characteristics of alpha/beta interferon induction after infection of murine fibroblasts with wild-type and mutant alphaviruses

    SciTech Connect

    Burke, Crystal W.; Gardner, Christina L.; Steffan, Joshua J.; Ryman, Kate D.; Klimstra, William B.

    2009-12-05

    We examined the characteristics of interferon alpha/beta (IFN-alpha/beta) induction after alphavirus or control Sendai virus (SeV) infection of murine fibroblasts (MEFs). As expected, SeV infection of wild-type (wt) MEFs resulted in strong dimerization of IRF3 and the production of high levels of IFN-alpha/beta. In contrast, infection of MEFs with multiple alphaviruses failed to elicit detectable IFN-alpha/beta. In more detailed studies, Sindbis virus (SINV) infection caused dimerization and nuclear migration of IRF3, but minimal IFN-beta promoter activity, although surprisingly, the infected cells were competent for IFN production by other stimuli early after infection. A SINV mutant defective in host macromolecular synthesis shutoff induced IFN-alpha/beta in the MEF cultures dependent upon the activities of the TBK1 IRF3 activating kinase and host pattern recognition receptors (PRRs) PKR and MDA5 but not RIG-I. These results suggest that wild-type alphaviruses antagonize IFN induction after IRF3 activation but also may avoid detection by host PRRs early after infection.

  9. Assessment of the effects of pH, formulation and deformulation on the conformation of interferon alpha-2 by NMR.

    PubMed

    Panjwani, Naim; Hodgson, Derek J; Sauvé, Simon; Aubin, Yves

    2010-08-01

    This article reports the results of our investigation of the effects of pH and various formulations on the conformation of interferon (IFN) alpha-2a and IFN alpha-2b using the NMR fingerprinting assay. Samples of (15)N-IFN alpha-2 were produced and their activity was inferred by comparing their NMR spectra with those recorded for the corresponding European Directorate for the Quality of Medicines (EDQM) reference standards. The proteins were then mixed with appropriate excipients to reproduce formulations used in innovator products of Roferon-A and Intron-A and deformulated via cation-exchange chromatography. The conformation of IFN alpha-2 was monitored by two-dimensional (2D)-NMR spectroscopy at various pHs, after formulation and deformulation procedures. Our results show that the process does not alter the conformation of IFN alpha-2 and that the optimal pH for deformulation is 4.0 +/- 0.5. Variation in pH below 3.0 causes the protein to unfold, whereas above pH 4.5, the three-dimensional (3D) fold is maintained, but the NMR spectra indicate a propensity to oligomerize. This behaviour is reversible upon readjusting the pH to 3.5-4.5. Here, we demonstrate the applicability of NMR to assess the structure of protein therapeutics. The proposed method can assist in validating analytical methods that require deformulation of IFN-based products. PMID:20186942

  10. Two Interferons Alpha Influence Each Other During Their Interaction With the Extracellular Domain of Human Type I Interferon Receptor Subunit 2

    PubMed Central

    Schmeisser, Hana; Gorshkova, Inna; Brown, Patrick H.; Kontsek, Peter; Schuck, Peter; Zoon, Kathryn C.

    2008-01-01

    The interaction between two human interferons alpha (IFN-αs) and the extracellular (EC) domain of human type I IFN receptor subunit 2 (IFNAR2) was analyzed. Previous experiments using Daudi cells showed that IFN-α21b and some IFN-α hybrids (made from IFN-α2c and 21b) competed poorly for the IFN-α2b binding site. This study examined the causes of the poor competition between these IFN-αs. IFN-α2c and the IFN hybrid CM3 {IFN-α21b(1-75)(81-95)/IFN-α2c(76-80)(96-166), Y86K} were selected for this study based on their cell binding and biological properties. Competitive binding ELISA, native electrophoresis followed by Western blot, electrospray ionization mass spectrometry (ESI-MS), surface plasmon resonance biosensor (SPR) analysis, as well as neutralization of antiproliferative activities on Daudi cells in the presence of soluble IFNAR2-EC show evidence that each of the described IFN-α subtypes affected the binding of the other IFN-α to IFNAR2-EC by affecting the stability of the complex, i.e. dissociation of the complex. Moreover, native electrophoresis with different IFNAR2-EC mutants showed that IFN-α2c and CM3 utilize different amino acids in the binding domain of IFNAR2-EC. In addition to that, analytical ultracentrifugation (AUC) revealed differences in the oligomeric state of the two studied interferons. Our results demonstrated that two individual IFN-αs interact differentially with IFNAR2-EC and influence each other during this interaction. This study contributes to the understanding of the mutual interaction between multiple IFN-α subtypes during the competition for binding to the receptor. PMID:18027911

  11. Impact of tumour necrosis factor-alpha and interferon-gamma on tetrahydrobiopterin synthesis in murine fibroblasts and macrophages.

    PubMed Central

    Werner, E R; Werner-Felmayer, G; Fuchs, D; Hausen, A; Reibnegger, G; Yim, J J; Wachter, H

    1991-01-01

    Tumour necrosis factor-alpha causes an up to 30-fold induction of GTP cyclohydrolase I (EC 3.5.4.16) activity in murine dermal fibroblasts in a dose-dependent manner. Owing to the high constitutive activities of 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase (EC 1.1.1.153), this potentiates biosynthesis of tetrahydrobiopterin. Murine macrophages already contain high activities of GTP cyclohydrolase I when unstimulated, and this is further augmented up to 4-fold by tumour necrosis factor-alpha/interferon-gamma. In Western blots an antiserum to murine liver GTP cyclohydrolase I does not stain cell extracts with high enzyme activities, suggesting that the cytokine induced peripheral form of GTP cyclohydrolase I might differ from the liver form. Images Fig. 2. PMID:1764035

  12. Maintenance therapy with interferon-alpha 2b, cyclophosphamide, and prednisone in aggressive diffuse large cell lymphoma.

    PubMed

    Avilés, Agustin; Neri, Natividad; Nambo, M Jesús; Castañeda, Claudia; Talavera, Alejandra; Huerta-Guzmán, Judith; Murillo, Edgar

    2004-04-01

    Maintenance therapy in patients with aggressive malignant lymphoma using biological modifiers remains uncertain. We conducted a controlled clinical trial to evaluate the efficacy and toxicity of interferon-alpha 2b, cyclophosphamide, and prednisone as maintenance therapy in patients with aggressive diffuse large B cell lymphomas in complete remission after aggressive chemotherapy. In an intent-to-treat analysis, 169 patients were eligible for this study; the end points were event-free survival (EFS) and overall survival (OS). With a median follow-up of 49.3 months, no statistical differences were observed and actuarial curves at 5 years showed that EFS was 71% (95% confidence interval [CI], 63-79%) for patients who received maintenance compared to 63% (95% CI, 59-71%) for patients in control group (p = 0.05). No statistical differences were observed in OS between maintenance arm: 84% (95% CI, 78-89%) and control group 83% (95% CI, 77-88%) in control group (p = 0.2). All patients received the maintenance therapy as planned and in time, thus dose intensity was considered 1.0 in all cases. Acute toxicity was mild, and no delay or suspension of treatment was necessary. Late toxicity was not evident until now. We conclude that use of maintenance therapy combining interferon-alpha 2b, cyclophosphamide, and prednisone is not useful in patients with aggressive lymphoma if they had been treated with aggressive combined chemotherapy. PMID:15186737

  13. Modulation of some Peyer's patch leukocyte functions following in vitro exposure to recombinant bovine alpha- and gamma-interferon.

    PubMed

    Nagi, A M; Babiuk, L A

    1988-09-01

    The immunomodulatory effects of recombinant bovine interferon-alpha 1(1) (rBoIFN-alpha 1(1] and -gamma (rBoIFN-gamma) on the response of bovine Peyer's patch leukocytes (PPL) to in vitro mitogenic stimulation were studied. The proliferative response of PPL to concanavalin A (Con A) and pokeweed mitogen (PWM) was significantly inhibited by the addition of 5-1000 units/ml of rBoIFN-alpha 1(1). In contrast, rBoIFN-gamma showed significant enhancement of 3H-Thymidine (3HTdR) incorporation of PPL cultures at concentrations of 5-500 units/ml. Although the results of this study substantiated the previously reported suppressive ability of IFN-alpha 1(1) and the stimulating capacity of IFN-gamma, suppression or enhancement of lymphocyte proliferation was shown to be dependent on the concentration of the polyclonal activator and the length of time the target cells were exposed to IFN. Pre-exposure of target cells to rBoIFN-alpha 1(1) significantly increased its suppressive activity against the PPL response to Con A stimulation. In contrast, pre-exposure of PPL to rBoIFN-gamma did not affect its stimulatory capacity. Prestimulation of target cells with Con A significantly decreased the stimulatory capacity of rBoIFN-gamma and the suppressive activity of rBoIFN-alpha 1(1). These data demonstrate qualitative differences in the effects of rBoIFN-alpha 1(1) compared to those of rBoIFN-gamma on immune cells other than commonly studied circulating leukocytes. PMID:3143664

  14. Chicken interferon alpha pretreatment reduces virus replication of pandemic H1N1 and H5N9 avian influenza viruses in lung cell cultures from different avian species

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Type I interferons, including interferon (IFN)-alpha, represent one of the first lines of innate immune defense against influenza virus infection. Following natural infection of chickens with avian influenza virus (AIV), transcription of IFN-alpha is quickly up regulated along with multiple other im...

  15. Subcutaneous administration of interleukin 2 and interferon-alpha-2b in advanced renal cell carcinoma: a confirmatory study.

    PubMed Central

    Facendola, G.; Locatelli, M. C.; Pizzocaro, G.; Piva, L.; Pegoraro, C.; Pallavicini, E. B.; Signaroldi, A.; Meregalli, M.; Lombardi, F.; Beretta, G. D.

    1995-01-01

    Recent clinical studies have suggested that the combination of subcutaneous recombinant human interleukin 2 (rIL-2) and interferon alpha (rIFN-alpha) is especially promising in advanced renal cell carcinoma. We assessed the safety, activity and toxicity of home therapy with these two agents in 50 patients. Each treatment cycle consisted of a 2 day pulse phase, with 9 x 10(6) IU m-2 of rIL-2 being given subcutaneously every 12 h, followed by a 6 week maintenance phase during which rIL-2 1.8 x 10(6) IU m-2 was administered subcutaneously every 12 h on days 1-5 and rIFN-alpha 2b 5 x 10(6) IU m-2 once a day on days 1, 3 and 5. Objective responses (CR+PR) occurred in 9/50 (18%) patients, six of whom (12%) achieved a complete response. Disease stabilisation was observed in 17 cases (34%) and 18 patients progressed during therapy. In the other six cases, treatment was interrupted early for toxicity or patient refusal. One patient died of myocardial infarction during the second cycle. The overall median survival was 12 months. Home therapy with subcutaneous rIL-2 + rIFN-alpha 2b proved to be active, feasible and moderately toxic, but serious adverse events can sometimes occur. PMID:8519672

  16. Association of alpha interferon production with natural killer cell lysis of U937 cells infected with human immunodeficiency virus.

    PubMed Central

    Rappocciolo, G; Toso, J F; Torpey, D J; Gupta, P; Rinaldo, C R

    1989-01-01

    Mononuclear leukocytes from human immunodeficiency virus (HIV)-seronegative and -seropositive homosexual men lysed HIV-infected U937 cells to a significantly greater degree than uninfected U937 cells. Depletion of cell subsets with monoclonal antibodies and complement indicated that the effector cells were primarily of the CD16+ phenotype. Acid-stable alpha interferon (IFN-alpha) production induced by the HIV-infected cells correlated with, although was not an absolute requisite for, preferential lysis of the infected targets. The activity of these CD16+, natural killer (NK) cells decreased in relation to the duration of HIV infection and the presence of acquired immunodeficiency syndrome. Pretreatment of peripheral blood mononuclear cells from HIV-seronegative subjects, but not HIV-seropositive men, with IFN-alpha or recombinant interleukin-2 enhanced lysis of both uninfected and HIV-infected U937 cells. These results suggest that IFN-alpha-associated, NK-like mechanisms are active in the cytotoxic response against HIV-infected cells and that HIV infection results in an early and progressive depression of such responses. Prospective investigations may be useful in determining the role of this NK cell response in the natural history and pathogenesis of HIV infection and the efficacy of therapeutic modalities. PMID:2913035

  17. Interferon-alpha 2b quantification in inclusion bodies using reversed phase-ultra performance liquid chromatography (RP-UPLC).

    PubMed

    Cueto-Rojas, H F; Pérez, N O; Pérez-Sánchez, G; Ocampo-Juárez, I; Medina-Rivero, E

    2010-04-15

    Interferon-alpha 2b (IFN-alpha 2b) is a recombinant therapeutic cytokine produced as inclusion bodies using a strain of Escherichia coli as expression system. After fermentation and recovery, it is necessary to know the amount of recombinant IFN-alpha 2b, in order to determine the yield and the load for solubilization, and chromatographic protein purification steps. The present work details the validation of a new short run-time and fast sample-preparation method to quantify IFN-alpha 2b in inclusion bodies using Reversed Phase-Ultra Performance Liquid Chromatography (RP-UPLC). The developed method demonstrated an accuracy of 100.28%; the relative standard deviations for method precision, repeatability and inter-day precision tests were found to be 0.57%, 1.54% and 1.83%, respectively. Linearity of the method was assessed in the range of concentrations from 0.05 mg/mL to 0.5 mg/mL, the curve obtained had a determination coefficient (r(2)) of 0.9989. Detection and quantification limits were found to be 0.008 mg/mL and 0.025 mg/mL, respectively. The method also demonstrated robustness for changes in column temperature, and specificity against host proteins and other recombinant protein expressed in the same E. coli strain. PMID:20299292

  18. [Interferon-alpha toxicity and reversible bilateral optical neuropathy: a timely withdrawal of the drug].

    PubMed

    Pérez-Carro, G; Fernández-Alonso, R; González-Diéguez, M L; Rodríguez-García, M; Junceda-Moreno, J

    2014-04-01

    Clinical case A patient with chronic, painless, bilateral loss of vision, after significant intake of interferon (IFNα) and ribavirina due to liver transplant. Ocular fundus is normal. A suspected retrobulbar optic neuropathy is confirmed by a prolongation of the latency of the patient's visual evoked potential. There being no prior record of risk factors and with the patient's systemic analysis giving normal results, the clinical improvement and the electro-physiological tests conducted after the drug was withdrawn point to interferon as negatively affecting the bilateral optic nerve. Discussion Interferon-α is used in the treatment of viral and neoplastic illnesses. Currently the drug is formulated as Interferon alfa pegilado (IFNα-p) in order to reduce toxicity and increase tolerance. The most common secondary effects are flu symptoms, asthenia and weigh loss. Affected ocular tissue is rare and optic neuropathy is also an infrequent complication: retinopathy at the beginning of treatment is, however, more frequent. The most widely accepted hypothesis as to the cause of toxicity is the presence of circulating immune complexes. It is, therefore, essential for ophthalmologists to be aware of the toxicity of this drug in order to be able to withdraw it in good time, thus preventing potentially irreversible sight loss. PMID:24269470

  19. A randomized phase II trial of interleukin 2 and interleukin 2-interferon alpha in advanced renal cancer.

    PubMed Central

    Jayson, G. C.; Middleton, M.; Lee, S. M.; Ashcroft, L.; Thatcher, N.

    1998-01-01

    A randomized phase II trial was performed to compare the efficacy and toxicity of interleukin 2 (IL-2) with an IL-2 and interferon alpha (IFN-alpha) regimen for the treatment of metastatic renal carcinoma. Sixty patients with recurrent renal cell carcinoma (RCC) who had previously undergone a nephrectomy were randomized to receive three cycles of IL-2 or IL-2 with IFN-alpha2b. Eighteen MU of IL-2 were administered subcutaneously on Mondays-Fridays for 3 weeks out of 4. Those patients randomized to receive the combination received the same regimen of IL-2 with 9 MU of IFN-alpha2b subcutaneously on Mondays, Wednesdays and Fridays for 3 weeks out of 4. Thirty patients were randomized to receive each arm. Twenty-nine were evaluable in each arm. Twenty-two patients received three cycles of IL-2 but only 14 patients received three cycles of IL-2/IFN-alpha because of the greater toxicity of the combination. The principal toxicities included nausea, fatigue and fever. There were no complete responses in either arm and only two patients who were treated with IL-2 attained a partial response. Twelve patients in each arm had stable disease and 15 patients in the IL-2 arm and 16 patients in the IL-2/IFN-alpha arm progressed through treatment. There were no significant differences in survival. Ten patients who received IL-2 are alive with a median follow-up of 266 days, whereas six patients who received IL-2/IFN-alpha are alive after a median of 278 days. The median survival from the time of identification of metastatic disease is 444 days in the IL-2 arm and 381 days in the IL-2/IFN-alpha arm. The IL-2/IFN-alpha combination is more toxic than IL-2 alone and this resulted in a reduced number of cycles of treatment. However, the median survival of the two groups was the same, suggesting that further evaluation of the IL-2/IFN-alpha combination should be confined to large prospective randomized clinical trials. PMID:9703284

  20. Topical Delivery of Interferon Alpha by Biphasic Vesicles: Evidence for a Novel Nanopathway across the Stratum Corneum

    SciTech Connect

    Foldvari, M.; Badea, B; Wettig, S; Baboolal, D; Kumar, P; Creagh, A; Haynes, C

    2010-01-01

    Noninvasive delivery of macromolecules across intact skin is challenging but would allow for needle-free administration of many pharmaceuticals. Biphasic vesicles, a novel lipid-based topical delivery system, have been shown to deliver macromolecules into the skin. Investigation of the delivery mechanism of interferon alpha (IFN {alpha}), as a model protein, by biphasic vesicles could improve understanding of molecular transport through the stratum corneum and allow for the design of more effective delivery systems. The interaction of biphasic vesicles with human skin and isolated stratum corneum membrane was investigated by confocal microscopy, differential scanning calorimetry (DSC) and small- and wide-angle X-ray scattering (SAXS and WAXS). Confocal microscopy revealed that biphasic vesicles delivered IFN {alpha} intercellularly, to a depth of 70 {micro}m, well below the stratum corneum and into the viable epidermis. DSC and SAXS/WAXS data suggest that the interaction of biphasic vesicles with SC lipids resulted in the formation of a three-dimensional cubic Pn3m polymorphic phase by the molecular rearrangement of intercellular lipids. This cubic phase could be an intercellular permeation nanopathway that may explain the increased delivery of IFN {alpha} by biphasic vesicles. Liposomes and submicrometer emulsion (the individual building blocks of biphasic vesicles) separately and methylcellulose gel, an alternative topical vehicle, did not induce a cubic phase and delivered low amounts of IFN {alpha} below the stratum corneum. Molecular modeling of the cubic Pn3m phase and lamellar-to-cubic phase transitions provides a plausible mechanism for transport of IFN {alpha}. It is hypothesized that induction of a Pn3m cubic phase in stratum corneum lipids could make dermal and transdermal delivery of other macromolecules also possible.

  1. Adenovirus-Mediated Expression of Interferon-Alpha Delays Viral Replication and Reduces Disease Signs in Swine Challenged with Porcine Reproductive and Respiratory Syndrome Virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In this study, pigs were injected with a nonreplicating human adenovirus type 5 vector expressing porcine interferon-alpha (Ad5-pIFNa) and then challenged with porcine reproductive and respiratory syndrome virus (PRRSV) to determine whether the presence of increased levels of IFNa would decrease vir...

  2. Presence of interferon-alpha delays viral replication and reduces disease signs in pigs challenged with porcine reproductive and respiratory syndrome virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Compared to other viruses that infect the respiratory system, porcine reproductive and respiratory syndrome virus (PRRSV) appears to induce only modest levels of interferon-alpha (IFNA). However, IFNA has been shown to inhibit PRRSV replication in vitro, and indirectly to inhibit replication in viv...

  3. Interferon alpha bioactivity critically depends on Scavenger receptor class B type I function.

    PubMed

    Vasquez, Marcos; Fioravanti, Jessica; Aranda, Fernando; Paredes, Vladimir; Gomar, Celia; Ardaiz, Nuria; Fernandez-Ruiz, Veronica; Méndez, Miriam; Nistal-Villan, Estanislao; Larrea, Esther; Gao, Qinshan; Gonzalez-Aseguinolaza, Gloria; Prieto, Jesus; Berraondo, Pedro

    2016-08-01

    Scavenger receptor class B type I (SR-B1) binds pathogen-associated molecular patterns participating in the regulation of the inflammatory reaction but there is no information regarding potential interactions between SR-B1 and the interferon system. Herein, we report that SR-B1 ligands strongly regulate the transcriptional response to interferon α (IFNα) and enhance its antiviral and antitumor activity. This effect was mediated by the activation of TLR2 and TLR4 as it was annulled by the addition of anti-TLR2 or anti-TLR4 blocking antibodies. In vivo, we maximized the antitumor activity of IFNα co-expressing in the liver a SR-B1 ligand and IFNα by adeno-associated viruses. This gene therapy strategy eradicated liver metastases from colon cancer with reduced toxicity. On the other hand, genetic and pharmacological inhibition of SR-B1 blocks the clathrin-dependent interferon receptor recycling pathway with a concomitant reduction in IFNα signaling and bioactivity. This effect can be applied to enhance cancer immunotherapy with oncolytic viruses. Indeed, SR-B1 antagonists facilitate replication of oncolytic viruses amplifying their tumoricidal potential. In conclusion, SR-B1 agonists behave as IFNα enhancers while SR-B1 inhibitors dampen IFNα activity. These results demonstrate that SR-B1 is a suitable pharmacology target to enhance cancer immunotherapy based on IFNα and oncolytic viruses. PMID:27622065

  4. Interferon alpha bioactivity critically depends on Scavenger receptor class B type I function

    PubMed Central

    Vasquez, Marcos; Fioravanti, Jessica; Aranda, Fernando; Paredes, Vladimir; Gomar, Celia; Ardaiz, Nuria; Fernandez-Ruiz, Veronica; Méndez, Miriam; Nistal-Villan, Estanislao; Larrea, Esther; Gao, Qinshan; Gonzalez-Aseguinolaza, Gloria; Prieto, Jesus; Berraondo, Pedro

    2016-01-01

    ABSTRACT Scavenger receptor class B type I (SR-B1) binds pathogen-associated molecular patterns participating in the regulation of the inflammatory reaction but there is no information regarding potential interactions between SR-B1 and the interferon system. Herein, we report that SR-B1 ligands strongly regulate the transcriptional response to interferon α (IFNα) and enhance its antiviral and antitumor activity. This effect was mediated by the activation of TLR2 and TLR4 as it was annulled by the addition of anti-TLR2 or anti-TLR4 blocking antibodies. In vivo, we maximized the antitumor activity of IFNα co-expressing in the liver a SR-B1 ligand and IFNα by adeno-associated viruses. This gene therapy strategy eradicated liver metastases from colon cancer with reduced toxicity. On the other hand, genetic and pharmacological inhibition of SR-B1 blocks the clathrin-dependent interferon receptor recycling pathway with a concomitant reduction in IFNα signaling and bioactivity. This effect can be applied to enhance cancer immunotherapy with oncolytic viruses. Indeed, SR-B1 antagonists facilitate replication of oncolytic viruses amplifying their tumoricidal potential. In conclusion, SR-B1 agonists behave as IFNα enhancers while SR-B1 inhibitors dampen IFNα activity. These results demonstrate that SR-B1 is a suitable pharmacology target to enhance cancer immunotherapy based on IFNα and oncolytic viruses. PMID:27622065

  5. Mouse pre-immunocytes as non-proliferating multipotent precursors of macrophages, interferon-producing cells, CD8alpha(+) and CD8alpha(-) dendritic cells.

    PubMed

    Bruno, L; Seidl, T; Lanzavecchia, A

    2001-11-01

    In this study we characterize in mouse bone marrow and peripheral blood a homogeneous cell subset expressing Ly6C, CD31 and CD11c, that can give rise to multiple cell types involved in the immune response. Under the aegis of M-CSF or GM-CSF these cells rapidly differentiate without division to either macrophages or immature dendritic cells, which can be further induced to mature by LPS stimulation. In fetal thymic organ cultures the same cells generate both CD8alpha(+) and CD8alpha(-) dendritic cells in comparable proportion as found in normal thymus. The Ly6C(+), CD31(+) and CD11c(+) cells express not only TLR2 and TLR4, which are characteristic of myeloid dendritic cells, but also TLR7 and TLR9, which conversely are characteristic of human interferon-producing cells. Moreover, following stimulation with influenza virus, they rapidly express high levels of IFN-alpha mRNA. Finally these precursors are increased in bone marrow and peripheral blood during systemic inflammation. These cells are defined as "pre-immunocytes" to underline the fact that they serve in a flexible fashion multiple, and often divergent, functions required for the immune response to pathogens. PMID:11745359

  6. Genetic Analysis of the Pathogenic Molecular Sub-phenotype Interferon Alpha Identifies Multiple Novel Loci Involved in Systemic Lupus Erythematosus

    PubMed Central

    Kariuki, Silvia N.; Ghodke-Puranik, Yogita; Dorschner, Jessica M.; Chrabot, Beverly S.; Kelly, Jennifer A.; Tsao, Betty P.; Kimberly, Robert P.; Alarcón-Riquelme, Marta E.; Jacob, Chaim O.; Criswell, Lindsey A.; Sivils, Kathy L.; Langefeld, Carl D.; Harley, John B.; Skol, Andrew D.; Niewold, Timothy B.

    2014-01-01

    Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disorder characterized by inflammation of multiple organ systems and dysregulated interferon responses. SLE is both genetically and phenotypically heterogeneous, greatly reducing the power of case-control studies in SLE. Elevated circulating interferon alpha (IFN-α) is a stable, heritable trait in SLE, which has been implicated in primary disease pathogenesis. 40–50% of patients have high IFN-α, and high levels correspond with clinical differences. To study genetic heterogeneity in SLE, we performed a case-case study comparing patients with high vs. low IFN-α in over 1550 SLE cases, including GWAS and replication cohorts. In meta-analysis, the top associations in European ancestry were PRKG1 rs7897633 (PMeta=2.75 × 10−8) and PNP rs1049564 (PMeta=1.24 × 10−7). We also found evidence for cross-ancestral background associations with the ANKRD44 and PLEKHF2 loci. These loci have not been previously identified in case-control SLE genetic studies. Bioinformatic analyses implicated these loci functionally in dendritic cells and natural killer cells, both of which are involved in IFN-α production in SLE. As case-control studies of heterogeneous diseases reach a limit of feasibility with respect to subject number and detectable effect size, the study of informative pathogenic subphenotypes becomes an attractive strategy for genetic discovery in complex disease. PMID:25338677

  7. MULTIPLEX PCR ASSAY FOR DETECTION OF HUMAN SOMATOTROPIN AND INTERFERON ALPHA2b GENES IN PLANT MATERIAL.

    PubMed

    Gerasymenko, I M; Mazur, M G; Sheludko, Y V; Kuchuk, N V

    2015-01-01

    Using transgenic plants as factories for production of physiologically active human proteins arouses special concern because occasional escape of such transgenes into environment may cause health problems. Creation of plant varieties producing pharmaceutically valuable proteins should be accompanied by development of detection methods suitable for controlling the transgene behavior. Here we describe a multiplex PCR protocol for revealing of two human genes (encoding growth hormone and interferon alpha2b) that have been successfully introduced into plant genomes. The primer pair designed for detection of human growth hormone coding sequence amplifies fragments of different size from the full-length gene in the human genome and the intronless coding sequence usually used for plant transformation. Application of this primer pair may be recommended for ruling out false positive results due to sample contamination with human DNA. Such a control may be useful also in PCR analysis during establishing of transgenic plants carrying genes of human origin. PMID:26214899

  8. CD4 Binding Affinity Determines Human Immunodeficiency Virus Type 1-Induced Alpha Interferon Production in Plasmacytoid Dendritic Cells ▿

    PubMed Central

    Haupt, Sabrina; Donhauser, Norbert; Chaipan, Chawaree; Schuster, Philipp; Puffer, Bridget; Daniels, Rod S.; Greenough, Thomas C.; Kirchhoff, Frank; Schmidt, Barbara

    2008-01-01

    Plasmacytoid dendritic cells (PDC) are major producers of type I interferons (IFN) in response to human immunodeficiency virus type 1 (HIV-1) infection. To better define the underlying mechanisms, we studied the magnitude of alpha IFN (IFN-α) induction by recombinant viruses containing changes in the Env protein that impair or disrupt CD4 binding or expressing primary env alleles with differential coreceptor tropism. We found that the CD4 binding affinity but not the viral coreceptor usage is critical for the attachment of autofluorescing HIV-1 to PDC and for subsequent IFN-α induction. Our results illustrate the importance of the gp120-CD4 interaction in determining HIV-1-induced immune stimulation via IFN-α production. PMID:18579609

  9. Microcystin-LR induces endoplasmatic reticulum stress and leads to induction of NFκB, interferon-alpha, and tumor necrosis factor-alpha.

    PubMed

    Christen, Verena; Meili, Nicole; Fent, Karl

    2013-04-01

    Microcystins (MCs) are hepatotoxins produced by cyanobacteria responsible for toxicity in humans and animals. Here, we investigate unexplored molecular pathways by which microcystin-LR (MC-LR) acts on hepatocytes to elucidate unknown modes of action. We focus on the endoplasmatic reticulum (ER) stress response or unfolded protein response (UPR), and on mechanisms that may contribute to the tumor-promoting effect of MCs in animals, including the activation of NFκB, the expression of interferon alpha (IFN-α) and the induction of interferon stimulated genes (ISGs), as well as the expression of tumor necrosis factor alpha (TNF-α). To this end, we exposed human hepatoma cells (Huh7) to 0.5 μM (nontoxic concentration), 5 μM (EC50 concentration), 25 μM and 50 μM (cytotoxic concentrations) MC-LR for 6, 24, 48, and 72 h. The expression of phosphatase 2A (PP2A) mRNA and protein was induced at 5 μM MC-LR. Phosphorylated P-CREB, a transcription factor for PP2A, leads to elevated expression of PP2A. Furthermore, all of the three ER stress pathways, the UPR and the endoplasmic reticulum-associated degradation were activated after exposure to 5, 25, and 50 μM MC-LR. Additionally, the expression of NFκB, IFN-α, and several INF-α-stimulated genes was strongly activated. The proinflammatory cytokine TNF-α was also induced. Our data demonstrate that MC-LR induces all ER stress response pathways. Consequently NFκB is activated, which in turn induces the expression of IFN-α and TNF-α. All of these activated pathways, which are analyzed here for the first time in detail, may contribute to the hepatotoxic, inflammatory, and tumorigenic action of MC-LR. PMID:23431999

  10. Safety and efficacy of Hansenula-derived PEGylated-interferon alpha-2a and ribavirin combination in chronic hepatitis C Egyptian children

    PubMed Central

    El Naghi, Suzan; Abdel-Ghaffar, Tawhida Y; El-Karaksy, Hanaa; Abdel-Aty, Elham F; El-Raziky, Mona S; Allam, Aleef A; Helmy, Heba; El-Araby, Hanaa A; Behairy, Behairy E; El-Guindi, Mohamed A; El-Sebaie, Hatem; Abdel-Ghaffar, Aisha Y; Ehsan, Nermin A; El-Hennawy, Ahmed M; Sira, Mostafa M

    2014-01-01

    AIM: To investigate the safety and efficacy of a Hansenula-derived PEGylated (polyethylene glycol) interferon (IFN)-alpha-2a (Reiferon Retard) plus ribavirin customized regimen in treatment-naïve and previously treated (non-responders and relapsers) Egyptian children with chronic hepatitis C infection. METHODS: Forty-six children with chronic hepatitis C virus (HCV) infection were selected from three tertiary pediatric hepatology centers. Clinical and laboratory evaluations were undertaken. Quantitative polymerase chain reaction (PCR) for HCV-RNA was performed before starting treatment, and again at 4, 12, 24, 48, 72 wk during treatment and 6 mo after treatment cessation. All patients were assigned to receive a weekly subcutaneous injection of PEG-IFN-alpha-2a plus daily oral ribavirin for 12 wk. Thirty-four patients were treatment-naïve and 12 had a previous treatment trial. Patients were then divided according to PCR results into two groups. Group I included patients who continued treatment on a weekly basis (7-d schedule), while group II included patients who continued treatment on a 5-d schedule. Patients from either group who were PCR-negative at week 48, but had at least one PCR-positive test during therapy, were assigned to have an extended treatment course up to 72 wk. The occurrence of adverse effects was assessed during treatment and follow up. The study was registered at www.ClinicalTrials.gov (NCT02027493). RESULTS: Only 11 out of 46 (23.9%) patients showed a sustained virological response (SVR), two patients were responders at the end of treatment; however, they were lost to follow up at 6 mo post treatment. Breakthrough was seen in 18 (39.1%) patients, one patient (2.17%) showed relapse and 14 (30.4%) were non-responders. Male gender, short duration of infection, low viral load, mild activity, and mild fibrosis were the factors related to a better response. On the other hand, patients with high viral load and absence of fibrosis failed to

  11. Epstein-Barr Virus BARF1 Protein Is Dispensable for B-Cell Transformation and Inhibits Alpha Interferon Secretion from Mononuclear Cells

    PubMed Central

    Cohen, Jeffrey I.; Lekstrom, Kristen

    1999-01-01

    The Epstein-Barr virus (EBV) BARF1 gene encodes a soluble colony-stimulating factor 1 (CSF-1) receptor that neutralizes the effects of CSF-1 in vitro. To study the effect of BARF1 on EBV-induced transformation, we added recombinant BARF1 to B cells in the presence of EBV. BARF1 did not enhance transformation of B cells by EBV in vitro. To study the role of BARF1 in the context of EBV infection, we constructed a recombinant EBV mutant with a large deletion followed by stop codons in the BARF1 gene as well as a recombinant virus with a wild-type BARF1 gene. While BARF1 has previously been shown to act as an oncogene in several cell lines, the EBV BARF1 deletion mutant transformed B cells and initiated latent infection, and the B cells transformed with the BARF1 mutant virus induced tumors in SCID mice with an efficiency similar to that of the wild-type recombinant virus. Since human CSF-1 stimulates secretion of alpha interferon from mononuclear cells and BARF1 encodes a soluble CSF-1 receptor, we examined whether recombinant BARF1 or BARF1 derived from EBV-infected B cells could inhibit alpha interferon secretion. Recombinant BARF1 inhibited alpha interferon secretion by mononuclear cells in a dose-dependent fashion. The B cells transformed with mutant BARF1 EBV showed reduced inhibition of alpha interferon secretion by human mononuclear cells when compared with the B cells transformed with wild-type recombinant virus. These experiments indicate that BARF1 expressed from the EBV genome directly inhibits alpha interferon secretion, which may modulate the innate host response to the virus. PMID:10438853

  12. Identification of alpha interferon-induced envelope mutations of hepatitis C virus in vitro associated with increased viral fitness and interferon resistance.

    PubMed

    Serre, Stéphanie B N; Krarup, Henrik B; Bukh, Jens; Gottwein, Judith M

    2013-12-01

    Alpha interferon (IFN-α) is an essential component of innate antiviral immunity and of treatment regimens for chronic hepatitis C virus (HCV) infection. Resistance to IFN might be important for HCV persistence and failure of IFN-based therapies. Evidence for HCV genetic correlates of IFN resistance is limited. Experimental studies were hampered by lack of HCV culture systems. Using genotype (strain) 1a(H77) and 3a(S52) Core-NS2 JFH1-based recombinants, we aimed at identifying viral correlates of IFN-α resistance in vitro. Long-term culture with IFN-α2b in Huh7.5 cells resulted in viral spread with acquisition of putative escape mutations in HCV structural and nonstructural proteins. Reverse genetic studies showed that primarily amino acid changes I348T in 1a(H77) E1 and F345V/V414A in 3a(S52) E1/E2 increased viral fitness. Single-cycle assays revealed that I348T and F345V/V414A enhanced viral entry and release, respectively. In assays allowing viral spread, these mutations conferred a level of IFN-α resistance exceeding the observed fitness effect. The identified mutations acted in a subtype-specific manner but were not found in genotype 1a and 3a patients, who failed IFN-α therapy. Studies with HCV recombinants with different degrees of culture adaptation confirmed the correlation between viral fitness and IFN-α resistance. In conclusion, in vitro escape experiments led to identification of HCV envelope mutations resulting in increased viral fitness and conferring IFN-α resistance. While we established a close link between viral fitness and IFN-α resistance, identified mutations acted via different mechanisms and appeared to be relatively specific to the infecting virus, possibly explaining difficulties in identifying signature mutations for IFN resistance. PMID:24049176

  13. A Double-Blind Randomized Controlled Study to Evaluate the Efficacy of Low-Dose Oral Interferon-Alpha in Preventing Hepatitis C Relapse

    PubMed Central

    Lee, Chuan-Mo; Chen, Chi-Yi; Chien, Rong-Nan; Tseng, Kuo-Chih; Peng, Cheng-Yuan; Tung, Shui-Yi; Fang, Yi-Jen; Huang, Yi-Hsiang; Lu, Sheng-Nan; Hung, Chao-Hung; Tsai, Tsung-Jang; Fang, Chien-Chung; Hsu, Chao-Wei

    2014-01-01

    Low-dose oral interferon could exert immune-modulating effects in human. We conducted a clinical trial to investigate the efficacy of oral interferon-alpha in preventing hepatitis C relapse. Totally 169 genotype 1b chronic hepatitis C patients having achieved end-of-therapy virological clearance were randomized to receive interferon-alpha lozenge 500 IU/day (n=59), 1,500 IU/day (n=53), or placebo (n=57) for 24 weeks. Overall, no significant differences were found for the relapse rates in the 3 groups (P>0.05). However, in patients with fibroindex 1.4–1.7, relapse occurred in 1/12 (8.3%) 500 IU-group patients versus 9/21 (42.9%) patients of the other groups (P=0.05). In 158 patients receiving at least 4 weeks of oral interferon, significantly higher platelet count was found at the end of trial in the 500 IU group (P=0.003). In thrombocytopenic patients, a significantly expedited recovery of platelet count was found in the 500 IU group (P=0.002). No drug-related severe adverse events were reported. In conclusion, at 500 IU/day, oral interferon exerted a borderline suppression effect of virological relapse in chronic hepatitis C patients with mild liver fibrosis. Additionally, it significantly expedited platelet count recovery after the end of peginterferon therapy. PMID:24237300

  14. Site-specific in situ growth of an interferon-polymer conjugate that outperforms PEGASYS in cancer therapy.

    PubMed

    Hu, Jin; Wang, Guilin; Zhao, Wenguo; Liu, Xinyu; Zhang, Libin; Gao, Weiping

    2016-07-01

    Conjugating poly(ethylene glycol) (PEG), PEGylation, to therapeutic proteins is widely used as a means to improve their pharmacokinetics and therapeutic potential. One prime example is PEGylated interferon-alpha (PEGASYS). However, PEGylation usually leads to a heterogeneous mixture of positional isomers with reduced bioactivity and low yield. Herein, we report site-specific in situ growth (SIG) of a PEG-like polymer, poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA), from the C-terminus of interferon-alpha to form a site-specific (C-terminal) and stoichiometric (1:1) POEGMA conjugate of interferon-alpha in high yield. The POEGMA conjugate showed significantly improved pharmacokinetics, tumor accumulation and anticancer efficacy as compared to interferon-alpha. Notably, the POEGMA conjugate possessed a 7.2-fold higher in vitro antiproliferative bioactivity than PEGASYS. More importantly, in a murine cancer model, the POEGMA conjugate completely inhibited tumor growth and eradicated tumors of 75% mice without appreciable systemic toxicity, whereas at the same dose, no mice treated with PEGASYS survived for over 58 days. The outperformance of a site-specific POEGMA conjugate prepared by SIG over PEGASYS that is the current gold standard for interferon-alpha delivery suggests that SIG is of interest for the development of next-generation protein therapeutics. PMID:27152679

  15. Interferon alpha2b gene delivery using adenoviral vector causes inhibition of tumor growth in xenograft models from a variety of cancers.

    PubMed

    Iqbal Ahmed, C M; Johnson, D E; Demers, G W; Engler, H; Howe, J A; Wills, K N; Wen, S F; Shinoda, J; Beltran, J; Nodelman, M; Machemer, T; Maneval, D C; Nagabhushan, T L; Sugarman, B J

    2001-10-01

    A recombinant adenovirus expressing human interferon alpha2b driven by the cytomegalovirus promoter, IACB, was shown to produce and secrete biologically active protein in vitro and in vivo. Intravenous administration of IACB in Buffalo rats resulted in circulating levels of biologically active human interferon at 70,000 international units/mL for up to 15 days. Distribution of interferon protein after IACB administration was different from that seen with the subcutaneous delivery of interferon protein. Higher levels of interferon protein were observed in liver and spleen after IACB delivery compared to protein delivery. The antitumor efficacy of IACB, as measured by suppression of tumor growth, was tested in athymic nude mice bearing established human tumor xenografts from different types of human cancer. Subcutaneous tumors most responsive to the intratumoral administration of IACB ranked as U87MG (glioblastoma) and K562 (chronic myelogenous leukemia), followed by Hep 3B (hepatocellular carcinoma) and LN229 cells (glioblastoma). Intravenous administration of IACB in animals bearing U87MG or Hep 3B xenografts was also effective in suppressing tumor growth, although to a lesser extent than the intratumoral administration. IACB was also tested in a metastatic model in beige/SCID mice generated with H69 (small cell lung carcinoma) cells and was found to prolong survival in tumor-bearing animals. This suggested that interferon gene delivery can be effective in suppressing tumor growth in a wide variety of cells. PMID:11687902

  16. Altered production of tumour necrosis factors alpha and beta and interferon gamma by HIV-infected individuals.

    PubMed Central

    Vyakarnam, A; Matear, P; Meager, A; Kelly, G; Stanley, B; Weller, I; Beverley, P

    1991-01-01

    In vitro studies shows that recombinant tumour necrosis factor (TNF) alpha and beta, and interferon-gamma (IFN-gamma) can enhance HIV replication, and peripheral blood mononuclear cells (PBMC) infected with HIV in vitro secrete high levels of the same cytokines. As T cells secrete all three mediators, the capacity of T cell activation signals to trigger cytokine production in PBMC from HIV-infected individuals was investigated as such patients may be immunocompromised. We demonstrate that asymptomatic seropositives in CDC group II/III as well as patients who have progressed to CDC group IV of the disease proliferate efficiently to anti-CD3 antibody, recombinant interleukin-2 (rIL-2), phytohaemagglutinin (PHA), PHA plus phorbol 12,13 dibutyrate (PMA) but secrete significantly (P less than 0.05) higher amounts of TNF-alpha, TNF-beta and IFN-gamma compared with controls in response to the same stimulants. We also show a difference between group II/III and group IV patients with the latter secreting more TNF-alpha and IFN-gamma. The kinetics of TNF-alpha and -beta, and IFN-gamma production was stimulus dependent with overall levels varying in time for each stimulus. Furthermore, the kinetics of the response to all three stimulants were altered in seropositives; CDC group II/III and group IV patients secreted higher levels of cytokines over several time points compared to controls. The altered production of these mediators by HIV-infected patients may contribute to disease progression and to the pathogenesis of AIDS. PMID:1901776

  17. Ocular avirulence of a herpes simplex virus type 1 strain is associated with heightened sensitivity to alpha/beta interferon.

    PubMed Central

    Su, Y H; Oakes, J E; Lausch, R N

    1990-01-01

    BALB/c mice infected on the scarified cornea with herpes simplex virus type 1 strain 35 [HSV-1(35)] rarely developed ocular disease even at challenge doses as high as 10(7) PFU per eye. In contrast, HSV-1(RE) consistently induced stromal keratitis at an inoculum of 2 x 10(4) PFU. The goal of this study was to determine the reason for the difference in virulence between the two HSV strains. Both HSV-1 strains replicated to similar titers in excised corneal "buttons." However, after in vivo infection of the cornea, the growth of strain 35 was evident only during the first 24 h postinfection, whereas the replication of strain RE persisted for at least 4 days. In vitro tests revealed that HSV-1(35) was greater than 10 times more sensitive to alpha/beta interferon (IFN-alpha/beta) than HSV-1(RE). Both strains induced comparable serum levels of IFN after intraperitoneal inoculation. The kinetics of HSV-1(35) clearance from the eye was markedly altered by treatment with rabbit anti-IFN-alpha/beta. Virus titers exceeding 10(4) PFU per eye could be demonstrated 4 to 5 days postinfection in mice given a single inoculation of antiserum 1 h after infection. Furthermore, anti-IFN treatment in 3-week-old mice infected with HSV-1(35) led to the development of clinically apparent corneal disease which subsequently progressed to stromal keratitis in the majority of recipients. These results indicate that the striking difference in the capacity of HSV-1(35) and HSV-1(RE) to induce corneal disease was related to the inherently greater sensitivity of strain 35 to IFN-alpha/beta produced by the host in response to infection. PMID:2157880

  18. Curcumin inhibits interferon-{alpha} induced NF-{kappa}B and COX-2 in human A549 non-small cell lung cancer cells

    SciTech Connect

    Lee, Jeeyun |; Im, Young-Hyuck | E-mail: imyh@smc.samsung.co.kr; Jung, Hae Hyun; Kim, Joo Hyun; Park, Joon Oh |; Kim, Kihyun |; Kim, Won Seog |; Ahn, Jin Seok

    2005-08-26

    The A549 cells, non-small cell lung cancer cell line from human, were resistant to interferon (IFN)-{alpha} treatment. The IFN-{alpha}-treated A549 cells showed increase in protein expression levels of NF-{kappa}B and COX-2. IFN-{alpha} induced NF-{kappa}B binding activity within 30 min and this increased binding activity was markedly suppressed with inclusion of curcumin. Curcumin also inhibited IFN-{alpha}-induced COX-2 expression in A549 cells. Within 10 min, IFN-{alpha} rapidly induced the binding activity of a {gamma}-{sup 32}P-labeled consensus GAS oligonucleotide probe, which was profoundly reversed by curcumin. Taken together, IFN-{alpha}-induced activations of NF-{kappa}B and COX-2 were inhibited by the addition of curcumin in A549 cells.

  19. Imatinib mesylate in Philadelphia chromosome-positive, chronic-phase myeloid leukemia after failure of interferon alpha.

    PubMed

    Tóthová, E; Kafková, A; Fricová, M; Benová, B; Kirschnerová, G; Tóthová, A

    2005-01-01

    Imatinib mesylate (STI 571; Glivec) is a potent and selective tyrosine kinase inhibitor. The introduction of imatinib has chanced the philosophy of mechanisms of cancer therapy and already changed current management of patients with chronic myeloid leukemia (CML). A total of 49 patients with later chronic phase CML in whom previous therapy with interferon alpha had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for hematologic and cytogenetic responses. Time to progression, survival, and toxic effects were also evaluated. Complete hematologic responses were reported for 48 of 49 patients studied (98 percent). The median time to a complete hematologic response was 1.2 month; 89% of patients who had a response did so within 4 months. Imatinib induced major cytogenetic responses in 73%; 62% had a complete responses. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 98% of patients, and 100 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were manageable. No one of patients discontinued treatment due to of drug-related adverse events, and no treatment-related deaths occurred. The results of current study indicate that imatinib has a significant therapy benefit in CML patients in whom treatment with IFN alpha had failed. Therefore, has favorably changed the prognosis for patients with chronic myelogenous leukemia. PMID:15739029

  20. Predictors of Pegylated Interferon Alpha and Ribavirin Efficacy and Long-Term Assessment of Relapse in Patients With Chronic Hepatitis C: A One-Center Experience From China

    PubMed Central

    Wu, Qin; Zhan, Feng Yu; Chen, En Qiang; Wang, Cong; Li, Zhen Zhen; Lei, Xue Zhong

    2015-01-01

    Background: Sustained virological response (SVR) and virological relapse maintain pivotal roles in the management of chronic hepatitis C (CHC); however, there is little data regarding the long-term outcomes of patients with CHC in China. Objectives: We aimed to investigate the predictive factors of therapeutic effect and viral relapse in patients who achieved end-of-treatment response (ETR). Patients and Methods: We retrospectively analyzed clinical, biochemical and virological data of 169 adult patients with CHC from China who were not treated with pegylated interferon-alpha (PEG IFN-α) and ribavirin, of which 142 achieved ETR and with a follow-up period ranging from six months to six years. Statistical analysis was performed by SPSS 20.0. Results: Of the 169 patients, 124 (73.4%) achieved SVR and 23 (16.2%) experienced relapses post-therapy in cases of ETR patients. We considered sex, age, alanine aminotransferase, aspartate transaminase, baseline hepatitis C virus RNA level, HCV genotypes, IL28B rs12979860 genotype, rapid virological response (RVR), and early virological response (EVR). For antiviral effect in patients with CHC, HCV genotypes (2, 3) (χ2 = 11.285, P = 0.001), IL28B genotype (rs12979860 CC) (χ2 = 16.552, P < 0.001), RVR (χ2 = 37.339, P < 0.001), and EVR (χ2 = 70.265, P < 0.001) were significantly correlated with achieving SVR. For ETR patients with long-term follow-up, the relapse rate within six months was significantly higher than within other periods during six-year follow-up (χ2 = 7.792, P = 0.005). Relapse was virtually not observed after therapy ceased for 48 weeks. The IL28B genotype (rs12979860 CT/TT) (OR = 0.102; 95% CI, 0.031-0.339; P < 0.001), lower RVR (OR = 0.239; 95% CI, 0.078-0.738; P = 0.013), and EVR (OR = 0.102; 95% CI, 0.016-0.661; P = 0.017) were independent risk factors for relapse. Conclusions: Our study comprehensively explored the predictive factors of therapeutic effect of administered drugs and analyzed viral

  1. Pronunciation Pegs

    ERIC Educational Resources Information Center

    Samuel, Carolyn

    2010-01-01

    An ESL instructor describes her experience of using pronunciation pegs, a method to foster the self-monitoring and self-correction of pronunciation mistakes with a view to helping university-level students deal with the ongoing challenge of producing target-like pronunciation. The appeal of pegs to students led the instructor to reflect on what…

  2. Ligand-independent pathway that controls stability of interferon alpha receptor

    SciTech Connect

    Liu Jianghuai; Plotnikov, Alexander; Banerjee, Anamika; Suresh Kumar, K.G.; Ragimbeau, Josiane; Marijanovic, Zrinka; Baker, Darren P.; Pellegrini, Sandra; Fuchs, Serge Y.

    2008-03-07

    Ligand-specific negative regulation of cytokine-induced signaling relies on down regulation of the cytokine receptors. Down regulation of the IFNAR1 sub-unit of the Type I interferon (IFN) receptor proceeds via lysosomal receptor proteolysis, which is triggered by ubiquitination that depends on IFNAR1 serine phosphorylation. While IFN-inducible phosphorylation, ubiquitination, and degradation requires the catalytic activity of the Tyk2 Janus kinase, here we found the ligand- and Tyk2-independent pathway that promotes IFNAR1 phosphorylation, ubiquitination, and degradation when IFNAR1 is expressed at high levels. A major cellular kinase activity that is responsible for IFNAR1 phosphorylation in vitro does not depend on either ligand or Tyk2 activity. Inhibition of ligand-independent IFNAR1 degradation suppresses cell proliferation. We discuss the signaling events that might lead to ubiquitination and degradation of IFNAR1 via ligand-dependent and independent pathways and their potential physiologic significance.

  3. Phase II study of recombinant leukocyte A interferon (rIFN-alpha A) in disseminated malignant melanoma.

    PubMed

    Creagan, E T; Ahmann, D L; Green, S J; Long, H J; Rubin, J; Schutt, A J; Dziewanowski, Z E

    1984-12-15

    Thirty-one patients with disseminated malignant melanoma received intramuscular recombinant leukocyte A interferon (rIFN-alpha A), 50 X 10(6) units/m2 three times weekly for a planned treatment duration of 3 months. Seven objective regressions (23%), which ranged in duration from 3 to 11.2+ months, were observed. Forty-two percent of 12 patients who were fully active (Eastern Cooperative Oncology Group [ECOG] performance score, 0) responded compared to 11% of 19 patients with impairment of performance status (ECOG, 1-3). Prior chemotherapy did not influence response rate. For all patients the median time to progression and of survival was 2 months and 6 months, respectively. Four patients had partial regressions in soft tissue (3, 4.6 months), pulmonary (7 months), and prostatic lesions (3 months). The latter was biopsy-proven and assessed by serial computerized tomography (CT) scans. Three had complete regressions of soft tissue disease (2 patients, 6.4 and 10+ months each), and liver involvement (11.2+ months). The major toxicities were moderate to severe fatigue (87%), anorexia (58%), and confusion (23%). Performance score deteriorated in 84% of patients during the time they were receiving rIFN-alpha A. Among the 13 patients whose tumors did not progress for at least 12 weeks, 7 required dose reductions or termination of treatment due to toxicities. Hematologic and hepatic toxicity was transient and of little clinical significance. The study indicates that rIFN-alpha A has some antitumor activity accompanied by difficult side effects in patients with disseminated malignant melanoma. PMID:6498762

  4. The Amino-Terminal Domain of Bovine Viral Diarrhea Virus Npro Protein Is Necessary for Alpha/Beta Interferon Antagonism

    PubMed Central

    Gil, Laura H. V. G.; Ansari, Israrul H.; Vassilev, Ventzislav; Liang, Delin; Lai, Vicky C. H.; Zhong, Weidong; Hong, Zhi; Dubovi, Edward J.; Donis, Ruben O.

    2006-01-01

    The alpha/beta interferon (IFN-α/β) system is the first line of defense against viral infection and a critical link between the innate and adaptive immune responses. IFN-α/β secretion is the hallmark of cellular responses to acute RNA virus infections. As part of their survival strategy, many viruses have evolved mechanisms to counteract the host IFN-α/β response. Bovine viral diarrhea virus (BVDV) (genus Pestivirus) was reported to trigger interferon production in infected cultured cells under certain circumstances or to suppress it under others. Our studies with various cultured fibroblasts and epithelial bovine cells indicated that cytopathic (cp) BVDV induces IFN-α/β very inefficiently. Using a set of engineered cp BVDVs expressing mutant Npro and appropriate controls, we found that the IFN-α/β response to infection was dependent on Npro expression and independent of viral replication efficiency. In order to investigate whether the protease activity of Npro is required for IFN-α/β antagonism, we engineered Npro mutants lacking protease activity by replacement of amino acid E22, H49, or C69. We found that E22 and H49 substitutions abolished the ability of Npro to suppress IFN, whereas C69 had no effect, suggesting that the structural integrity of the N terminus of Npro was more important than its catalytic activity for IFN-α/β suppression. A catalytically active mutant with a change at a conserved Npro region near the N terminus (L8P) in both BVDV biotypes did not antagonize IFN-α/β production, confirming its involvement in this process. Taken together, these results not only provide direct evidence for the role of Npro in blocking IFN-α/β induction, but also implicate the amino-terminal domain of the protein in this function. PMID:16378992

  5. Single amino acid changes in the viral glycoprotein M affect induction of alpha interferon by the coronavirus transmissible gastroenteritis virus.

    PubMed Central

    Laude, H; Gelfi, J; Lavenant, L; Charley, B

    1992-01-01

    Transmissible gastroenteritis virus, an enteropathogenic coronavirus of swine, is a potent inducer of alpha interferon (IFN-alpha) both in vitro and in vivo. Previous studies have shown that virus-infected fixed cells or viral suspensions were able to induce an early and strong IFN-alpha synthesis by naive lymphocytes. Two monoclonal antibodies directed against the viral membrane glycoprotein M (29,000; formerly E1) were found to markedly inhibit virus-induced IFN production, thus assigning to M protein a potential effector role in this phenomenon (B. Charley and H. Laude, J. Virol. 62:8-11, 1988). The present report describes the selection and characterization of a collection of 125 mutant viruses which escaped complement-mediated neutralization by two IFN induction-blocking anti-M protein monoclonal antibodies. Two of these mutants, designated H92 and dm49-4, were found to exhibit a markedly reduced interferogenic activity. IFN synthesis by lymphocytes incubated with purified suspensions of these mutants was 30- to 300-fold lower than that of the parental virus. The transcription of IFN-alpha genes following induction by each mutant was decreased proportionally, as evidenced by Northern (RNA) blot analysis. The sequence of the M gene of 20 complement-mediated neutralization-resistant mutants, including the 2 defective mutants, was determined by direct sequencing of genome RNA. Thirteen distinct amino acid changes were predicted, all located at positions 6 to 22 from the N terminus of the mature M protein and within the putative ectodomain of the molecule. Two substitutions, Thr-17 to Ile and Ser-19 to Pro, were assumed to generate the defective phenotypes of mutants dm49-4 and H92, respectively. The alteration of an Asn-Ser-Thr sequence in dm49-4 virus led to the synthesis of an M protein devoid of a glycan side chain, which suggests a possible involvement of this structure in IFN induction. Overall, these data supported the view that an interferogenic

  6. Induction of autoantibodies to the adrenal cortex and pancreatic islet cells by interferon alpha therapy for chronic hepatitis C

    PubMed Central

    Wesche, B; Jaeckel, E; Trautwein, C; Wedemeyer, H; Falorni, A; Frank, H; von zur Muhlen, A; Manns, M; Brabant, G

    2001-01-01

    BACKGROUND/AIMS—Interferon alpha (IFN-α) therapy for chronic hepatitis C may trigger induction of autoimmunity against several organs. Immune reactions against distinct adrenocortical protein antigens involved in adrenal autoimmune disease have not been reported to date. Therefore, we investigated the development of highly sensitive and specific adrenal autoantibodies in patients with chronic hepatitis C in response to IFN-α treatment. In addition, we studied induction of pancreatic islet and thyroid autoantibodies.
PATIENTS/METHODS—Sera of 75 patients (42 males, 33 females; mean age 47 (13) years) were analysed before, during, and after IFN-α therapy (9-18×106 IE/week; mean duration 8.3 (3.5) months). Autoantibodies (Abs) to adrenal 21-hydroxylase (21OH-Abs), and to islet glutamic acid decarboxylase (GAD65-Abs) and protein tyrosine phosphatase (IA2-Abs) were determined by a radiobinding assay using 35S labelled protein generated by an in vitro translation system. Thyroid antibodies were measured by a commercially available ELISA.
RESULTS—Thirteen of 75 patients were initially positive for some of the autoantibodies. During or after IFN-α therapy, 3/62 initially negative patients (4.8%) developed 21OH-Abs. GAD65-Abs or IA2-Abs appeared in 5/62 and 1/62 patients, respectively (9.7% in total). In 12/62 patients (19.4%), thyroid specific antibodies appeared. In none of the 21OH-Ab positive subjects was adrenal dysfunction observed, and no patient with islet autoantibodies developed diabetes mellitus or impaired glucose tolerance.
CONCLUSIONS—IFN-α induces 21OH-Abs in some cases, while islet and thyroid specific autoantibodies are more frequently found. However, our results indicate for the first time that the adrenal cortex also has to be considered as a potential target of IFN-α related autoimmunity.


Keywords: hepatitis C; interferon alpha; autoantibodies; adrenal cortex; pancreatic islet cells PMID:11171829

  7. Analysis of sequences of hepatitis C virus NS5A genotype 1 in HIV-coinfected patients with a null response to nitazoxanide or peg-interferon plus ribavirin.

    PubMed

    Sede, M; Laufer, N; Ojeda, D; Gun, A; Cahn, P; Quarleri, J

    2013-09-01

    Even though new drugs have been approved for treatment of hepatitis C virus (HCV) infection, the risk of drug-drug interactions and concern about overlapping toxicities has hindered the development of studies in HIV/HCV-coinfected individuals. Traditional treatment with pegylated interferon plus ribavirin (peg-IFN + RBV) is very expensive and has a low rate of sustained virological response in coinfected patients, especially if they are infected with HCV genotype 1. Nitazoxanide (NTZ) is a drug that is being evaluated for the treatment of chronic HCV infection, both in HCV-monoinfected and HIV/HCV-coinfected patients. Understanding the NTZ resistance mechanism could allow the development of resistance to be minimized and would expand the treatment options, mainly in special populations such as HIV/HCV-coinfected patients. Similarly to IFN, NTZ increases the activity of the cellular protein kinase activated by double-stranded RNA (PKR), a key kinase in the innate antiviral response. In order to elucidate whether sequence heterogeneity in the PKR-binding domain of HCV NS5A genotype 1 could influence the antiviral activity of either NTZ monotherapy or peg-IFN + RBV, baseline and end-of-therapy plasma samples from two groups of eleven non-responder HIV/HCV-coinfected patients that had received NTZ or peg-IFN + RBV were studied. Most of the HCV NS5A sequences examined at the end of therapy did not change from the baseline, even after 30 days course of antiviral therapy. An extensive comparison of HCV NS5A genotype 1 and 4 sequences from the database with reported IFN therapy outcome was performed in order to infer their phylogenetic relationships. The HCV genotype 1 NS5A nucleotide sequences from therapy-non-responder patients were intermingled amongst those from the database, irrespective of their IFN-therapy outcome. When comparing NS5A-PKRBD amino acid sequences, significant differences were observed in genotype 4, but not in genotype 1 (p < 0.0001 and p

  8. Interstitial pneumonitis associated with pegylated interferon alpha-2b therapy for chronic hepatitis C: case report.

    PubMed

    Carrillo-Esper, Raúl; González-Avila, Daniela; Uribe-Ríos, Marittza; Méndez-Sánchez, Nahum

    2008-01-01

    Since 2004, pegylated interferon (P-IFN) in combination with ribavirin has become the optimal choice of therapy for chronic hepatitis C virus (HCV) infection. IFN a-2b suppresses HCV replication and restores elevated serum aminotransferase levels, leading to improvements in the histological changes in the livers of patients with chronic hepatitis C. Unfortunately, P-IFN has several adverse effects, including pneumonitis. This complication has been reported in the treatment of malignant diseases and CHC. We report a patient with interstitial pneumonitis thought to be caused by an IFN-based treatment in an unusual scenario of a patient with HCV-related Child-Pugh stage A cirrhosis, who experienced dyspnea, fever, and cough after 12 months of treatment with P-IFN a-2b. Her lung injury and pulmonary symptoms did not disappear despite discontinuation of IFN and the administration of corticosteroid. We concluded that the patient developed a fatal interstitial pneumonitis associated with P-INF a-2b therapy. PMID:18376374

  9. Survival in renal cell carcinoma-a randomized evaluation of tamoxifen vs interleukin 2, alpha-interferon (leucocyte) and tamoxifen.

    PubMed Central

    Henriksson, R.; Nilsson, S.; Colleen, S.; Wersäll, P.; Helsing, M.; Zimmerman, R.; Engman, K.

    1998-01-01

    Metastatic renal cell carcinoma (RCC) has a poor prognosis. Conventional treatment strategies, including chemotherapy and hormonal therapy, have limited value. Although encouraging results have been achieved in terms of objective response using immunological manipulations, no conclusive studies yet exist with a controlled comparative evaluation of survival. Therefore, the present study was undertaken, which compared one of the present (and presumed best) treatments, interleukin 2/interferon-alpha (IL-2/IFN-alpha) and tamoxifen, with a control arm of tamoxifen only. Tamoxifen has been shown to potentiate in vivo anti-tumour activity of IL-2, and because of its non-toxic behaviour it was included in both groups. The study was open, randomized and included seven institutions in Sweden. The patients were stratified according to the different centres involved. An interim analysis was planned when a minimum of 100 patients were evaluable. The 128 patients finally included had a histologically documented metastatic RCC, with a life expectancy of more than 3 months, a performance status WHO 0-2 and no prior chemo- or immunotherapy. Informed consent was obtained from each patient. The patients randomized to the control arm (n = 63) received only tamoxifen 40 mg p.o. daily for at least 1 year or until progression. The patients (n = 65) randomized to biotherapy received subcutaneous recombinant IL-2, leucocyte IFN-alpha in a treatment cycle of 42 days, as well as tamoxifen p.o. In the absence of undue toxicity or disease progression, these patients received one additional treatment cycle of 42 days followed by maintenance treatment, consisting of 5 days therapy every 4 weeks, for 1 year, or until proven progression. Only two patients in the tamoxifen-only group received immunotherapy when the disease progressed, but without any beneficial effect. All patients received appropriate local treatment when indicated. The interim analysis demonstrated no survival advantage for

  10. A phase II trial of concomitant human interleukin-2 and interferon-alpha-2a in patients with disseminated malignant melanoma.

    PubMed

    Whitehead, R P; Figlin, R; Citron, M L; Pfile, J; Moldawer, N; Patel, D; Jones, G; Levitt, D; Zeffren, J

    1993-02-01

    Interleukin-2 (IL-2) and alpha-interferon have each shown antitumor activity in patients with disseminated malignant melanoma. Because animal studies suggest enhanced activity for the combination over each agent used alone, this trial using a relatively low-dose outpatient regimen was undertaken. IL-2 at a dose of 2 x 10(6) U/m2/day (Roche units) was given by continuous intravenous infusion for 4 days a week with interferon-alpha-2a at a dose of 6 x 10(6) U/m2/day given by s.c. or i.m. injection on days 1 and 4 of each treatment week. One cycle consisted of 4 consecutive weeks of treatment followed by a 2-week rest period. Fourteen patients were entered in this study. No complete or partial responses were seen. One patient required dose reduction because of grade 3 diarrhea and two patients had interruption of treatment because of central-line-related sepsis. Fatigue was common in all patients. This low-dose combination regimen of IL-2 and alpha-interferon does not appear to be better than the single agents used alone in optimal dosage. PMID:8318496

  11. Acridinium ester labelled cytokines: receptor binding studies with human interleukin-1 alpha, interleukin-1 beta and interferon-gamma.

    PubMed

    Joss, U R; Towbin, H

    1994-01-01

    As a consequence of environmental protection and legal restrictions, increasing efforts are made to avoid radioactivity. One alternative is the labelling of ligands with chemiluminescent acridinium esters such as 2,6-dimethyl-4-(N-succinimidyloxy-carbonyl)phenyl 10-methylacridinium-9-carboxylate methosulphate (DMAE-NHS). When exposed to hydrogen peroxide in a basic solution, the DMAE-moiety decays with emission of a short-lasting chemiluminescent flash. With the goal of replacing the radioactive label in protein ligands with a DMAE label, and of increasing the efficiency by using microtitre plate technology for DMAE detection, we compared the receptor binding properties of iodinated interleukin-1 alpha (125I-IL-1 alpha), interleukin-1 beta (125I-IL-1 beta) and interferon-gamma (125I-IFN-gamma) with the corresponding DMAE-labelled ligands. The luminescence signal was assessed in a single-tube luminometer and in the prototype of a chemiluminescent microtitre plate reader. Derivatization of the three proteins with DMAE-N-hydroxy-succinimide resulted in photon yields of up to 100,000 counts per femtomole. As shown by Scatchard analysis, no significant loss of receptor binding affinity was observed, which might have been expected as a consequence of the chemical modification of the proteins. The use of DMAE labelling of proteins has the following advantages as compared to iodination: (i) the coupling reaction and binding assay can be performed in a normal laboratory, (ii) since there is no radiolysis, the DMAE-labelled proteins remain stable, (iii) the detection sensitivity may be improved as a consequence of higher specific activity of the DMAE label.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8154300

  12. Recombinant chicken interferon-alpha inhibits the replication of exogenous avian leukosis virus (ALV) in DF-1 cells.

    PubMed

    Dai, Manman; Wu, Siyu; Feng, Min; Feng, Saixiang; Sun, Chao; Bai, Dayong; Gu, Mingzhu; Liao, Ming; Cao, Weisheng

    2016-08-01

    Chickeninterferon alpha (ChIFNα) belongs to type I IFNs that are important antiviral cytokines. We investigated whether ChIFNα plays a role in avian leukosis virus (ALV) infections of chickens. Firstly, we explored the immune response to ALV in vivo by measuring cytokine expression profiles in the spleens and bursas of chickens during the late stages of ALV-J infection. The results indicated that ALV-J infection could induce a mixed Th1/Th2 cytokine response by elevating levels of both interleukin-2 (IL-2) and IL-10. In contrast, tumor necrosis factor alpha (TNF-α) levels decreased in the spleen while interferon beta (IFNβ) and Toll-like receptor 7 (TLR7) expression levels in the bursa increased significantly. This indicated that ALV-J stimulates a Type I IFN response. Next, we found that different ALV subgroups or strains up-regulated chicken IFN regulatory factor 3 (ChIRF-3) promoter activity, suggesting that ALV infection could trigger Type I IFNs pathway in vitro. Accordingly, we further investigated ChIFNα antiviral effects on ALV replication in DF-1 cells by successfully expressing recombinant ChIFNα in Escherichia coli (E. coli) strain BL21. The specific activity of the purified rChIFNα protein was determined to be 4×10(7)U/mL. When added at 4000U/mL, the recombinant protein restrained ALV replication as measured by decreases in viral protein p27 levels and mRNA expression. This new reagent may be useful for prophylactic and therapeutic drug design. PMID:27372921

  13. Anger induced by interferon-alpha is moderated by ratio of arachidonic acid to omega-3 fatty acids

    PubMed Central

    Lotrich, Francis E.; Sears, Barry; McNamara, Robert K.

    2013-01-01

    Objective Anger worsens in some patients during interferon-alpha (IFN-α) therapy. Elevated anger has also been associated with lower long-chain omega-3 (LCn-3) fatty acid levels. We examined whether fatty acids could influence vulnerability to anger during IFN-α exposure. Methods Plasma arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) levels were determined prior to IFN-α therapy by mass spectroscopy. Repeated-measure analyses examined the relationship between AA/EPA+DHA and the subsequent development of labile anger and irritability in 82 subjects who prospectively completed the Anger, Irritability, and Assault Questionnaire (AIAQ) during the first eight weeks of IFN-α therapy. Results Prior to IFN-α therapy, AA/EPA+DHA did not correlate with either labile anger or irritability. Pre-treatment AA/EPA+DHA did correlate with the subsequent maximal increase in labile anger during IFN-α therapy (r=0.33; p=0.005). Over time, labile anger increased more in subjects with above median AA/EPA+DHA ratios (p<0.05). Of the 17 subjects ultimately requiring psychiatric intervention for anger, 14/17 had above-median AA/EPA+DHA ratios (p=0.009). There was also an interaction with the tumor necrosis factor-alpha (TNF-α) promoter polymorphism (A-308G), such that only those with both elevated AA/EPA+DHA and the A allele had increased labile anger (p=0.001). In an additional 18 subjects, we conversely observed that selective serotonin reuptake inhibitor treatment was associated with increased irritability during IFN-α therapy. Conclusion LCn-3 fatty acid status may influence anger development during exposure to elevated inflammatory cytokines, and may interact with genetic risk for increased brain TNF-α. LCn-3 supplements may be one strategy for minimizing this adverse side effect of IFN-α. PMID:24182638

  14. Complex Interplay between HIV-1 Capsid and MX2-Independent Alpha Interferon-Induced Antiviral Factors

    PubMed Central

    Bulli, Lorenzo; Apolonia, Luis; Kutzner, Juliane; Pollpeter, Darja; Goujon, Caroline; Herold, Nikolas; Schwarz, Sarah-Marie; Giernat, Yannick; Keppler, Oliver T.

    2016-01-01

    ABSTRACT Type I interferons (IFNs), including IFN-α, upregulate an array of IFN-stimulated genes (ISGs) and potently suppress Human immunodeficiency virus type 1 (HIV-1) infectivity in CD4+ T cells, monocyte-derived macrophages, and dendritic cells. Recently, we and others identified ISG myxovirus resistance 2 (MX2) as an inhibitor of HIV-1 nuclear entry. However, additional antiviral blocks exist upstream of nuclear import, but the ISGs that suppress infection, e.g., prior to (or during) reverse transcription, remain to be defined. We show here that the HIV-1 CA mutations N74D and A105T, both of which allow escape from inhibition by MX2 and the truncated version of cleavage and polyadenylation specific factor 6 (CPSF6), as well as the cyclophilin A (CypA)-binding loop mutation P90A, all increase sensitivity to IFN-α-mediated inhibition. Using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 technology, we demonstrate that the IFN-α hypersensitivity of these mutants in THP-1 cells is independent of MX2 or CPSF6. As expected, CypA depletion had no additional effect on the behavior of the P90A mutant but modestly increased the IFN-α sensitivity of wild-type virus. Interestingly, the infectivity of wild-type or P90A virus could be rescued from the MX2-independent IFN-α-induced blocks in THP-1 cells by treatment with cyclosporine (Cs) or its nonimmunosuppressive analogue SDZ-NIM811, indicating that Cs-sensitive host cell cyclophilins other than CypA contribute to the activity of IFN-α-induced blocks. We propose that cellular interactions with incoming HIV-1 capsids help shield the virus from recognition by antiviral effector mechanisms. Thus, the CA protein is a fulcrum for the dynamic interplay between cell-encoded functions that inhibit or promote HIV-1 infection. IMPORTANCE HIV-1 is the causative agent of AIDS. During acute HIV-1 infection, numerous proinflammatory cytokines are produced, including type I interferons (IFNs). IFNs can

  15. Tumour necrosis factor-alpha and interferon-gamma production measured at the single cell level in normal and inflamed human intestine.

    PubMed Central

    MacDonald, T T; Hutchings, P; Choy, M Y; Murch, S; Cooke, A

    1990-01-01

    The spot-ELISA technique has been used to enumerate the frequency of cells secreting tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), isolated from biopsies of normal intestine and from biopsies of children with inflammatory bowel disease. TNF-alpha production was undetectable in six out of 12 biopsies from normal intestine and in the other six biopsies it ranged from 60 to 580 TNF-alpha-secreting cells/10(6) isolated intestinal cells. In contrast, cells isolated from biopsies of children with Crohn's disease (n = 9) all showed elevated frequencies of TNF-alpha-secreting cells (500-12,000 secreting cells/10(6) cells). In ulcerative colitis, four out of eight children had increased production of TNF-alpha and in children with indeterminate colitis two out of three had elevated levels. There was no correlation between plasma TNF-alpha levels and the number of intestinal cells secreting TNF-alpha. In controls and all groups of patients IFN-gamma-secreting cells were uncommon. These results suggest that TNF-alpha is an important mediator of inflammation in the human gut, and, furthermore, may play a role in the growth failure frequently seen in children with inflammatory bowel disease. PMID:2117510

  16. Chemokine gene expression in the murine renal cell carcinoma, RENCA, following treatment in vivo with interferon-alpha and interleukin-2.

    PubMed Central

    Sonouchi, K.; Hamilton, T. A.; Tannenbaum, C. S.; Tubbs, R. R.; Bukowski, R.; Finke, J. H.

    1994-01-01

    The expression of three chemoattractant cytokine (chemokine) messenger (m)RNAs in the murine renal cell carcinoma (RENCA) from mice treated with a combination of interferon-alpha (IFN-alpha) and interleukin-2 was examined and related to tumor infiltration by inflammatory leukocytes. Using a semi-quantitative reverse transcriptase polymerase chain reaction assay, mRNAs encoding the KC, JE, and IP-10 genes were all elevated in tumor tissue from mice treated systemically with IFN-alpha/interleukin-2 for 4 days. Similarly, the mRNA for tumor necrosis factor-alpha (TNF-alpha) was also increased in tumors from treated as compared to control animals. The same tumors showed a significant increase in Mac-1+ leukocytes, which correlated well with the increase in chemokine and TNF-alpha gene expression. The renal cell carcinoma tumor itself may be responsible for the expression of chemokine genes in the tumor bed following cytokine therapy. Cultures of freshly explanted RENCA cells expressed significant levels of chemokine mRNAs when stimulated in vitro with IFN alpha, IFN gamma, and/or interleukin-2, demonstrating that this tumor cell has potential for expression of these genes in vivo. In contrast, TNF-alpha expression was not detected in cultured tumor cells. Thus TNF-alpha may be expressed by infiltrating monocytes following exposure to recombinant cytokine therapy. Images Figure 1 Figure 2 Figure 4 PMID:8160774

  17. Chemotherapy plus interferon-alpha2b versus chemotherapy in the treatment of follicular lymphoma.

    PubMed

    Neri, N; Avilés, A; Cleto, S; Díaz, N; Talavera, A; García, E L; Díaz-Maqueo, J C

    2001-10-01

    The best treatment of follicular lymphoma remains to be determined because the long natural history of follicular lymphoma requires mature data for accurate analysis. Although the goal of primary treatment remains durable remission, the sequential application of effective treatments may also result in a prolongation of median survival time. The use of interferon (IFN) with doxorubicin-based chemotherapy has demonstrated an increase of event-free survival but not in overall survival; however, its acute and late cardiac toxicity limits its use. For this reason, we began a controlled clinical trial to assess the efficacy and toxicity of chemotherapy: COPP (cyclophosphamide, vincristine, prednisone, and procarbazine) + IFN alternating every month for six cycles compared to six cycles of chemotherapy. In an intent-to treat analysis, 55 patients were enrolled (median age 61 years). Most cases (91%) with advanced disease were randomly assigned to chemotherapy + IFN (28 cases) or chemotherapy (27 cases). Complete remission was observed in 16 patients: 59% (95% CI, 53-70%) in the chemotherapy arm compared to 20 patients 71% (95% CI, 58-79%) in the chemotherapy + IFN arm; total responses were 74% and 86%, respectively. At a median follow-up of 60 months, event-free survival was 100% for patients treated with chemotherapy + IFN, which was statistically different from patients treated with chemotherapy 70%. At 7 years, median survival has not yet been reached; 72% of patients chemotherapy + IFN remain alive without disease (95% CI, 59-81%), which is not statistically different from 72% (95%CI, 50-73%) in the chemotherapy arm. Non-hematological toxicity was most frequent and severe in the chemotherapy arm; hematological toxicity was similar in both groups. Thus, it appears that chemotherapy + IFN, as described herein, improves event-free survival but the overall survival rates remain unchanged. The use of COPP appears to be better that anthracycline-based chemotherapy because

  18. Operational cures after interferon-alpha in patients with chronic myeloid leukemia in Central and Northern Moravia.

    PubMed

    Faber, Edgar; Kuba, Adam; Zapletalová, Jana; Divoká, Martina; Rožmanová, Šárka; Rohoň, Peter; Holzerová, Milena; Jarošová, Marie; Indrák, Karel

    2012-05-01

    We assessed long-term outcome of 118 consecutive patients in chronic phase of chronic myeloid leukemia (CML) treated with interferon-alpha (IFN-α) in the Central and Northern Moravia region between 1989 and 2006 with focus on operational cure. The median follow-up was 82.6 months (range 12.4-212.6). Eighteen (15.3%) patients achieved complete cytogenetic response (CCyR) after median 16.7 (3.7-40.8) months. Nine of these patients (7.6%) achieved BCR-ABL negativity in nested reverse transcriptase-polymerase chain reaction ["complete" molecular response (CMR)] and 6 of them have been operationally cured without any treatment for median 6 (4-10) years, while 2 continue with IFN-α and 1 died from CML-unrelated cause. Operationally cured patients had a significantly lower percentage of initial peripheral promyelocytes, blasts, and erythroblasts than the rest of patients treated for more than 12 months (P=0.01-0.03). Unlike patients with sole CCyR, the majority of whom lost CCyR despite continuing IFN-α therapy and required imatinib, patients who achieved CMR had excellent long-term outcome. PMID:22191465

  19. N-acetylcysteine improves antitumoural response of Interferon alpha by NF-kB downregulation in liver cancer cells

    PubMed Central

    2012-01-01

    Background Liver cancer is one of the most common malignancies in the world and at the moment, there is no drug intervention effective for the treatment of liver tumours. Investigate the effect of N-acetylcysteine (NAC), which has been studied for its antitumoural properties, on the toxicity of hepatocarcinoma (HCC) cells in vitro when used with the drug interferon alpha-2A (IFN), which is used clinically to treat HCC. Results NAC, IFN and NAC plus IFN reduced cell viability, as determined by MTT assay. More importantly, NAC potentiates the cytotoxic effect of IFN, with the best response achieved with 10 mM of NAC and 2.5 x 104 of IFN. These results were confirmed by Annexin/PI staining through flow cytometry and morphologic analyses. Co-treatment reduced the expression of the nuclear transcription factor kappa-B (NF-kB). In a similar way to NAC, RNAi against p65 potentiated the toxic effect of IFN, suggesting that, indeed, NAC may be enhancing the effect of IFN through inhibition of NF-kB. Conclusions Our results support the notion that NAC may be an important drug for the treatment of liver tumours as primary or adjuvant therapy. IFN has a limited clinical response, and therefore, the anti-proliferative properties of NAC in the liver should be explored further as an alternative for non-responders to IFN treatment. PMID:23206959

  20. [Combined treatment in recurrent laryngeal papillomatosis with CO2 laser microlaryngoscopic resection and interferon alpha 2b].

    PubMed

    Montero Mora, P; Hernández Colín, D D; Enríquez Palomec, O; Mejía Ortega, J

    1996-01-01

    Laryngeal papillomatosis of viral origin and bad prognosis is characterized by multiple recurrence that induced obstruction of air pathways. Surgical remove with laser CO2 is the elected treatment and the its combination with interferon (INF) has improved the prognosis of this recurrent viral disease. Here is a presents a preliminary study based upon such therapeutic scheme. Twelve patients diagnosed with laryngeal papillomatosis; 6 women and 6 men from 32 to 72 years of age were included into two therapeutic schemes: Group B, Combined: One woman and 5 men to whom the surgical procedure was followed by a initial local dose of 3 x 10(6) IU of INF alpha 2b (Intron A) and subsequently 10 X 10(6) (of the same INF were administered intramuscular every days during 15 months the statistical analysis (Fisher test) between patients of the both groups of treatment showed a significant (p < 0.0001) clinical improvement of the patients who received the combined treatment (B). In this group of patients was found incidence of the collateral effects such as: headache, fever arthralgias, depression and anorexia. PMID:9005006

  1. A recombinant DNA vaccine protects mice deficient in the alpha/beta interferon receptor against lethal challenge with Usutu virus.

    PubMed

    Martín-Acebes, Miguel A; Blázquez, Ana-Belén; Cañas-Arranz, Rodrigo; Vázquez-Calvo, Ángela; Merino-Ramos, Teresa; Escribano-Romero, Estela; Sobrino, Francisco; Saiz, Juan-Carlos

    2016-04-19

    Usutu virus (USUV) is a mosquito-borne flavivirus whose circulation had been confined to Africa since it was first detected in 1959. However, in the last decade USUV has emerged in Europe causing episodes of avian mortality and sporadic severe neuroinvasive infections in humans. Remarkably, adult laboratory mice exhibit limited susceptibility to USUV infection, which has impaired the analysis of the immune responses, thus complicating the evaluation of virus-host interactions and of vaccine candidates against this pathogen. In this work, we showed that mice deficient in the alpha/beta interferon receptor (IFNAR (-/-) mice) were highly susceptible to USUV infection and provided a lethal challenge model for vaccine testing. To validate this infection model, a plasmid DNA vaccine candidate encoding the precursor of membrane (prM) and envelope (E) proteins of USUV was engineered. Transfection of cultured cells with this plasmid resulted in expression of USUV antigens and the assembly and secretion of small virus-like particles also known as recombinant subviral particles (RSPs). A single intramuscular immunization with this plasmid was sufficient to elicit a significant level of protection against challenge with USUV in IFNAR (-/-) mice. The characterization of the humoral response induced revealed that DNA vaccination primed anti-USUV antibodies, including neutralizing antibodies. Overall, these results probe the suitability of IFNAR (-/-) mice as an amenable small animal model for the study of USUV host virus interactions and vaccine testing, as well as the feasibility of DNA-based vaccine strategies for the control of this pathogen. PMID:26993334

  2. Development of a drug-coated microneedle array and its application for transdermal delivery of interferon alpha.

    PubMed

    Kusamori, Kosuke; Katsumi, Hidemasa; Sakai, Ryota; Hayashi, Rie; Hirai, Yuka; Tanaka, Yutaro; Hitomi, Kaori; Quan, Ying-Shu; Kamiyama, Fumio; Yamada, Keigo; Sumida, Shun-ichiro; Kishi, Kazumasa; Hashiba, Katsunori; Sakane, Toshiyasu; Yamamoto, Akira

    2016-03-01

    Interferon alpha (IFNα) is one of the most famous drugs for the treatment of chronic hepatitis C and various types of human malignancy. Protein drugs, including IFNα, are generally administered by subcutaneous or intramuscular injection due to their poor permeability and low stability in the bloodstream or gastrointestinal tract. Therefore, in the present study, novel IFNα-coated polyvinyl alcohol-based microneedle arrays (IFNα-MNs) were fabricated for the transdermal delivery of IFNα without the painful injection. IFNα was rapidly released from MNs in phosphate buffered solution and these MNs presented piercing ability in the rat skin. Slight erythema and irritation were observed when MNs were applied to the rat skin, but these skin damages completely disappeared within 24 h after removing the IFNα-MNs. Furthermore, the pharmacokinetic parameters of IFNα-MNs were similar to those of IFNα subcutaneous administration. Finally, IFNα-MNs showed a significant antitumor effect in tumor bearing mice similar to that of IFNα subcutaneous administration. These results indicate that IFNα-MNs are a useful biomaterial tool for protein drug therapy and can improve the quality of life in patients by avoidance of painful injections. PMID:26756832

  3. Protein crystal growth in microgravity review of large scale temperature induction method: bovine insulin, human insulin and human alpha interferon

    NASA Astrophysics Data System (ADS)

    Long, Marianna M.; Bishop, John Bradford; Nagabhushan, Tattanahalli L.; Reichert, Paul; Smith, G. David; DeLucas, Lawrence J.

    1996-10-01

    The protein crystal growth facility (PCF) is space-flight hardware that accommodates large scale protein crystal growth experiments using temperature change as the inductive step. Recent modifications include specialized instrumentation for monitoring crystal nucleation with laser light scattering. This paper reviews results from the PCF's first seven flights on the Space Shuttle, the last with laser light scattering instrumentation. The PCF's objective is twofold: (1) production of high quality protein crystals for X-ray analysis and subsequent structure based drug design and (2) preparation of a large quantity of relatively contaminant free crystals for use as time-release protein pharmaceuticals. The first three Shuttle flights with bovine insulin constituted the PCF's proof of concept, demonstrating that the space-grown crystals were larger and diffracted to higher resolution than their earth-grown counterparts. The later four PCF missions were used to grow recombinant human insulin crystals for X-ray analysis and to continue productions trials aimed at the development of a processing facility for crystalline recombinant alpha interferon.

  4. Interferon alpha 2b as maintenance therapy in low grade malignant lymphoma improves duration of remission and survival.

    PubMed

    Aviles, A; Duque, G; Talavera, A; Guzman, R

    1996-02-01

    We assessed the efficacy and toxicity of interferon alpha 2b (IFN) as maintenance therapy in patients with low grade malignant lymphoma. Between March 1986 and December 1989, 98 patients with low-grade malignant lymphoma in complete remission after conventional chemotherapy were randomly assigned to received IFN, 5.0 MU three times a week for one year, as maintenance therapy (n = 48), or to receive no treatment (control group, n = 50). In March 1994, the median duration of response had not yet been reached in the patients treated with IFN compared to 46 months in the control group. At 9-years 62% of the patients in the IFN arm remain in first complete remission compared to only 25% in the control group (p <.001). In addition, the median duration of survival has not yet been reached in either the IFN arm compared to 74 months in the control group (p <.001). Quality of life was excellent in both groups and severe side effects secondary to IFN treatment were not observed. All patients completed the planned dose of IFN. We conclude that IFN as maintenance therapy in low-grade malignant lymphoma is an excellent therapeutic option because it improves the duration of remission and survival without producing severe side effects or reducing the quality of life. PMID:8833409

  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. PMID

  6. Peculiarities of production technology and properties of natural animal alpha-interferon preparations.

    PubMed

    Kishko, Ia H

    1999-01-01

    Principally new biotechnology of production of natural animal alpha-IFNs was created. Normative technical documentation on industrial production of these preparations was transmitted to the plants of Ukraine for their industrial obtaining. The peculiarity of proposed technology consists in usage of non-traditional raw-material--lymphoid organs and tissues (perhaps spleen), and also in introduction of coinduction into industrial cycle with the help of camizole (compound of phenilimidazothiazole family) which increased the output of final product by 3-8 times. Obtained preparations were tested in vitro and in vivo experiments. As it was shown in both cases bactericidal and absorbed activity of monocytes and neutrophils increased by 2-5 times, antibody genesis sharply increased after immunization of pigs and calves by colibacteriosis vaccine: titers were higher by 3-8 times (comparatively with control), especially two month after revaccination, but they were more stable too. Fractions of 12 and 18 kDa responsible for antibacterial and antitoxic activity respectively were found in non-purified preparations of alpha-IFNs. PMID:10441967

  7. Interferon-alpha inhibits murine macrophage transforming growth factor-beta mRNA expression.

    PubMed

    Dhanani, S; Huang, M; Wang, J; Dubinett, S M

    1994-06-01

    Transforming growth factor-beta (TGF-beta), a multifunctional polypeptide is produced by a wide variety of cells and regulates a broad array of physiological and pathological functions. TGF-beta appears to play a central role in pulmonary fibrosis and may contribute to tumor-associated immunosuppression. Alveolar macrophages are a rich source of TGF-beta and are intimately involved in lung inflammation. We therefore chose to study TGF-beta regulation in murine alveolar macrophages as well as an immortalized peritoneal macrophage cell line (IC-21). Murine macrophages were incubated with cytokines to evaluate their role in regulating TGF-beta mRNA expression. We conclude that IFN-alpha downregulates TGF-beta mRNA expression in murine macrophages. PMID:8088926

  8. Myxovirus Resistance Gene A (MxA) Expression Suppresses Influenza A Virus Replication in Alpha Interferon-Treated Primate Cells

    PubMed Central

    Matzinger, Shannon R.; Carroll, Timothy D.; Dutra, Joseph C.; Ma, Zhong-Min

    2013-01-01

    Alpha interferon (IFN-α) production is triggered when influenza virus RNA is detected by appropriate pattern recognition receptors in the host cell. IFN-α induces the expression of more than 300 interferon-stimulated genes (ISGs), and this blunts influenza virus replication. The human ISG MxA can inhibit influenza A virus replication in mouse cells by interfering with a step in the virus replication cycle after primary transcription of the negative-strand RNA genome to mRNA (J. Pavlovic, O. Haller, and P. Staeheli, J. Virol. 66:2564–2569, 1992). To determine the role of MxA in blocking human influenza A virus replication in primate cells, we manipulated MxA expression in rhesus kidney epithelial cells (LLC-MK2) and human lung carcinoma cells (A549). We found that IFN-α treatment prior to influenza virus infection suppressed virus replication and induced the expression of many ISGs, including MxA. However, IFN-α-mediated suppression of virus replication was abolished by small interfering RNA (siRNA) knockdown of MxA expression in IFN-treated cells. In addition, influenza virus replication was suppressed in Vero cells stably transfected with MxA. A strand-specific reverse transcription-PCR (RT-PCR) assay showed that positive-strand influenza virus mRNA and negative-strand genomic RNA (gRNA) accumulated to high levels at 8 h after infection in control Vero cells containing the empty vector. However, in Vero cells stably transfected with MxA positive-strand influenza virus mRNA, complementary positive-strand influenza virus genome RNA (cRNA) and influenza virus gRNA were drastically suppressed. Thus, in primate cells, MxA inhibits human seasonal influenza virus replication at a step prior to primary transcription of gRNA into mRNA. Taken together, these results demonstrate that MxA mediates control of influenza virus replication in primate cells treated with IFN-α. PMID:23152507

  9. Incidence and severity of infections according to the development of neutropenia during combined therapy with pegylated interferon-alpha2a plus ribavirin in chronic hepatitis C infection.

    PubMed

    Juarez-Navarro, A; Vera-de-León, L; Navarro, J M; Chirino-Sprung, R; Díaz-Hernandez, M; Casillas-Davila, L; Dehesa-Violante, M

    2005-06-01

    The evolution of treatment of chronic hepatitis C virus infection has led to improved therapeutic efficacy. However, a major problem is the presence of side effects that require modification or withdrawal of drug therapy in 15-20% of cases. This could potentially influence the lack of sustained viral response in 50% of the cases. Side effects are common, even with pegylated interferon. This study aimed to assess the incidence and severity of infections based on the development of neutropenia associated with combined therapy with pegylated interferon-alpha2a plus ribavirin in 209 patients with chronic hepatitis C infection. All patients were administered pegylated interferon-alpha2a (180 microg/week) plus ribavirin (800 mg/day for 24 weeks in cases of nongenotype 1, or 1000-1200 mg/day for 48 weeks for genotype 1, according to whether patients weighed more or less than 75 kg). Patients with preexisting neutropenia of any cause or cirrhosis were excluded. Neutropenia was defined as a neutrophil count (NC) of <1500 cells/microl. Neutropenia was classified into three levels during treatment: 750interferon-alpha2a plus ribavirin did not show a higher infection rate or increased severity of the disease. PMID:16082419

  10. Tumour necrosis factor-alpha and interferon-gamma synergistically activate the RANTES promoter through nuclear factor kappaB and interferon regulatory factor 1 (IRF-1) transcription factors.

    PubMed

    Lee, A H; Hong, J H; Seo, Y S

    2000-08-15

    Inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) synergistically activate expression of the RANTES (regulated upon activation, normal T-cell expressed and secreted) gene, which plays a crucial role in the chemoattraction of leukocytes during the inflammatory response. To understand at the molecular level the mechanism by which the two cytokines activate RANTES gene expression, we determined the requirement of cis-acting elements in the RANTES promoter and trans-acting factors. The murine RANTES promoter contained one putative interferon regulatory factor, IRF, and three putative nuclear factor kappaB (NF-kappaB) binding sites. Specific destruction of the IRF binding site and one of the three NF-kappaB binding sites abolished the inducibility of promoter activity by IFN-gamma and TNF-alpha, respectively. In contrast, mutation of the other two putative NF-kappaB binding sites did not affect RANTES promoter activity significantly. In addition, the RANTES promoter was stimulated by co-transfection of plasmids that expressed either p65, an NF-kappaB family protein, or the IRF-1 transcription factor. RANTES promoters with mutations in the NF-kappaB or IRF binding sites were not stimulated by p65 or IRF-1 expression, respectively. In electrophoretic mobility-shift and immunologic assays, we showed that IRF-1 was induced after cells were treated with IFN-gamma and that NF-kappaB was activated by TNF-alpha treatment. These results demonstrate that both NF-kappaB and IRF-1 transcription factors mediate the induction of RANTES expression via their cognate cis-acting elements when cells are stimulated by TNF-alpha and IFN-gamma. PMID:10926836

  11. Infectious salmon anaemia virus replication and induction of alpha interferon in Atlantic salmon erythrocytes

    PubMed Central

    Workenhe, Samuel T; Kibenge, Molly JT; Wright, Glenda M; Wadowska, Dorota W; Groman, David B; Kibenge, Frederick SB

    2008-01-01

    Background Infectious salmon anaemia (ISA) virus (ISAV), which causes ISA in marine-farmed Atlantic salmon, is an orthomyxovirus belonging to the genus Isavirus, family Orthomyxoviridae. ISAV agglutinates erythrocytes of several fish species and it is generally accepted that the ISAV receptor destroying enzyme dissolves this haemagglutination except for Atlantic salmon erythrocytes. Recent work indicates that ISAV isolates that are able to elute from Atlantic salmon erythrocytes cause low mortality in challenge experiments using Atlantic salmon. Previous work on ISAV-induced haemagglutination using the highly pathogenic ISAV strain NBISA01 and the low pathogenic ISAV strain RPC/NB-04-0851, showed endocytosis of NBISA01 but not RPC/NB-04-0851. Real-time RT-PCR was used to assess the viral RNA levels in the ISAV-induced haemagglutination reaction samples, and we observed a slight increase in viral RNA transcripts by 36 hours in the haemagglutination reaction with NBISA01 virus when the experiment was terminated. However, a longer sampling interval was considered necessary to confirm ISAV replication in fish erythrocytes and to determine if the infected cells mounted any innate immune response. This study examined the possible ISAV replication and Type I interferon (IFN) system gene induction in Atlantic salmon erythrocytes following ISAV haemagglutination. Results Haemagglutination assays were performed using Atlantic salmon erythrocytes and one haemagglutination unit of the two ISAV strains, NBISA01 and RPC/NB-04-0851, of differing genotypes and pathogenicities. Haemagglutination induced by the highly pathogenic NBISA01 but not the low pathogenic RPC/NB-04-0851 resulted in productive infection as evidenced by increased ISAV segment 8 transcripts and increase in the median tissue culture infectious dose (TCID50) by 5 days of incubation. Moreover, reverse transcription (RT) quantitative PCR used to compare mRNA levels of key Type I IFN system genes in erythrocyte

  12. The effect of alpha-interferon, cyclosporine A, and radiation-induced immune suppression on morphine-induced hypothermia and tolerance.

    PubMed

    Dougherty, P M; Harper, C; Dafny, N

    1986-12-01

    An interconnection between the immune and the central nervous systems has been suggested by investigators studying the actions of several types of immune modifying agents and procedures upon opiate related phenomena. These studies have included the effects of altering immune system function by administration of either alpha-interferon, cyclosporine or radiation exposure upon naloxone-precipitated opiate withdrawal and upon opioid antinociceptive effects. The present study extends these earlier investigations by examining the effect of immune modulation upon opiate induced hypothermia. The results demonstrate that interferon and cyclosporine have no effects on baseline temperature or morphine induced hypothermia, while irradiation exposure elicits hyperthermia without affecting morphine-induced hypothermia. Finally, neither cyclosporine nor irradiation affect the development of tolerance to morphine induced hypothermia, while a single injection of the immune system modifier interferon was able to prevent the development of such tolerance. These observations suggest that yet another opiate-related phenomenon may be regulated at least in part by the immune system. These results together with our previous findings are further evidence of a link between the immune system and the CNS mediated through the opioid system. In addition, these studies further support our earlier hypothesis that "Interferon" is one of the endogenous substances which serves to prevent the development of tolerance and dependence to endogenous opioids. PMID:3784774

  13. [Interferon alpha 2b in pain caused by herpes zoster. Preliminary report].

    PubMed

    Montero Mora, P; Colín, D; González Espinosa, A; Almeida Arvizu, V

    1996-01-01

    We studied forty patients with Zoster Herpes, twenty two of them, with this acute disease, eighteen with postherpetic neuralgia, to those that were considered chronic. The evaluation of the effect of INF alpha 2b, in the secondary pain of Zoster Herpes acute disease, in the patients with chronic severe secondary neuralgia they shared; the evolution with the treatment for half for visual pain analog scale in both groups the patients with acute pain, entered for visual pain analog scale between 10 and two points, with medium of 8.2 SD 2.1. They did not find any significance difference with this values p < 0.6. Most of the patients with acute pain was of 6 a 0 points with the medium a 0.27 y SD: 1,2 in the chronics went from. 6 to 0 points with a medium of 1.27 (SD:2.4), with a significative difference for t Student for comparation the initial scale in final in both groups of (p < 0.0001). The comparation of the best days, the disease bettered in acute quicker than the chronics with significance difference: (p < 0.001). PMID:9053126

  14. Phosphorylation of 20S proteasome alpha subunit C8 (alpha7) stabilizes the 26S proteasome and plays a role in the regulation of proteasome complexes by gamma-interferon.

    PubMed Central

    Bose, Suchira; Stratford, Fiona L L; Broadfoot, Kerry I; Mason, Grant G F; Rivett, A Jennifer

    2004-01-01

    In animal cells there are several regulatory complexes which interact with 20S proteasomes and give rise to functionally distinct proteasome complexes. gamma-Interferon upregulates three immuno beta catalytic subunits of the 20S proteasome and the PA28 regulator, and decreases the level of 26S proteasomes. It also decreases the level of phosphorylation of two proteasome alpha subunits, C8 (alpha7) and C9 (alpha3). In the present study we have investigated the role of phosphorylation of C8 by protein kinase CK2 in the formation and stability of 26S proteasomes. An epitope-tagged C8 subunit expressed in mammalian cells was efficiently incorporated into both 20S proteasomes and 26S proteasomes. Investigation of mutants of C8 at the two known CK2 phosphorylation sites demonstrated that these are the two phosphorylation sites of C8 in animal cells. Although phosphorylation of C8 was not absolutely essential for the formation of 26S proteasomes, it did have a substantial effect on their stability. Also, when cells were treated with gamma-interferon, there was a marked decrease in phosphorylation of C8, a decrease in the level of 26S proteasomes, and an increase in immunoproteasomes and PA28 complexes. These results suggest that the down-regulation of 26S proteasomes after gamma-interferon treatment results from the destabilization that occurs after dephosphorylation of the C8 subunit. PMID:14583091

  15. Analysis of HCV resistance mutations during combination therapy with protease inhibitor boceprevir and PEG-IFN alpha-2b using TaqMan mismatch amplification mutation assay.

    PubMed

    Curry, Stephanie; Qiu, Ping; Tong, Xiao

    2008-11-01

    TaqMan Mismatch Amplification Mutation Assay (TaqMAMA) is a highly sensitive allelic discrimination method. The mismatch amplification mutation assay (MAMA) is based on preferential amplification of mutant allele by the 'MAMA' primer, which is designed to have two mismatches with the wild-type allele and only one mismatch with the mutant allele. In this report, the TaqMAMA method was adapted for the detection and quantitation of minor HCV variants resistant to the protease inhibitor boceprevir (SCH 503034) from clinical samples. A good correlation of mutant frequency was observed between TaqMAMA and the results of clonal sequencing. TaqMAMA detected consistently minor variants at a level as low as 0.1%. Using TaqMAMA, it was demonstrated that resistant variants existed in the viral population before boceprevir treatment. The frequency of two resistant mutants (T54A and V170A) increased significantly during treatment with boceprevir, but was suppressed by combination treatment of PEG-IFN alpha-2b and boceprevir. The prevalence of both mutants decreased at the end of the two-week follow-up period. These results show that TaqMAMA can be used to detect minor resistant variants in pretreatment samples and to study in detail the evolution of mutant viruses during targeted antiviral therapy. PMID:18755220

  16. Comparison of the effects of early pregnancy with human interferon, alpha 2 (IFNA2), on gene expression in bovine endometrium.

    PubMed

    Bauersachs, Stefan; Ulbrich, Susanne E; Reichenbach, Horst-Dieter; Reichenbach, Myriam; Büttner, Mathias; Meyer, Heinrich H D; Spencer, Thomas E; Minten, Megan; Sax, Gerhard; Winter, Gerhard; Wolf, Eckhard

    2012-02-01

    Interferon tau (IFNT), a type I IFN similar to alpha IFNs (IFNA), is the pregnancy recognition signal produced by the ruminant conceptus. To elucidate specific effects of bovine IFNT and of other conceptus-derived factors, endometrial gene expression changes during early pregnancy were compared to gene expression changes after intrauterine application of human IFNA2. In experiment 1, endometrial tissue samples were obtained on Day (D) 12, D15, and D18 postmating from nonpregnant or pregnant heifers. In experiment 2, heifers were treated from D14 to D16 of the estrous cycle with an intrauterine device releasing IFNA2 or, as controls, placebo lipid extrudates or PBS only. Endometrial biopsies were performed after flushing the uterus. All samples from both experiments were analyzed with an Affymetrix Bovine Genome Array. Experiment 1 revealed differential gene expression between pregnant and nonpregnant endometria on D15 and D18. In experiment 2, IFNA2 treatment resulted in differential gene expression in the bovine endometrium. Comparison of the data sets from both studies identified genes that were differentially expressed in response to IFNA2 but not in response to pregnancy on D15 or D18. In addition, genes were found that were differentially expressed during pregnancy but not after IFNA2 treatment. In experiment 3, spatiotemporal alterations in expression of selected genes were determined in uteri from nonpregnant and early pregnant heifers using in situ hybridization. The overall findings of this study suggest differential effects of bovine IFNT compared to human IFNA2 and that some pregnancy-specific changes in the endometrium are elicited by conceptus-derived factors other than IFNT. PMID:22034527

  17. Ribavirin and alpha interferon enhance death receptor-mediated apoptosis and caspase activation in human hepatoma cells.

    PubMed

    Schlosser, Stephan F; Schuler, Markus; Berg, Christoph P; Lauber, Kirsten; Schulze-Osthoff, Klaus; Schmahl, Friedrich Wilhelm; Wesselborg, Sebastian

    2003-06-01

    The molecular mechanisms underlying the clinical effects of alpha interferon (IFN) and ribavirin are not understood. Elimination of infected cells occurs in part by cytotoxic T lymphocytes (CTLs) expressing CD95 ligand and thereby attacking target cells which are positive for the death receptor CD95. Since many viruses have evolved mechanisms to inhibit apoptosis, the opposite, namely, promotion of apoptosis, could be a strategy to strengthen the host antiviral response. In the present study, we have asked whether the antiviral substances IFN and ribavirin could support CD95-mediated apoptosis by interfering with the activation of caspases, a family of proteases known for their essential role in apoptosis. HepG2 cells, stimulated with the agonistic anti-CD95 antibody, served as a minimal model to mimic the CD95 stimulation occurring during a CTL attack of target cells in vivo. Apoptosis was quantitated by flow cytometric detection of hypodiploid nuclei. Caspase activity was measured by cytofluorometry, immunocytochemistry, and immunoblot analysis. IFN and ribavirin sensitized HepG2 cells for CD95-mediated apoptosis. This effect was correlated with an increase in CD95-mediated caspase activation and enhanced cleavage of the caspase substrate poly(ADP-ribose) polymerase. Furthermore, the positive effect on CD95-mediated caspase activation by IFN and ribavirin was confirmed by immunocytochemistry for activated caspase-3 and by immunoblot detection of activated caspase-3, caspase-7, and caspase-8. Our data demonstrate that the antiviral substances IFN and ribavirin are able to sensitize for CD95-mediated apoptosis. IFN and ribavirin also enhance CD95-mediated caspase activation, which might in part be responsible for the apoptosis-promoting effect of these antiviral compounds. PMID:12760867

  18. A phase II randomised trial of 5-fluorouracil with or without interferon alpha-2a in advanced colorectal cancer.

    PubMed Central

    Piga, A.; Cascinu, S.; Latini, L.; Marcellini, M.; Bavosi, M.; Acito, L.; Bascioni, R.; Giustini, L.; Francini, G.; Pancotti, A.; Rossi, G.; Del Papa, M.; Carle, F.; Cellerino, R.

    1996-01-01

    With the association of 5-fluorouracil (5-FU) and alpha-interferon (IFN), objective responses as high as 26 63% have been reported in untreated patients with advanced colorectal cancer. However, grade 3-4 toxicity has also been reported. We have conducted a prospective phase II randomised study comparing 5-FU to 5-FU + IFN, to investigate whether the addition of IFN to a weekly 5-FU regimen devoid of significant toxicity used at our institutions could improve the effectiveness of 5-FU while maintaining acceptable toxicity. Patients with histologically proven advanced colorectal carcinoma were randomised to receive 5-FU 500 mg m-2 intravenous (i.v.) bolus on days 1-5 followed by 5-FU 500 mg m-2 i.v. bolus weekly from day 15, with or without IFN alpha-2a intramuscularly (i.m.) 1.5 mU daily on days 6-12 and 3 mU i.m. daily thereafter. The treatment was administered on an outpatient basis. Response was evaluated every 3 months, and treatment continued until progression or after two consecutive judgements of stable disease. Response rate was the main end point of the study. Of 141 patients eligible, 72 were randomised to 5-FU alone (arm A) and 69 to 5-FU + IFN (arm B). Responses were 9/72 (12.5%) in arm A and 6/69 (8.7%) in arm B; complete responses were three in arm A and two in arm B. Progression-free survival (median 4 months) and survival (median 12 months) were identical in the two arms. Toxicity was almost absent in arm A and moderate in arm B, represented mainly by haematological toxicity (usually leucopenia). In conclusion, overall survival was good in both arms of treatment and toxicity was moderate. While the response rate with 5-FU alone was in accord with the literature data, response to 5-FU + IFN was lower than expected. At least at this dosage and schedule, the association of 5-FU and IFN is no better than 5-FU alone and is of no clinical interest. PMID:8826868

  19. OBTAINING OF THE TRANSGENIC HELIANTHUS TUBEROSUS L. PLANTS, CALLUS AND "HAIRY" ROOT CULTURES ABLE TO EXPRESS THE RECOMBINANT HUMAN INTERFERON ALPHA-2b GENE.

    PubMed

    Maistrenko, O M; Luchakivska, Yu S; Zholobak, N M; Spivak, M Ya; Kuchuk, M V

    2015-01-01

    This work is the first to our knowledge to describe the successful attempt of Agrobacterium rhizogenes-mediated transformation of topinambour in order to obtain the transgenic H. tuberosus plants, callus and "hairy" root cultures. The plasmid vectors contained the sequence of interferon gene fused with Nicotiana plumbagenifolia L. calreticulin apoplast targeting signal driven by 35S CaMV promoter or root-specific Mll promoter. Nearly 75% isolated Ri-root lines and callus cultures were proved (by PCR analysis) to contain HuINFa-2b transgene. We also managed to obtain H. tuberosus transgenic plants through somatic embryogenesis on the transgenic "hairy" root culture. The obtained transgenic H. tuberosus cultures exhibited high-level antiviral activity that ranged from 2000 to 54500 IU/g FW that makes this crop considered a promising source of recombinant interferon alpha 2b protein. PMID:26638495

  20. Treatment of putative non-A, non-B, non-C hepatitis with alpha interferon: a preliminary trial.

    PubMed

    Van Thiel, D H; Gavaler, J S; Baddour, N; Friedlander, L; Wright, H I

    1994-08-01

    Chronic hepatitis due to putative non-A, non-B, non-C hepatitis occurring in an individual who is negative for HBV and HCV markers has been identifiable only recently. Little or nothing is known about its natural history or response to interferon therapy. In the present study, 13 subjects with chronic non-A, non-B, non-C hepatitis were treated with interferon for 6 months (5 million units, three times per week). Prior to and after 6 months of therapy and again 6 weeks after discontinuing interferon therapy, each subject underwent a liver biopsy. These tissues were used to define the histopathology, the character of the cellular infiltrate within the liver, and the changes in histopathology and inflammatory infiltrate achieved in response to interferon therapy and withdrawal. No differences for age, gender, initial AST, bilirubin, histopathology, or Knodell score were evident between responders (n = 7) and non-responders (n = 6). Only the number of NK cells was altered significantly as a result of IFN treatment and distinguished responders from non-responders. These data demonstrate that: (1) chronic non-A, non-B, non-hepatitis can be treated with interferon; (2) interferon activates NK cells and enhances hepatocyte expression of Class II MHC antigens; and (3) interferon also increases the number of CD3, CD4, and CD8 cells found within the liver but these changes do not distinguish between responders and non-responders. PMID:7931774

  1. Adverse skin reactions due to pegylated interferon alpha 2b plus ribavirin combination therapy in a patient with chronic hepatitis C virus.

    PubMed

    Hashimoto, Yuki; Kanto, Hiromi; Itoh, Masatoshi

    2007-08-01

    Pegylated interferon (IFN)-alpha-2b with ribavirin has recently replaced "standard" IFN-alpha for the treatment of chronic hepatitis C. The most common side-effect of pegylated IFN-alpha-2b plus ribavirin combination therapy is localized inflammatory skin lesions at the site of injection. A 66-year-old female treated with once-weekly pegylated IFN-alpha-2b plus ribavirin for active chronic hepatitis C developed inflammatory skin lesions 2 months after starting antiviral treatment. The type of skin reactions observed were vesicle erythematous eruptions at the injection sites, and pruritic papular erythematous eruptions located on the face, neck, distal limbs, dorsa of the hands, trunk and buttocks away from the injection sites. Histological examination was performed on the pruritic papular erythematous eruption located on the left forearm, away from the injection sites. It showed epidermal spongiosis, a spongiotic microvesicle, and perivascular infiltration of the upper dermis with lymphocytes. The treatment was interrupted subsequently and the patient was rechallenged with pegylated IFN-alpha-2b plus ribavirin combination therapy, oral prednisolone with olopatadine hydrochloride and topical 0.1% diflucortolone valerate, which led to a significant improvement of skin lesions. Erythema with infiltration can occur at the injection sites of pegylated IFN-alpha-2b. However, the occurrence of vesicle erythematous eruptions away from the injection sites and autosensitization dermatitis apart from injection sites have not yet been frequently reported. PMID:17683392

  2. Effects of tumor necrosis factor-alpha and interferon-gamma on expressions of matrix metalloproteinase-2 and -9 in human bladder cancer cells.

    PubMed

    Shin, K Y; Moon, H S; Park, H Y; Lee, T Y; Woo, Y N; Kim, H J; Lee, S J; Kong, G

    2000-10-31

    We have investigated the effects of tumor necrosis factor-alpha (TNF-alpha) and interferon (INF-gamma), the potent Bacillus Calmette-Guerin (BCG)-induced cytokines on the production of MMP-2, MMP-9, TIMP-1, TIMP-2 and MT1-MMP in high grade human bladder cancer cell lines, T-24, J-82 and HT-1376 cell lines. MMP-2 expression and activity were decreased in T-24 cells treated with both cytokines in a dose dependent manner. However, J-82 cells treated with TNF-alpha and INF-gamma revealed dose dependent increases of MMP-9 expression and activity with similar baseline expression and activity of MMP-2. HT-1376 cells after exposure to TNF-alpha only enhanced the expression and activity of MMP-9. These results indicate that TNF-alpha and INF-gamma could regulate the production of MMP-2 or MMP-9 on bladder cancer cells and their patterns of regulation are cell specific. Furthermore, this diverse response of bladder cancer cells to TNF-alpha and INF-gamma suggests that BCG immunotherapy may enhance the invasiveness of bladder cancer in certain conditions with induction of MMPs. PMID:10996723

  3. Unique side effects of interferon.

    PubMed

    Aslam, Hina; Qadeer, Rashid; Kashif, Syed Mohammad; Rehan, Muhammad; Afsar, Salahuddin

    2015-08-01

    Interferon-alpha, a potent mediator of host immune response, has immunomodulatory properties in addition to its antiviral effects. A wide spectrum of autoimmune diseases can occur in patients treated with interferon-alpha for chronic hepatitis B and D, of which clinical systemic lupus erythematosus (SLE) accounts for less than 1% and hypothyroidism for 2-4 %. We report herein a case of a 16-year-old male who developed antinuclear antibody (ANA)-negative SLE and hypothyroidism after treatment with interferon-alpha for chronic hepatitis. High index of suspicion is therefore necessary in all patients treated with interferon for early diagnosis and treatment. PMID:26228341

  4. Nonstructural protein 1{alpha} subunit-based inhibition of NF-{kappa}B activation and suppression of interferon-{beta} production by porcine reproductive and respiratory syndrome virus

    SciTech Connect

    Song Cheng; Krell, Peter; Yoo, Dongwan

    2010-11-25

    Induction of type I interferon (IFN-{alpha}/{beta}) is an early antiviral response of the host, and porcine reproductive and respiratory syndrome virus (PRRSV) has been reported to downregulate the IFN response during infection in cells and pigs. We report that the PRRSV nonstructural protein 1{alpha} (Nsp1{alpha}) subunit of Nsp1 is a nuclear-cytoplasmic protein distributed to the nucleus and contains a strong suppressive activity for IFN-{beta} production that is mediated through the retinoic acid-inducible gene I (RIG-I) signaling pathway. Nsp1{alpha} suppressed the activation of nuclear factor (NF)-{kappa}B when stimulated with dsRNA or tumor necrosis factor (TNF)-{alpha}, and NF-{kappa}B suppression was RIG-I-dependent. The suppression of NF-{kappa}B activation was associated with the poor production of IFN-{beta} during PRRSV infection. The C-terminal 14 amino acids of the Nsp1{alpha} subunit were critical in maintaining immunosuppressive activity of Nsp1{alpha} for both IFN-{beta} and NF-{kappa}B, suggesting that the newly identified zinc finger configuration comprising of Met180 may be crucial for inhibitory activities. Nsp1{alpha} inhibited I{kappa}B phosphorylation and as a consequence NF-{kappa}B translocation to the nucleus was blocked, leading to the inhibition of NF-{kappa}B stimulated gene expression. Our results suggest that PRRSV Nsp1{alpha} is a multifunctional nuclear protein participating in the modulation of the host IFN system.

  5. Design of an efficient medium for heterologous protein production in Yarrowia lipolytica: case of human interferon alpha 2b

    PubMed Central

    2011-01-01

    Background The non conventional yeast Yarrowia lipolytica has aroused a strong industrial interest for heterologous protein production. However most of the studies describing recombinant protein production by this yeast rely on the use of complex media, such media are not convenient for large scale production particularly for products intended for pharmaceutical applications. In addition medium composition can also affect the production yield. Hence it is necessary to design an efficient medium for therapeutic protein expression by this host. Results Five different media, including four minimal media and a complex medium, were assessed in shake flasks for the production of human interferon alpha 2b (hIFN α2b) by Y. lipolytica under the control of POX2 promoter inducible with oleic acid. The chemically defined medium SM4 formulated by Invitrogen for Pichia pastoris growth was the most suitable. Using statistical experimental design this medium was further optimized. The selected minimal medium consisting in SM4 supplemented with 10 mg/l FeCl3, 1 g/l glutamate, 5 ml/l PTM1 (Pichia Trace Metals) solution and a vitamin solution composed of myo-inositol, thiamin and biotin was called GNY medium. Compared to shake flask, bioreactor culture in GNY medium resulted in 416-fold increase of hIFN α2b production and 2-fold increase of the biological activity. Furthermore, SM4 enrichment with 5 ml/l PTM1 solution contributed to protect hIFN α2b against the degradation by the 28 kDa protease identified by zymography gel in culture supernatant. The screening of the inhibitory effect of the trace elements present in PTM1 solution on the activity of this protease was achieved using a Box-Behnken design. Statistical data analysis showed that FeCl3 and MnSO4 had the most inhibitory effect. Conclusion We have designed an efficient medium for large scale production of heterologous proteins by Y. lipolytica. The optimized medium GNY is suitable for the production of hIFN α2b with the

  6. Production of interferon-gamma and tumour necrosis factor-alpha by human T-cell clones expressing different forms of the gamma delta receptor.

    PubMed Central

    Christmas, S E; Meager, A

    1990-01-01

    Panels of human T-cell clones bearing the gamma delta T-cell receptor (TcR) were obtained from peripheral blood and decidual tissue and maintained in the presence of interleukin-2 (IL-2). TcR V gamma and V delta gene expression was determined in 40 TcR delta 1+ clones using the gamma delta T-cell subset markers Ti gamma A and delta TCS1, in conjunction with Southern blot analysis using TcR J gamma and J delta probes. gamma delta T-cell clones, together with control alpha beta T-cell clones derived from the same lymphocyte populations, were stimulated with phytohaemagglutinin (PHA) and their ability to produce interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) tested using specific ELISA. Many clones representative of the major peripheral V gamma 9/V delta 2J1 subset produced high amounts of both cytokines and mean levels were not significantly different from those produced by alpha beta T-cell clones. Panels of clones expressing V gamma 9 and V delta 2J1 produced significantly higher levels of TNF-alpha than clones not expressing V delta 2J1 and those expressing V delta 1J1. There was no relationship between levels of IFN-gamma and TNF-alpha produced by individual gamma delta T-cell clones and also no relationship between their non-major histocompatibility complex (MHC)-restricted cytotoxic activity and levels of either cytokine. There was a significant tendency for gamma delta T-cell clones to produce more TNF-alpha than IFN-gamma in comparison to alpha beta T-cell clones. The significance of these findings is discussed in the light of the reported differences in distribution in vivo of V delta 1J1+ and V delta 2J1+ cells. Images Figure 1 PMID:2126252

  7. Interferon-alpha and transfer factor in the treatment of multiple sclerosis: a double-blind, placebo-controlled trial. AUSTIMS Research Group.

    PubMed Central

    1989-01-01

    The role of interferon-alpha (IFN-alpha) and transfer factor (TF) in the treatment of multiple sclerosis was investigated in a prospective, multi-centric, three year, double-blind, placebo-controlled trial. One hundred and eighty two patients with clinically definite multiple sclerosis were randomised into three treatment groups whose compositions were found to be similar for demographic and prognostic variables including HLA status. Subcutaneous injections of IFN-alpha (3 x 10(6) units), TF (0.5 units) manufactured from leucocytes of cohabiting donors, or placebo were given twice weekly for two months, once weekly for 10 months then fortnightly for 24 months. One hundred and fifty three patients completed the injection regimen. There was no significant difference in the progression of disability for multiple sclerosis patients in either the IFN-alpha or TF-treated groups compared with the placebo group. Similarly, change in visual evoked responses (VER), and in number of oligoclonal bands (OCB) and the level of myelin basic protein (MBP) in the cerebrospinal fluid (CSF) over the trial period did not differ significantly between the three groups. However, the IFN-alpha-treated group had significantly more reported adverse drug reactions and patient withdrawals than either of the other two groups. PMID:2659737

  8. Continuous oral cytarabine ocfosfate with interferon-alpha-2b for patients with newly diagnosed chronic myeloid leukaemia: a pilot study.

    PubMed

    del Cañizo, M C; Fisac, M P; Galende, J; Hurtado, J A; Moro, M J; Rodriguez, J A; Rivas, J M; Tabernero, M D

    2001-12-01

    Recombinant(R) interferon alpha (r-IFN-alpha) has been shown to be an effective drug for chronic myeloid leukaemia (CML). However, higher response rates can be achieved using cytarabine along with r-IFN-alpha. YNK01 is a derivative of cytosine arabinoside for oral administration. So far, the only published experience with continuous YNK01 was in advanced CML (10 cases). We have performed a pilot study to evaluate the efficacy and toxicity of the combined therapy r-IFN-alpha and daily oral YNK01 in patients with newly diagnosed Ph+ CML. Ten previously untreated patients were included in the study. Among those patients evaluable for cytogenetic response, 87% (seven out of eight) reached a major cytogenetic response with four reaching complete cytogenetic response (50%). The most significant side-effects were gastrointestinal. Macrocytic anaemia was observed in three patients. In conclusion, continuous oral administration of YNK01 in combination with IFN-alpha is safe and can result in high-cytogenetic response rates. PMID:11736933

  9. Treatment of advanced pancreatic cancer with 5-fluorouracil, folinic acid and interferon alpha-2A: results of a phase II trial.

    PubMed Central

    Bernhard, H.; Jäger-Arand, E.; Bernhard, G.; Heike, M.; Klein, O.; Riemann, J. F.; Meyer zum Büschenfelde, K. H.; Dippold, W.; Knuth, A.

    1995-01-01

    Interferon alpha-2a (IFN-alpha) and folinic acid (FA) have been shown to modulate the cytotoxic effects of 5-fluorouracil (5-FU) in the treatment of cancer. A phase II study was initiated to evaluate the effect of a combination of 5-FU/FA/IFN-alpha in patients with advanced pancreatic cancer. Sixty previously untreated patients with advanced adenocarcinoma of the pancreas were treated with 500 mg m-2 FU via an intravenous bolus 1 h after the initiation of a 2 h infusion of 500 mg m-2 FA. Before starting the FA infusion, 6 million units (MU) of IFN-alpha was administered subcutaneously. The treatment was repeated once a week. Of 57 evaluable patients, eight (14%) had a partial response (PR), eight (14%) a minor response (MR) and 28 (49%) no change of disease (NC). Thirteen patients (23%) had progressive disease (PD). The median survival time was 10 months for all patients, 22 months for patients with partial remission and 5 months for patients with progressive disease. Many patients with tumour-related pain whose tumours were affected in terms of PR, MR, NC were free of pain during treatment with this regimen (22/36 patients). The common toxicities observed were fever (56%), nausea (37%) and diarrhoea (33%). These data suggest that biochemical modulation of 5-FU with FA and IFN-alpha has some positive effects in the treatment of pancreatic cancer of moderate toxicity. PMID:7819023

  10. Interferon-alpha suppresses proliferation of chronic myelogenous leukemia cells K562 by extending cell cycle S-phase without inducing apoptosis.

    PubMed

    Grebenová, Dana; Kuzelová, Katerina; Fuchs, Ota; Halada, Petr; Havlícek, Vladimír; Marinov, Iuri; Hrkal, Zbynĕk

    2004-01-01

    We examined the effects of interferon-alpha (IFN-alpha) treatment on the growth, cell cycle, proliferation, and apoptotic parameters as well as adhesive properties and proteome of chronic myelogenous leukemia (CML)-derived K562 cells. IFN-alpha treatment (200 to 600 U/ml, 24 to 72 h) suppressed growth and caused accumulation of K562 cells in the S-phase of cell cycle (increase in S-phase cells by up to 52% in comparison with the untreated controls) at the expenses of cells in G1-phase. No transition of cells to G0-phase occurred as followed from Ki-67 protein determination. Although the level of chimeric gene product, BCR-ABL mRNA coding for BCR-ABL protein with anti-apoptotic properties, decreased by 30%, apoptosis was not triggered as judged from Annexin-V, APO2.7, and TUNEL assays. Adhesion of K562 cells to fibronectin-coated surfaces increased by up to 52% as determined by calcein assay. The proteomic analysis (2-D electrophoresis in combination with mass spectrometry, MALDI-MS) revealed a single protein, ubiquitine cross-reactive protein (UBCR), whose level markedly increased due to IFN-alpha treatment. The ubiquitination-like directed degradation processes may thus play a role in the mechanism of IFN-alpha antiproliferative effects. PMID:14757443

  11. Interferon Alpha Induces Sustained Changes in NK Cell Responsiveness to Hepatitis B Viral Load Suppression In Vivo

    PubMed Central

    Gill, Upkar S.; Peppa, Dimitra; Micco, Lorenzo; Singh, Harsimran D.; Carey, Ivana; Foster, Graham R.; Maini, Mala K.; Kennedy, Patrick T. F.

    2016-01-01

    NK cells are important antiviral effectors, highly enriched in the liver, with the potential to regulate immunopathogenesis in persistent viral infections. Here we examined whether changes in the NK pool are induced when patients with eAg-positive CHB are ‘primed’ with PegIFNα and importantly, whether these changes are sustained or further modulated long-term after switching to nucleos(t)ides (sequential NUC therapy), an approach currently tested in the clinic. Longitudinal sampling of a prospectively recruited cohort of patients with eAg+CHB showed that the cumulative expansion of CD56bright NK cells driven by 48-weeks of PegIFNα was maintained at higher than baseline levels throughout the subsequent 9 months of sequential NUCs. Unexpectedly, PegIFNα-expanded NK cells showed further augmentation in their expression of the activating NK cell receptors NKp30 and NKp46 during sequential NUCs. The expansion in proliferating, functional NK cells was more pronounced following sequential NUCs than in comparison cohorts of patients treated with de novo NUCs or PegIFNα only. Reduction in circulating HBsAg concentrations, a key goal in the path towards functional cure of CHB, was only achieved in those patients with enhancement of NK cell IFNγ and cytotoxicity but decrease in their expression of the death ligand TRAIL. In summary, we conclude that PegIFNα priming can expand a population of functional NK cells with an altered responsiveness to subsequent antiviral suppression by NUCs. Patients on sequential NUCs with a distinct NK cell profile show a decline in HBsAg, providing mechanistic insights for the further optimisation of treatment strategies to achieve sustained responses in CHB. PMID:27487232

  12. Treatment of naïve patients with chronic hepatitis C genotypes 2 and 3 with pegylated interferon alpha and ribavirin in a real world setting: relevance for the new era of DAA.

    PubMed

    Heidrich, Benjamin; Wiegand, Steffen B; Buggisch, Peter; Hinrichsen, Holger; Link, Ralph; Möller, Bernd; Böker, Klaus H W; Teuber, Gerlinde; Klinker, Hartwig; Zehnter, Elmar; Naumann, Uwe; Busch, Heiner W; Maasoumy, Benjamin; Baum, Undine; Hardtke, Svenja; Manns, Michael P; Wedemeyer, Heiner; Petersen, Jörg; Cornberg, Markus

    2014-01-01

    Evidence based clinical guidelines are implemented to treat patients efficiently that include efficacy, tolerability but also health economic considerations. This is of particular relevance to the new direct acting antiviral agents that have revolutionized treatment of chronic hepatitis C. For hepatitis C genotypes 2/3 interferon free treatment is already available with sofosbuvir plus ribavirin. However, treatment with sofosbuvir-based regimens is 10-20 times more expensive compared to pegylated interferon alfa and ribavirin (PegIFN/RBV). It has to be discussed if PegIFN/RBV is still an option for easy to treat patients. We assessed the treatment of patients with chronic hepatitis C genotypes 2/3 with PegIFN/RBV in a real world setting according to the latest German guidelines. Overall, 1006 patients were recruited into a prospective patient registry with 959 having started treatment. The intention-to-treat analysis showed poor SVR (GT2 61%, GT3 47%) while patients with adherence had excellent SVR in the per protocol analysis (GT2 96%, GT3 90%). According to guidelines, 283 patients were candidates for shorter treatment duration, namely a treatment of 16 weeks (baseline HCV-RNA <800.000 IU/mL, no cirrhosis and RVR). However, 65% of these easy to treat patients have been treated longer than recommended that resulted in higher costs but not higher SVR rates. In conclusion, treatment with PegIFN/RBV in a real world setting can be highly effective yet similar effective than PegIFN± sofosbuvir/RBV in well-selected naïve G2/3 patients. Full adherence to guidelines could be further improved, because it would be important in the new era with DAA, especially to safe resources. PMID:25302676

  13. Treatment of Naïve Patients with Chronic Hepatitis C Genotypes 2 and 3 with Pegylated Interferon Alpha and Ribavirin in a Real World Setting: Relevance for the New Era of DAA

    PubMed Central

    Buggisch, Peter; Hinrichsen, Holger; Link, Ralph; Möller, Bernd; Böker, Klaus H. W.; Teuber, Gerlinde; Klinker, Hartwig; Zehnter, Elmar; Naumann, Uwe; Busch, Heiner W.; Maasoumy, Benjamin; Baum, Undine; Hardtke, Svenja; Manns, Michael P.; Wedemeyer, Heiner; Petersen, Jörg; Cornberg, Markus

    2014-01-01

    Evidence based clinical guidelines are implemented to treat patients efficiently that include efficacy, tolerability but also health economic considerations. This is of particular relevance to the new direct acting antiviral agents that have revolutionized treatment of chronic hepatitis C. For hepatitis C genotypes 2/3 interferon free treatment is already available with sofosbuvir plus ribavirin. However, treatment with sofosbuvir-based regimens is 10–20 times more expensive compared to pegylated interferon alfa and ribavirin (PegIFN/RBV). It has to be discussed if PegIFN/RBV is still an option for easy to treat patients. We assessed the treatment of patients with chronic hepatitis C genotypes 2/3 with PegIFN/RBV in a real world setting according to the latest German guidelines. Overall, 1006 patients were recruited into a prospective patient registry with 959 having started treatment. The intention-to-treat analysis showed poor SVR (GT2 61%, GT3 47%) while patients with adherence had excellent SVR in the per protocol analysis (GT2 96%, GT3 90%). According to guidelines, 283 patients were candidates for shorter treatment duration, namely a treatment of 16 weeks (baseline HCV-RNA <800.000 IU/mL, no cirrhosis and RVR). However, 65% of these easy to treat patients have been treated longer than recommended that resulted in higher costs but not higher SVR rates. In conclusion, treatment with PegIFN/RBV in a real world setting can be highly effective yet similar effective than PegIFN± sofosbuvir/RBV in well-selected naïve G2/3 patients. Full adherence to guidelines could be further improved, because it would be important in the new era with DAA, especially to safe resources. PMID:25302676

  14. STAT1, STAT3 and p38MAPK are involved in the apoptotic effect induced by a chimeric cyclic interferon-{alpha}2b peptide

    SciTech Connect

    Blank, Viviana C.; Pena, Clara; Roguin, Leonor P.

    2010-02-15

    In the search of mimetic peptides of the interferon-{alpha}2b molecule (IFN-{alpha}2b), we have previously designed and synthesized a chimeric cyclic peptide of the IFN-{alpha}2b that inhibits WISH cell proliferation by inducing an apoptotic response. Here, we first studied the ability of this peptide to activate intracellular signaling pathways and then evaluated the participation of some signals in the induction of apoptosis. Stimulation of WISH cells with the cyclic peptide showed tyrosine phosphorylation of Jak1 and Tyk2 kinases, tyrosine and serine phosphorylation of STAT1 and STAT3 transcription factors and activation of p38 MAPK pathway, although phosphorylation levels or kinetics were in some conditions different to those obtained under IFN-{alpha}2b stimulus. JNK and p44/42 pathways were not activated by the peptide in WISH cells. We also showed that STAT1 and STAT3 downregulation by RNA interference decreased the antiproliferative activity and the amount of apoptotic cells induced by the peptide. Pharmacological inhibition of p38 MAPK also reduced the peptide growth inhibitory activity and the apoptotic effect. Thus, we demonstrated that the cyclic peptide regulates WISH cell proliferation through the activation of Jak/STAT signaling pathway. In addition, our results indicate that p38 MAPK may also be involved in cell growth regulation. This study suggests that STAT1, STAT3 and p38 MAPK would be mediating the antitumor and apoptotic response triggered by the cyclic peptide in WISH cells.

  15. Interferon Alpha Production by Circulating Dendritic Cells is Inhibited During Acute Infection with Foot-and-Mouth Disease Virus (FMDV)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Viruses have evolved multiple mechanisms to evade the innate immune response, particularly the actions of interferons (IFN). We have previously reported that exposure of dendritic cells (DCs) to foot-and-mouth disease virus (FMDV) in vitro yields no infection and induces a strong IFN response indica...

  16. Interferon Alpha Production by Swine Dendritic Cells is Inhibited During Acute Infection with Foot-and-Mouth Disease Virus (FMDV)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Viruses have evolved multiple mechanisms to evade the innate immune response, particularly the actions of interferons (IFN). We have previously reported that exposure of dendritic cells (DCs) to foot-and-mouth disease virus (FMDV) in vitro yields no infection and induces a strong IFN response indic...

  17. Randomized trial of high-dose interferon-alpha-2b combined with ribavirin in patients with chronic hepatitis C: Correlation between amino acid substitutions in the core/NS5A region and virological response to interferon therapy.

    PubMed

    Mori, Nami; Imamura, Michio; Kawakami, Yoshiiku; Saneto, Hiromi; Kawaoka, Tomokazu; Takaki, Shintaro; Aikata, Hiroshi; Takahashi, Shoichi; Chayama, Kazuaki

    2009-04-01

    The aim of this study was to compare the efficacy of high-dose interferon (IFN)-alpha-2b with standard dose of IFN-alpha-2b in combination with ribavirin (RBV) for patients with chronic hepatitis C virus (HCV) infection, and to investigate the predictive factors associated with virological response. Two hundred Japanese patients with high HCV viral load (>100 KIU/ml) were randomized to 6 or 10 mega units (MU) of 24-week IFN-alpha-2b with RBV. Predictive factors were investigated; including pretreatment amino acid (aa) sequences of the core region and the IFN-sensitive determining region (ISDR). The sustained virological response rate was not different in the two groups (24% vs. 30%) but the incidence of depression was significantly higher in the 10 MU group than 6 MU group (7% vs. 0%, P = 0.02). Younger age (<60) and HCV genotype (2a/b) were significant predictors of sustained virological response. In patients infected with genotype 1b, substitutions of core aa 70 and/or 91 were predictive for non-virological response (P < 0.001), and substitutions in the ISDR was observed frequently in virological responders. Early viral kinetics study showed that serum HCV core antigen decreased more slowly in both patients with aa 70 and/or 91 substitutions in the core and with absence of substitutions in the ISDR. In conclusion, the use of a higher dose of IFN-alpha-2b in combination with RBV did not improve virological response but resulted in higher incidence of depression. Amino acid substitutions in the core and ISDR are predictive of virological response to the therapy in patients with genotype 1b and high viral load. PMID:19235866

  18. Efficient Virus Assembly, but Not Infectivity, Determines the Magnitude of Hepatitis C Virus-Induced Interferon Alpha Responses of Plasmacytoid Dendritic Cells

    PubMed Central

    Grabski, Elena; Wappler, Ilka; Pfaender, Stephanie; Steinmann, Eike; Haid, Sibylle; Dzionek, Andrzej

    2014-01-01

    ABSTRACT Worldwide, approximately 160 million people are chronically infected with hepatitis C virus (HCV), seven distinct genotypes of which are discriminated. The hallmarks of HCV are its genetic variability and the divergent courses of hepatitis C progression in patients. We assessed whether intragenotypic HCV variations would differentially trigger host innate immunity. To this end, we stimulated human primary plasmacytoid dendritic cells (pDC) with crude preparations of different cell culture-derived genotype 2a HCV variants. Parental Japanese fulminant hepatitis C virus (JFH1) did not induce interferon alpha (IFN-α), whereas the intragenotypic chimera Jc1 triggered massive IFN-α responses. Purified Jc1 retained full infectivity but no longer induced IFN-α. Coculture of pDC with HCV-infected hepatoma cells retrieved the capacity to induce IFN-α, whereas Jc1-infected cells triggered stronger responses than JFH1-infected cells. Since the infectivity of virus particles did not seem to affect pDC activation, we next tested Jc1 mutants that were arrested at different stages of particle assembly. These experiments revealed that efficient assembly and core protein envelopment were critically needed to trigger IFN-α. Of note, sequences within domain 2 of the core that vitally affect virus assembly also crucially influenced the IFN-α responses of pDC. These data showed that viral determinants shaped host innate IFN-α responses to HCV. IMPORTANCE Although pegylated IFN-α plus ribavirin currently is the standard of care for the treatment of chronic hepatitis C virus infection, not much is known about the relevance of early interferon responses in the pathogenesis of hepatitis C virus infection. Here, we addressed whether intragenotypic variations of hepatitis C virus would account for differential induction of type I interferon responses mounted by primary blood-derived plasmacytoid dendritic cells. Surprisingly, a chimeric genotype 2a virus carrying the

  19. Combination of interferon-alpha and 5-fluorouracil inhibits endothelial cell growth directly and by regulation of angiogenic factors released by tumor cells

    PubMed Central

    2009-01-01

    Background The combination therapy of interferon (IFN)-alpha and 5-fluorouracil (5-FU) improved the prognosis of the patients with hepatocellular carcinoma (HCC). To determine the molecular mechanisms of the anti-tumor and anti-angiogenic effects, we examined the direct anti-proliferative effects on human umbilical vein endothelial cells (HUVEC) and indirect effects by regulating secretion of angiogenic factors from HCC cells. Methods The direct effects on HUVEC were examined by TUNEL, Annexin-V assays and cell cycles analysis. For analysis of the indirect effects, the apoptosis induced by the conditioned medium from HCC cell treated by IFN-alpha/5-FU and expression of angiogenic factors was examined. Results IFN-alpha and 5-FU alone had anti-proliferative properties on HUVEC and their combination significantly inhibited the growth (compared with control, 5-FU or IFN alone). TUNEL and Annexin-V assays showed no apoptosis. Cell cycle analysis revealed that IFN-alpha and 5-FU delayed cell cycle progression in HUVEC with S-phase accumulation. The conditioned medium from HuH-7 cells after treatment with IFN/5-FU significantly inhibited HUVEC growth and induced apoptosis, and contained high levels of angiopoietin (Ang)-1 and low levels of vascular endothelial growth factor (VEGF) and Ang-2. Knockdown of Ang-1 in HuH-7 cells abrogated the anti-proliferative effects on HUVEC while knockdown of Ang-2 partially rescue the cells. Conclusion These results suggested that IFN-alpha and 5-FU had direct growth inhibitory effects on endothelial cells, as well as anti-angiogenic effects through regulation of angiogenic factors released from HCC cells. Modulation of VEGF and Angs secretion by IFN-alpha and 5-FU may contribute to their anti-angiogenic and anti-tumor effects on HCC. PMID:19821965

  20. Prediction of successful outcome in a randomised controlled trial of the long-term efficacy of interferon alpha treatment for chronic hepatitis C.

    PubMed

    Vandelli, C; Renzo, F; Braun, H B; Tisminetzky, S; Albrecht, M; De Palma, M; Ranzi, A; Di Marco, G; Stroffolini, T; Baralle, F; Ventura, E; Michel, G

    1999-05-01

    To evaluate the efficacy of a 12-month course of recombinant interferon alpha (IFN-alpha2b), and to assess predictive factors of successful response to IFN therapy in chronic active hepatitis C (HCV CAH), 242 patients with histologically proven HCV CAH were assigned randomly to two groups, one treated with IFN-alpha2b (3 MU three times weekly, intramuscularly), the other untreated. To determine the efficacy of IFN-alpha2b 12 months after therapy, a second liver biopsy was carried out on 100 treated patients and 27 untreated patients. The biochemical, virological, and serological response of patients followed up for at least 50 months after treatment was also evaluated to confirm the efficacy of IFN-alpha2b. The genotypes of infecting HCV, anti-HCV core IgM, and HCV-RNA concentrations were also analysed and the predictors of response determined by univariate and multivariate analyses. Response was defined in terms of the normalisation of aminotransferase activities and the disappearance of HCV-RNA. The overall long-term response was 39.4%. Anti-HCV core IgM levels were significantly lower in long-term responders. Patients with increased levels of IgM anti HCV core (>3.8 sample/cut-off), infected with genotype 1b were nonresponders. Liver histology improved significantly in patients with long-term response. Multivariate analysis identified three independent predictors of the likelihood of long-term response to IFN therapy: age younger than 40 years, basal anti-HCV core IgM levels < or = 3.8, and genotypes other than 1b. These data indicate that the treatment with IFN-alpha2b used in this randomised controlled trial is effective in HCV CAH. Anti-HCV core IgM was the strongest predictor of long-term response in the present study. PMID:10223542

  1. Inhibition of sup 125 I organification and thyroid hormone release by interleukin-1, tumor necrosis factor-alpha, and interferon-gamma in human thyrocytes in suspension culture

    SciTech Connect

    Sato, K.; Satoh, T.; Shizume, K.; Ozawa, M.; Han, D.C.; Imamura, H.; Tsushima, T.; Demura, H.; Kanaji, Y.; Ito, Y. )

    1990-06-01

    To elucidate the mechanism of decreased 131I uptake by the thyroid gland in patients with subacute thyroiditis and painless thyroiditis, human thyroid follicles were cultured with interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF alpha), and/or interferon-gamma (IFN gamma), and the effects of these cytokines on thyroid function were studied in vitro. When human thyrocytes were cultured in RPMI-1640 medium containing 0.5% fetal calf serum and TSH for 5-8 days, the cells incorporated 125I, synthesized de novo (125I)iodotyrosines and (125I)iodothyronines, and secreted (125I)T4 and (125I)T3 into the medium. IL-1 alpha and IL-1 beta inhibited 125I incorporation and (125I)iodothyronine release in a concentration-dependent manner. The minimal inhibitory effect was detected at 10 pg/ml. Electron microscopic examination revealed a marked decrease in lysosome formation in IL-1-treated thyrocytes. TNF alpha and IFN gamma also inhibited thyroid function in a concentration-dependent manner. Furthermore, when thyrocytes were cultured with IL-1, TNF alpha and IFN gamma, these cytokines more than additively inhibited thyroid function. Although the main mechanism of 131I uptake suppression in the thyroid gland in subacute thyroiditis is due to cellular damage and suppression of TSH release, our present findings suggest that IL-1, TNF alpha, and IFN gamma produced in the inflammatory process within the thyroid gland further inhibit iodine incorporation and at least partly account for the decreased 131I uptake by the thyroid gland in destruction-induced hyperthyroidism.

  2. Induction of thymidine phosphorylase as a pharmacodynamic end-point in patients with advanced carcinoma treated with 5-fluorouracil, folinic acid and interferon alpha

    PubMed Central

    Braybrooke, J P; Propper, D J; O’Byrne, K J; Koukourakis, M I; Patterson, A V; Houlbrook, S; Love, S D; Varcoe, S; Taylor, M; Ganesan, T S; Talbot, D C; Harris, A L

    2000-01-01

    Thymidine phosphorylase (TP) is an essential enzyme for the biochemical activation of 5-fluorouracil (5-FU). Interferon upregulates TP in vivo, although the dose and schedule of interferon for optimal biomodulation of 5-FU is not known. In this study, TP activity was measured in peripheral blood lymphocytes (PBLs) from patients with advanced carcinoma receiving treatment with 5-FU and folinic acid. Cohorts of patients were treated with interferon alpha (IFNα), immediately prior to 5-FU/folinic acid, at doses of 3 MIU m–2, 9 MIU m–2and 18 MIUm–2. IFNα was administered on day 0 cycle two, day –1 and day 0 cycle three and day –2, day –1 and day 0 cycle four. A fourth cohort was treated with IFNα 9 MIU m–2three times per week from cycle 2 onwards. Twenty-one patients were entered into the study with 19 evaluable for response. Six patients (32%) had stable disease and 13 (68%) progressive disease. There were no grade-IV toxicities. TP activity was detected in PBLs from all patients with wide interpatient variability in constitutive TP activity prior to chemotherapy, and in response to IFNα. 5-FU/folinic acid alone did not induce TP activity but a single dose of IFNα led to upregulation of TP within 2 h of administration with a further increase by 24 h (signed rank test, P = 0.006). TP activity remained elevated for at least 13 days (signed rank test, P = 0.02). There were no significant differences in TP activity between schedules or with additional doses of IFNα. A single dose of IFNα as low as 3 MIU m–2can cause sustained elevation of PBL TP activity in vivo indicating that biochemical markers are important pharmacodynamic endpoints for developing optimal schedules of IFNα for biomodulation of 5-FU. © 2000 Cancer Research Campaign PMID:10901374

  3. Differential effects of angiostatin, endostatin and interferon-alpha(1) gene transfer on in vivo growth of human breast cancer cells.

    PubMed

    Indraccolo, S; Gola, E; Rosato, A; Minuzzo, S; Habeler, W; Tisato, V; Roni, V; Esposito, G; Morini, M; Albini, A; Noonan, D M; Ferrantini, M; Amadori, A; Chieco-Bianchi, L

    2002-07-01

    The administration of different angiogenesis inhibitors by gene transfer has been shown to result in inhibition of tumor growth in animal tumor models, but the potency of these genes has been only partially evaluated in comparative studies to date. To identify the most effective anti-angiogenic molecule for delivery by retroviral vectors, we investigated the effects of angiostatin, endostatin and interferon(IFN)-alpha(1) gene transfer in in vivo models of breast cancer induced neovascularization and tumor growth. Moloney leukemia virus-based retroviral vectors for expression of murine angiostatin, endostatin and IFN-alpha(1) were generated, characterized, and used to transduce human breast cancer cell lines (MCF7 and MDA-MB435). Secretion of the recombinant proteins was confirmed by biological and Western blotting assays. Their production did not impair in vitro growth of these breast cancer cells nor their viability, and did not interfere with the expression of angiogenic factors. However, primary endothelial cell proliferation and migration in vitro were inhibited by supernatants of the transduced cells containing angiostatin, endostatin, and IFN-alpha(1). Stable gene transfer of the IFN-alpha(1) cDNA by retroviral vectors in both MCF7 and MDA-MB435 cells resulted in a marked and long-lasting inhibition of tumor growth in nude mice that was associated with reduced vascularization. Endostatin reduced the in vivo growth of MDA-MB435, but not MCF7 cells, despite similar levels of in vivo production, and angiostatin did not impair the in vivo growth of either cell line. These findings indicate heterogeneity in the therapeutic efficacy of angiostatic molecules delivered by viral vectors and suggest that gene therapy with IFN-alpha(1) and endostatin might be useful for treatment of breast cancer. PMID:12080381

  4. Human T-cell leukemia virus type 1 Tax modulates interferon-alpha signal transduction through competitive usage of the coactivator CBP/p300.

    PubMed

    Zhang, Jing; Yamada, Osamu; Kawagishi, Kenji; Araki, Hiromasa; Yamaoka, Shoji; Hattori, Toshio; Shimotohno, Kunitada

    2008-09-30

    We describe here Tax protein of human T-cell leukemia virus type 1 (HTLV-1) as an interferon (IFN)-alpha antagonist counteracting the transactivation function of IFN-stimulated gene factor 3 (ISGF3). Co-expression of Tax, but not the Tax mutant unable to bind to CBP, significantly inhibited the reporter gene expression directed by IFN-stimulated regulatory elements, despite that the formation of DNA-binding ISGF3 complex was unaffected. Gene activation induced by STAT2 transcription domain was also inhibited by expression of Tax. Furthermore, Tax-mediated transcriptional inhibition was reversed by overexpression of p300. These observations indicate that Tax interferes with IFN-alpha-induced JAK-STAT pathway by competition with STAT2 for CBP/p300 binding. Consistently, GST pull-down assay showed that Tax dose-dependently inhibited binding of STAT2 to p300. This study suggests that Tax may prevent IFN-alpha from exerting its antiviral, antiproliferative and proapoptotic effects, thereby contributing to persistent viral infection and HTLV-1-associated oncogenesis. PMID:18678383

  5. Association of Interferon-Alpha and Ribavirin-Induced Thyroid Dysfunction with Severity of Disease and Response to Treatment in Pakistani Asian Patients of Chronic Hepatitis C

    PubMed Central

    Nadeem, Amina; Aslam, Muhammad

    2012-01-01

    Objective. To determine the association of thyroid dysfunction with the severity of the disease and response to treatment in patients of chronic hepatitis C. Design. Cohort study. Patients. One hundred and sixty seven noncirrhotic chronic hepatitis C patients were grouped into treatment group (n = 107) and control group (n = 60). Measurements. Baseline S. ALT and S. AST by IFCC and S. TSH, S. free T4, and S.T3 level were measured by chemiluminescence method. The severity of the disease was measured by Knodell histopathological index (HPI) on liver biopsy. Study group patients underwent 24-weeks IFN and ribavirin therapy and thyroid functions were determined at weeks 0, 12, and 24. Response to therapy was determined by PCR-HCV test. Results. 20 treated patients (18.69%) developed thyroid dysfunction with relative risk (RR) of 11.25 and attributable risk (AR) of 91%. Females were at higher risk. Hypothyroidism was common than hyperthyroidism. There was no significant association between thyroid dysfunction and severity of the disease (P = 0.81) and response to therapy (P = 0.79). Conclusion. Interferon-alpha and ribavirin therapy induces thyroid dysfunction in chronic hepatitis C patients. There is no association between severity of disease and response to therapy with interferon-induced thyroid dysfunction. PMID:22973506

  6. Phase III trial of chemotherapy using 5-fluorouracil and streptozotocin compared with interferon alpha for advanced carcinoid tumors: FNCLCC-FFCD 9710.

    PubMed

    Dahan, Laetitia; Bonnetain, Frank; Rougier, Philippe; Raoul, Jean-Luc; Gamelin, Eric; Etienne, Pierre-Luc; Cadiot, Guillaume; Mitry, Emmanuel; Smith, Denis; Cvitkovic, Frédérique; Coudert, Bruno; Ricard, Floriane; Bedenne, Laurent; Seitz, Jean-François

    2009-12-01

    The aim of this randomized multicenter phase III trial was to compare chemotherapy and interferon (IFN) in patients with metastatic carcinoid tumors. Patients with documented progressive, unresectable, metastatic carcinoid tumors were randomized between 5-fluorouracil plus streptozotocin (day 1-5) and recombinant IFN-alpha-2a (3 MU x 3 per week). Primary endpoint was progression-free survival (PFS). From February 1998 to June 2004, 64 patients were included. The two arms were well matched for median age, sex ratio, PS 0-1, previous chemotherapy, surgery, or radiotherapy. The median PFS for chemotherapy was 5.5 months versus 14.1 for IFN (hazard ratio=0.75 (0.41-1.36)). Overall survival (OS), tolerance, and effects on carcinoid symptoms were not significantly different. Despite a trend in favor of IFN, there was no difference in PFS and OS in advanced metastatic carcinoid tumors and therapeutic effect of both treatments was mild. PMID:19726540

  7. Effects of S-adenosyl-L-methionine and interferon-alpha2b on liver damage induced by bile duct ligation in rats.

    PubMed

    Muriel, P; Castro, V

    1998-01-01

    Interferon-alpha2b (IFN) is known to prevent and to reverse experimental liver fibrosis and damage. S-Adenosyl-L-methionine (SAM) is a well-known hepatoprotective substance. The aim of the present work was to determine the effect of the administration of both drugs simultaneously to bile duct-ligated rats. Administration of IFN (50000 IU s.c.) and/or SAM (10 mg kg[-1] i.m.) began 15 days after biliary obstruction and continued for a further 15 days. The liver was used for glycogen and collagen quantification. Bilirubins and enzyme activities were measured in serum. Either SAM or IFN ameliorated all markers of liver damage studied. However, when administered together their beneficial effects were markedly reduced. It is not possible to explain the antagonistic effect of these compounds on liver damage with the present data. More studies are needed to determine SAM-IFN interactions. PMID:9570697

  8. Lipopolysaccharide and Tumor Necrosis Factor Alpha Inhibit Interferon Signaling in Hepatocytes by Increasing Ubiquitin-Like Protease 18 (USP18) Expression

    PubMed Central

    MacParland, Sonya A.; Ma, Xue-Zhong; Chen, Limin; Khattar, Ramzi; Cherepanov, Vera; Selzner, Markus; Feld, Jordan J.; Selzner, Nazia

    2016-01-01

    ABSTRACT Inflammation may be maladaptive to the control of viral infection when it impairs interferon (IFN) responses, enhancing viral replication and spread. Dysregulated immunity as a result of inappropriate innate inflammatory responses is a hallmark of chronic viral infections such as, hepatitis B virus and hepatitis C virus (HCV). Previous studies from our laboratory have shown that expression of an IFN-stimulated gene (ISG), ubiquitin-like protease (USP)18 is upregulated in chronic HCV infection, leading to impaired hepatocyte responses to IFN-α. We examined the ability of inflammatory stimuli, including tumor necrosis factor alpha (TNF-α), lipopolysaccharide (LPS), interleukin-6 (IL-6) and IL-10 to upregulate hepatocyte USP18 expression and blunt the IFN-α response. Human hepatoma cells and primary murine hepatocytes were treated with TNF-α/LPS/IL-6/IL-10 and USP18, phosphorylated (p)-STAT1 and myxovirus (influenza virus) resistance 1 (Mx1) expression was determined. Treatment of Huh7.5 cells and primary murine hepatocytes with LPS and TNF-α, but not IL-6 or IL-10, led to upregulated USP18 expression and induced an IFN-α refractory state, which was reversed by USP18 knockdown. Liver inflammation was induced in vivo using a murine model of hepatic ischemia/reperfusion injury. Hepatic ischemia/reperfusion injury led to an induction of USP18 expression in liver tissue and promotion of lymphocytic choriomeningitis replication. These data demonstrate that certain inflammatory stimuli (TNF-α and LPS) but not others (IL-6 and IL-10) target USP18 expression and thus inhibit IFN signaling. These findings represent a new paradigm for how inflammation alters hepatic innate immune responses, with USP18 representing a potential target for intervention in various inflammatory states. IMPORTANCE Inflammation may prevent the control of viral infection when it impairs the innate immune response, enhancing viral replication and spread. Blunted immunity as a result of

  9. Vaccination of renal cell cancer patients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax) alone or administered in combination with interferon-alpha (IFN-alpha): a phase 2 trial.

    PubMed

    Amato, Robert J; Shingler, William; Goonewardena, Madusha; de Belin, Jackie; Naylor, Stuart; Jac, Jaroslaw; Willis, James; Saxena, Somyata; Hernandez-McClain, Joan; Harrop, Richard

    2009-09-01

    Attenuated vaccinia virus, modified vaccinia Ankara (MVA) has been engineered to deliver the tumor antigen 5T4 (TroVax). MVA-5T4 has been evaluated in an open-label phase 2 trial in metastatic renal cell cancer patients in which the vaccine was administered alone or in combination with interferon-alpha-2b (IFN-alpha). The safety, immunologic, and clinical efficacy of MVA-5T4 with or without IFN-alpha was determined. Twenty-eight patients with metastatic renal cell cancer were treated with MVA-5T4 alone (13) or plus IFN-alpha (15). The 5T4-specific cellular and humoral responses were monitored throughout the study. Clinical responses were assessed by measuring changes in tumor burden by computed tomography or magnetic resonance imaging scan. MVA-5T4 was well tolerated with no serious adverse event attributed to vaccination. Of 23 intent-to-treat patients tested for immune responses postvaccination, 22 (96%) mounted 5T4-specific antibody and/or cellular responses. One patient treated with MVA-5T4 plus IFN-alpha showed a partial response for >7 months, whereas an additional 14 patients (7 receiving MVA-5T4 plus IFN and 7 receiving MVA-5T4 alone) showed periods of disease stabilization ranging from 1.73 to 9.60 months. Median progression free survival and overall survival for all intent-to-treat patients was 3.8 months (range: 1 to 11.47 mo) and 12.1 months (range: 1 to 27 mo), respectively. MVA-5T4 administered alone or in combination with IFN-alpha was well tolerated in all patients. Despite the high frequency of 5T4-specific immune responses, it is not possible to conclude that patients are receiving clinical benefit. The results are encouraging and warrant further investigation. PMID:19561532

  10. Antitumor activities of interferon alpha, beta, and gamma and their combinations on human melanoma cells in vitro: changes of proliferation, melanin synthesis, and immunophenotype.

    PubMed

    Garbe, C; Krasagakis, K; Zouboulis, C C; Schröder, K; Krüger, S; Stadler, R; Orfanos, C E

    1990-12-01

    The antitumor activities of human interferon (IFN) alpha, beta, and gamma alone or in combination were studied on four human melanoma cell lines (StML-11, StML-12, StML-14, and SKMel-28) in various concentrations (1-50,000 IU/ml IFN alpha, 0.1-1000 IU/ml IFN beta, 1-10,000 IU/ml IFN gamma) in vitro. In all experiments IFN beta exhibited the most potent antiproliferative effect of all IFN tested. After 3 d of incubation a 50% growth inhibition was achieved with 20-40 IU/ml for natural IFN beta and with 600-1200 U/ml for recombinant IFN gamma. Substantially higher doses (7,000 to more than 50,000 IU/ml) of recombinant IFN alpha 2a were required to achieve a 50% growth inhibition. A strong synergistic antiproliferative activity resulted from the combination of IFN alpha with IFN gamma and IFN beta with IFN gamma. None of the IFN tested induced terminal differentiation of melanoma cells in vitro. The formation of dendrites was inhibited, and the portion of differentiated cells in vitro was reduced after treatment with IFN in comparison to the untreated controls (untreated controls: 100%; portion of differentiated cells after treatment with IFN alpha: 58%-74%, IFN beta: 48%-96%, IFN gamma: 10%-33%). The melanin synthesis was slightly elevated after treatment with IFN alpha (untreated controls: 100%; after treatment with IFN alpha: 103%-157%, ns.) and decreased significantly after treatment with IFN beta (49%-71%, p less than 0.05) as well as with IFN gamma (80%-88%, ns.). Cell surface markers were modulated varyingly by the IFN: HLA-I antigens were enhanced by all IFN, with IFN beta emerging as the most potent inducer. Only IFN gamma, however, induced a de novo expression of HLA-DR and -DQ antigens and increased the expression of the ICAM-1 molecule and of the melanoma progression marker A.1.43. Possibly, these findings indicate a biologically more aggressive phenotype of melanoma cells. PMID:2124247