Early immune-mediated response to ribavirin combined with IFN in patients with chronic hepatitis C.
ABSTRACT This study was to investigate the immunomodulatory effects of ribavirin combined with interferon (IFN)-alpha 2b (R+IFN) compared with consensus IFN monotherapy (IFN-Con) in chronic hepatitis C (CHC) patients.
Thirty-four adult patients with biopsy-proven CHC, who were infected with HCV genotype 2a or 2b, were studied. A 24-week regimen of IFN-alpha 2b (6MU daily for 2 weeks followed by 6MU tiw for 22 weeks) and ribavirin (600-800mg/day for 24 weeks) was given to 17 patients. The other 17 patients were treated with a 24-week regimen of IFN-Con (18MU daily for 2 weeks followed by 18MU tiw for 22 weeks). Flow cytometric determination of cytoplasmic IFN-gamma and IL-4 expression in peripheral blood CD4+ T cells was performed, and the percentage of IFN-gamma+ and IL-4- (Th1), IFN-gamma- and IL-4+ (Th2) cells were calculated before and 3, 7, 14, and 28 days after the start of therapy.
In the R+IFN group, the percentage of Th1 cell peaked on day 3, and then decreased to near baseline by day 14, while the percentage of Th2 cell did not change. In the IFN-Con group, the percentage of Th1 cell peaked on day 14 and the percentage of Th2 cell peaked on day 3, and then decreased to near baseline by day 14.
Our results suggest that ribavirin induces an early immune response by peripheral blood CD4+ T cells in CHC patients.
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ABSTRACT: To study whether the host's immune response determines viral clearance in chronic hepatitis C, virological markers and antigen-specific T cell reactions were analysed in 30 chronic HCV carriers followed up during interferon-alpha therapy, 11 untreated anti-HCV positive individuals and 10 healthy controls. Proliferative T helper cell responses to recombinant HCV core and non-structural antigens were monitored by 3H-thymidine uptake assay and compared to quantitative viraemia levels and HCV genotypes. Of the 30 treated patients, six had sustained complete responses (20%), another six were transient therapy responders (20%) and 18 were non-responders (60%). Viral clearance was associated with the HCV genotype 3 and low pretreatment viral load. In a substantial proportion of complete and transient therapy responders, increased NS3-, helicase- and NS4-antigen-specific T cell responses were observed during interferon-alpha therapy. In non-responders and in the later clinical courses of transient therapy responders, core and NS5-specific T cell responses dominated. In addition, 11 untreated anti-HCV antibody positive individuals were studied. Two HCV-RNA negative patients who might have recovered from HCV infection showed strong persistent lymphoproliferative responses to NS3, helicase and NS4 antigens, whereas seven of the nine viraemic patients reacted with HCV core or NS5 antigens. Interferon-alpha treatment enhances NS3-, helicase- and NS4-antigen-specific T helper cell responses in patients with viral clearance, whereas viral persistence was associated with increased T cell reactivities against core and NS5 antigens. Immunogenetical, immunological and virological factors that may influence differential T cell induction in chronic hepatitis C are discussed.Journal of Hepatology 11/1998; 29(4):524-32. · 9.86 Impact Factor
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ABSTRACT: Cell-mediated cytotoxicity is exerted via perforin and Fas ligand (FasL). We have recently shown that IFN-alpha up-regulates FasL expression in T cells isolated from healthy volunteers and augments activation-induced T cell death. Since the Fas/FasL system is implicated in the pathogenesis of hepatic failure and both molecules have been shown to be up-regulated in hepatitis C virus (HCV) infection, we studied whether cytotoxicity via the FasL system is enhanced by IFN-alpha and therefore could contribute to hepatic injury. We investigated FasL and perforin expression in peripheral blood mononuclear cells (PBMC) derived from HCV+ donors by Northern analysis and soluble FasL synthesis by ELISA. Natural killer (NK) cell and cytotoxic T lymphocyte (CTL) cytotoxicity was studied by 51Cr-release assays. IFN-alpha up-regulates FasL mRNA and protein synthesis in mitogen-activated PBMC of HCV+ individuals, as previously found in healthy subjects. Stimulation with IFN-alpha increases perforin mRNA levels in PBMC. In NK cytotoxicity assays, the enhancement of cytotoxicity by IFN-alpha is mainly due to the perforin pathway, while the FasL pathway plays only a minor role. In CTL cytotoxicity experiments neither the FasL nor the perforin pathway is further enhanced by IFN-alpha. Our data suggest that up-regulation of perforin by IFN-alpha results in elevated cytotoxicity, suggesting that IFN-alpha might support elimination of virally infected cells via this pathway. In contrast, the major effect of IFN-alpha on the Fas/FasL system might be the enhanced elimination of activated T cells as a means of finally limiting a T cell response.Clinical & Experimental Immunology 11/1999; 118(1):71-7. · 3.41 Impact Factor
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ABSTRACT: BACKGROUND/AIM: The mechanisms that determine the persistence or clearance of viral infection in patients with chronic hepatitis C (CHC) are not well known. The goal of this study was to clarify changes of the Th1 and Th2 cell subsets of peripheral blood CD4-positive T cells (PB-CD4+Tc) in CHC patients after successful elimination of HCV. PATIENTS AND METHODS: Eighteen CHC patients received natural IFN-alpha at a dose of 5-10MU daily for 2 weeks and three times weekly for 22 weeks, and then were followed for 24 weeks after the completion of IFN therapy (Week 48). Based on the response to IFN, the subjects were divided into two groups: non-responders had detectable serum HCV-RNA at the end of follow-up (Week 48), while responders did not. Before treatment and in Weeks 2, 24, and 48, the intracellular cytokines of peripheral CD4+ T cells were detected by flow cytometry to separate IFN-gamma+/IL-4- (Th1) cells from IFN-gamma-/IL-4+ (Th2) cells. RESULTS: The percentage of Th1 and Th2 cells peaked in Week 2 and then decreased to near baseline by Weeks 24 or 48 in both groups. However, a statistically significant change in the percentage of Th1 cells was only seen in the responders. The baseline percentage of Th1 cells was significantly lower in the responders than in the non-responders, while the percentage of Th2 cells at baseline, Week 24 and 48 was significantly lower in responders than in non-responders. CONCLUSIONS: Our results suggest that the baseline Th1 and Th2 cells may be related to the IFN response to IFN.Hepatology Research 01/2004; 27(4):260-265. · 2.07 Impact Factor