BACKGROUND/AIM: An understanding of ribavirin's beneficial effects on treatment outcome in chronic hepatitis C (CH-C) may help to develop new treatment approaches. Here we investigated whether ribavirin directly affects HCV-specific reactivity of CD4+T-lymphocytes from patients with CH-C. METHODS: Peripheral blood mononuclear cells from forty HCV RNA positive patients were cultured ex vivo with HCV core, NS3, NS4 alone, and with different concentrations of ribavirin. Virus-specific CD4+ T-cell reactivity was analysed by a proliferation assay; quantitation of cytokine (interferon-gamma, IL-10, IL-5, IL-12p35, IL-12p40) mRNA levels; measurement of interferon-gamma and IL-10 production (by ELISA) and enumeration of interferon-gamma and IL-10 producing T-cells by Elispot assays. RESULTS: At 2-5 microM ribavirin induced de novo or enhanced T-cell proliferation to HCV antigens in a proportion of patients. Increased T-cell proliferation was associated with decreased IL-10 production in response to HCV core and reduced frequency of IL-10 producing CD4+ T-cells, while interferon-gamma levels remained unchanged. At 20 microM ribavirin markedly suppressed T-cell proliferation, and interferon-gamma mRNA expression to HCV antigens. CONCLUSIONS: Ribavirin, at clinically achievable plasma levels, modulates directly the T-cell responses to HCV antigens in some CH-C patients. Suppression of IL-10 production may represent a useful strategy to induce/augment T-cell reactivity to HCV.
BACKGROUND/AIM: An understanding of ribavirin's beneficial effects on treatment outcome in chronic hepatitis C (CH-C) may help to develop new treatment approaches. Here we investigated whether ribavirin directly affects HCV-specific reactivity of CD4+T-lymphocytes from patients with CH-C. METHODS: Peripheral blood mononuclear cells from forty HCV RNA positive patients were cultured ex vivo with HCV core, NS3, NS4 alone, and with different concentrations of ribavirin. Virus-specific CD4+ T-cell reactivity was analysed by a proliferation assay; quantitation of cytokine (interferon-gamma, IL-10, IL-5, IL-12p35, IL-12p40) mRNA levels; measurement of interferon-gamma and IL-10 production (by ELISA) and enumeration of interferon-gamma and IL-10 producing T-cells by Elispot assays. RESULTS: At 2-5 microM ribavirin induced de novo or enhanced T-cell proliferation to HCV antigens in a proportion of patients. Increased T-cell proliferation was associated with decreased IL-10 production in response to HCV core and reduced frequency of IL-10 producing CD4+ T-cells, while interferon-gamma levels remained unchanged. At 20 microM ribavirin markedly suppressed T-cell proliferation, and interferon-gamma mRNA expression to HCV antigens. CONCLUSIONS:Ribavirin, at clinically achievable plasma levels, modulates directly the T-cell responses to HCV antigens in some CH-Cpatients. Suppression of IL-10 production may represent a useful strategy to induce/augment T-cell reactivity to HCV.
Authors: Curtis L Cooper; Navneet K Ahluwalia; Susan M Efler; Jörg Vollmer; Arthur M Krieg; Heather L Davis Journal: J Immune Based Ther Vaccines Date: 2008-06-09