title: Negative regulation of hepatitis C virus specific immunity is highly heterogeneous and modulated by pegylated interferon-alpha/ribavirin therapy.
abstract: Specific inhibitory mechanisms suppress the T-cell response against the hepatitis C virus (HCV) in chronically infected patients. However, the relative importance of suppression by IL-10, TGF-β and regulatory T-cells and the impact of pegylated interferon-alpha and ribavirin (PegIFN-α/ribavirin) therapy on these inhibitory mechanisms are still unclear. We revealed that coregulation of the HCV-specific T-cell responses in blood of 43 chronic HCV patients showed a highly heterogeneous pattern before, during and after PegIFN-α/ribavirin. Prior to treatment, IL-10 mediated suppression of HCV-specific IFN-γ production in therapy-naive chronic HCV patients was associated with higher HCV-RNA loads, which suggests that protective antiviral immunity is controlled by IL-10. In addition, as a consequence of PegIFN-α/ribavirin therapy, negative regulation of especially HCV-specific IFN-γ production by TGF-β and IL-10 changed dramatically. Our findings emphasize the importance of negative regulation for the dysfunctional HCV-specific immunity, which should be considered in the design of future immunomodulatory therapies.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Mark A A
authors.initials: MA
authors.lastname: Claassen
authors.forename: Robert J
authors.initials: RJ
authors.lastname: de Knegt
authors.forename: Duygu
authors.initials: D
authors.lastname: Turgut
authors.forename: Zwier M A
authors.initials: ZM
authors.lastname: Groothuismink
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.forename: André
authors.initials: A
authors.lastname: Boonstra
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D049109:Cell Proliferation; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000502:physiology*; D016898:Interferon-alpha / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D012254:Ribavirin / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D012254:Ribavirin