Hepatitis c virus-specific t-cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis§

Authors

  • Shaoyong Li,

    1. Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA
    2. College of Veterinary Medicine, China Agricultural University, Beijing, China
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  • Lianne E.M. Vriend,

    1. Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA
    2. Vrije University Medical Center, Amsterdam, Netherlands
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    • These authors participated equally in this study.

  • Imad A. Nasser,

    1. Department of Pathology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA
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  • Yury Popov,

    1. Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA
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  • Nezam H. Afdhal,

    1. Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA
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  • Margaret J. Koziel,

    1. Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA
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  • Detlef Schuppan,

    1. Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA
    2. Molecular and Translational Medicine, Dept. of Medicine I, Mainz University Medical School, Mainz, Germany
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  • Mark A. Exley,

    1. Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA
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  • Nadia Alatrakchi

    Corresponding author
    1. Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA
    • Instructor in Medicine, Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Dana/RW663C, 330 Brookline Ave., Boston, MA 02215

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    • fax: 617-667-8154


  • Potential conflict of interest: Nothing to report.

  • Financial support: U19 AI066313 to N.A., M.E., and D.S., R01 DK066917 and R21 CA143748 to M.E., China Scholarship Council to S.L., and U01 AI068636 to N.A.

  • Present address for M.J. Koziel: Vertex Pharmaceuticals, Cambridge, MA.

  • The protocol was reviewed and approved by the Investigational Review Board of Beth Israel Deaconess Medical Center and all subjects gave informed consent for the collection of specimens.

Abstract

Hepatitis C virus (HCV)-specific immune effector responses can cause liver damage in chronic infection. Hepatic stellate cells (HSC) are the main effectors of liver fibrosis. TGFβ, produced by HCV-specific CD8+ T cells, is a key regulatory cytokine modulating HCV-specific effector T cells. Here we studied TGFβ as well as other factors produced by HCV-specific intrahepatic lymphocytes (IHL) and peripheral blood cells in hepatic inflammation and fibrogenesis. This was a cross-sectional study of two well-defined groups of HCV-infected subjects with slow (≤0.1 Metavir units/year, n = 13) or rapid (n = 6) liver fibrosis progression. HCV-specific T-cell responses were studied using interferon-gamma (IFNγ)-ELISpot ±monoclonal antibodies (mAbs) blocking regulatory cytokines, along with multiplex, enzyme-linked immunosorbent assay (ELISA) and multiparameter fluorescence-activated cell sorting (FACS). The effects of IHL stimulated with HCV-core peptides on HSC expression of profibrotic and fibrolytic genes were determined. Blocking regulatory cytokines significantly raised detection of HCV-specific effector (IFNγ) responses only in slow fibrosis progressors, both in the periphery (P = 0.003) and liver (P = 0.01). Regulatory cytokine blockade revealed HCV-specific IFNγ responses strongly correlated with HCV-specific TGFβ, measured before blockade (R = 0.84, P = 0.0003), with only a trend to correlation with HCV-specific IL-10. HCV-specific TGFβ was produced by CD8 and CD4 T cells. HCV-specific TGFβ, not interleukin (IL)-10, inversely correlated with liver inflammation (R = −0.63, P = 0.008) and, unexpectedly, fibrosis (R = −0.46, P = 0.05). In addition, supernatants from HCV-stimulated IHL of slow progressors specifically increased fibrolytic gene expression in HSC and treatment with anti-TGFβ mAb abrogated such expression. Conclusion: Although TGFβ is considered a major profibrogenic cytokine, local production of TGFβ by HCV-specific T cells appeared to have a protective role in HCV-infected liver, together with other T-cell-derived factors, ameliorating HCV liver disease progression. (HEPATOLOGY 2012;56:2094–2105)

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