These authors participated equally in this study.
Article first published online: 4 DEC 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 6, pages 2094–2105, December 2012
How to Cite
Li, S., Vriend, L. E.M., Nasser, I. A., Popov, Y., Afdhal, N. H., Koziel, M. J., Schuppan, D., Exley, M. A. and Alatrakchi, N. (2012), Hepatitis c virus-specific t-cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis. Hepatology, 56: 2094–2105. doi: 10.1002/hep.25951
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.
- Issue published online: 4 DEC 2012
- Article first published online: 4 DEC 2012
- Accepted manuscript online: 14 JUL 2012 03:10AM EST
- Manuscript Accepted: 11 JUN 2012
- Manuscript Received: 13 JUL 2011
- China Scholarship Council. Grant Numbers: U19 AI066313, R01 DK066917, R21 CA143748, U01 AI068636
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)