Fas/FasL interaction in liver damage

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DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infection in humans is remarkably efficient in the establishment of persistent infection by evading host immune surveillance. HCV persistent infection is a major risk factor for the development of hepatocellular carcinoma and autoimmune disease. In our prior studies, we demonstrated that HCV core protein, a first protein produced during viral infection contains the immunomodulatory function to suppress anti-viral CTL activity through its interaction with Fas to increase the Fas-mediated apoptotic pathway. To dissect the molecular mechanism of immune modulation by HCV core and immunopathogenesis of liver damage, we have developed a murine model of CD2/core transgenic mice by directing the expression of HCV core protein in T cells because T cells support HCV infection and replication of virus. In these CD2/core transgenic mice, similar to chronic hepatitis C in humans, massive lymphocytic infiltration was notable in the portal tract of liver along with profound immune dysregulation. In addition, the expression of core protein in OVA-specific CD4+ T cells induces severe liver damage by facilitating recruitment of lymphocytes to liver in core-TCR mice upon OVA323-339 peptide injection. Based on these findings, we hypothesize that FasL of liver-infiltrating T cells may be responsible for inducing liver damage as a bystander killing mechanism by promoting FasL-mediated pro-apoptotic and inflammatory responses. In order to test this hypothesis and further investigate the molecular mechanism of hepatocyte damage by liver-infiltrating T cells, we will first explore the mechanism of hepatocyte damage by liver-infiltrating T lymphocytes. Secondly, we will characterize the status of T cell activation and differentiation of liver-infiltrating T cells in core-TCR mice. Lastly, we will analyze the regulation of hepatocyte inflammatory activation by liver-infiltrating T cells. The studies proposed here will provide new and useful information on the pathogenesis of liver damage by Fas/FasL-induced inflammatory response and will help to provide a basis for the rational design of novel therapeutic agents to liver damage.