Hepatitis C virus is a leading cause of liver failure in the United States. A striking feature of this infection is the propensity to develop chronic infection and disease, with at least 50-60 percent of chronically infected individuals sustaining liver damage. However, the pathogenesis of hepatocellular damage in HCV is poorly understood. Infiltrates in chronic HCV infection are composed of numerous CD4+ and CD8+ cells, but their role in control of viremia or induction of tissue damage is not understood. In general, HCV exhibits few direct cytopathic effects and current models strongly suggest that liver disease in this infection is secondary to the host immune response. Moreover, transgenic mice developed in the PI's laboratories that express HCV structural proteins do not develop hepatitis. However, it does appear that some component of the cellular immune response helps limit HCV replication, since persons with depressed immunity often have higher viral titers and more rapid progression of HCV-related liver disease. The applicant's laboratories have previously characterized human HCV-specific cytolytic T lymphocytes (CTL). The investigators have shown that the immune response against HCV is polyclonal and multispecific in chronically infected individuals. Moreover, these cells produce cytokines that may be involved in both control of viral replication and recruitment of inflammatory cells. They propose that the CTL response against HCV is marked not only by apopotosis of infected hepatocytes, but also by production of cytokines that recruit other inflammatory cells and eventually lead to liver fibrosis. This hypothesis suggests that blockade of either the apoptosis or the cytokines produced might ameliorate HCV-induced liver damage. They propose to use the transgenic mouse that expresses the structural proteins of HCV model to study the mechanisms of liver damage in hepatitis C virus infection and test this hypothesis.
The specific aims of this proposal include the following: 1) Develop a model for HCV hepatitis using adoptive transfer of cloned murine HCV-specific CTL into transgenic mice; 2) Define the mechanism of killing used by these HCV-specific CTL; 3) Determine whether expression of HCV structural proteins leads to modulation of immune responses in vivo; and 4) Characterize the cytokines produced by these CTL and their role in the recruitment of non-specific inflammatory cells to the liver. It is hoped that by defining the role of cellular immunity in the pathogenesis of chronic HCV hepatitis and liver damage, novel therapeutic strategies might be suggested for this infection.
