Hepatitis C virus (HCV) is a significant cause of end stage liver disease in the United States, and in most transplant centers is a major indication for transplantation. Following liver transplantation, HCV viremia occurs in nearly 100% of HCV-infected individuals. Approximately half of infected liver transplant recipients will develop clinically significant hepatitis, which has a more rapid progression than HCV hepatitis in the immunocompetent host. A subset of HCV infected transplant recipients may have rapid graft loss and impaired survival. The only currently licensed therapy for HCV infection, interferon-alpha (IFN-a), has a low sustained response rate and increases the risk of chronic rejection in allograft recipients. Given the impact of HCV on transplant recipients, there is a need for a greater understanding of pathogenesis of this infection. Neither the viral nor the host factors which determine outcome are defined. At present, there is no small animal model for HCV infection; so examination of host responses in infected individuals is critical to understanding the possible role of host factors in determining clinical outcome. Cellular immune responses are a crucial component of host defenses in most viral infections and are attenuated in transplant recipients. In particular, cytotoxic T lymphocytes (CTL) are an important element of protective host immunity, but under certain circumstances may induce host tissue damage without clearing viral infection. By comparing the immune response against HCV in immunocompetent hosts and transplant recipients, it may be possible to determine which host factors are important in controlling viremia and which host factors may be responsible for accelerated disease. The goal of this proposal is understanding the role of cytotoxic T lymphocytes in limiting viral replication.
The specific aims of this proposal are to: 1) define HCV-specific cellular immune responses in transplant recipients; 2) correlate the spectrum of HCV-specific CTL responses with disease activity in transplant recipients; and 3) characterize the role of cytokines in HCV-specific CTL responses in transplant recipients. These studies will provide the necessary scientific background for the development of vaccines or immunotherapies.
