Cytotoxic T lymphocytes (CTL) contribute to the clearance of many viruses such as CMV, EBV, HBV and influenza virus. Although CTL have also been isolated from the peripheral blood and liver of HCV-infected patients, their role in the resolution of disease is still unclear because only patients with chronic hepatitis C have been studied so far. In previous studies, we have analyzed the HLA-A2 restricted CTL response in a unique patient population, infected during a single source outbreak of hepatitis C with a virus of known sequence. The main findings were that the cytotoxic and helper T cell response persisted for two decades in the blood of patients who cleared HCV infection with sustained biochemical and virological recovery, while the cellular immune response was much weaker in patients with chronic infection. We also observed viral mutations in or close to CTL epitopes in chronically infected patients which may interfere with antigen processing and recognition. In order to characterize the effects of the HLA-A2 restricted CTL response, we have started to cross HLA-A2 transgenic mice with HCV transgenic mice and at the same time immunized HLA-A2 transgenic mice to generate HCV-specific T cell lines and clones. We are currently using this model to analyze factors that may determine the strength and quality of the virus-specific immune response, i.e. compare in vivo priming of HLA-A2 restricted CTL by different routes of immunization in the mouse model and in vitro stimulation of CTL via the interaction of dendritic cells, T helper cells and CD8 positive T cells in HLA-A2 positive, HCV-infected patiens. Multispecific T cell lines and monospecific clones will then be adoptively transferred to HCV / HLA-A2 double-transgenic mice. Questions related to whether these cells are able to break the pre-existing tolerance against the HCV transgene and whether they will induce immune-mediated hepatitis depending on the strength and effector function of the induced T cell response will be studied.
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