The goal of this Project is to investigate the safety, durability and mechanism of allogeneic transplantation tolerance induced in host deliberately infected with virus. It has previously been shown that treatment with donor-specific transfusion (DST) plus a brief course of anti-CD154 monoclonal antibody (mAb( leads to permanent islet allograft survival in euthymic mice and greatly prolonged skin allograft survival (100 days) in thymectomized recipients. In preliminary experiments, we have demonstrated that infection of thymectomized mice with non- cytopathic lymphocytic choriomeningitis virus (LCMV) during tolerance induction, although not harmful to the animal does lead to eventual rejection of 100% of skin allografts. In contrast, LCMV infection 30 or more days after transplantation rarely lead to graft rejection. The dependancy of allograft survival on the timing of viral infection suggests that different mechanisms are involved in the induction versus maintenance """"""""phases"""""""" of tolerance. Our working hypothesis is that different viruses exert distinct effects on tolerance and allograft survival. We hypothesize that these distinct effects depend on: 1) the timing of viral infection in relation to the phase of tolerance, 2) the specific host immune response to a given virus, and 3) the interaction of that response with the phase-dependent tolerance process in effect at the time of infection.
Specific Aim NO. 1 is to test the hypothesis that the timing of viral infection in relation to the phase of tolerance and the specific host immune responses to different viruses will predict the outcome of islet and skin allograft survival in normal recipients and in alloantigen-specific T cell receptor transgenic models tolerized with DST and anti-CD154 mAb.
Specific Aim NO.2 is to understand the mechanism by which the host immune response to virus interacts with phase-dependent tolerance events to determine allograft survival. TcR transgenic mice already available to us all will enable us to ascertain directly the fate of alloreactive T cells in response to tolerance induction and viral injection. The data that are generated should enable us to gain significant understanding of the safety, durability and mechanism of allogeneic transplantation tolerance induced in hosts infected with virus. That understanding should facilitate the design and execution of the clinical trials of tolerance-based islet transplantation that are currently being planned.
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