SOLUBLE MHC ANTIGENS IN TRANSPLANTATION TOLERANCE

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DESCRIPTION: Success in clinical organ transplantation is currently limited by the need for immunosuppressive drugs that non-specifically down regulate the immune system. Improvements in organ transplantation will likely be based on an approach to donor-specific immunosuppression, which refers to a suppression of lymphocytes directed specifically against the major histocompatibility complex (MHC) antigen of the transplant donor. With this type of therapy the immune response towards donor tissue expressing foreign MHC antigens is downregulated to prevent organ rejection, but immunity to fight off common microorganisms and any newly arising cancer cells is preserved. There is evidence to suggest that donor-specific immunosuppression may be possible by introducing donor MHC class I antigens to the recipient near the time of organ transplantation. In support of this theory immune privilege associated with liver transplants compared to other organs, may be due to the special ability of a liver to produce large quantities of secreted donor MHC class I antigen immediately after transplantation. Since other organs express membrane-bound MHC class I antigen, but little or no secreted antigen, the MHC antigen form may be a critical factor involved in inducing donor-specific unresponsiveness. It has been difficult to study the immunologic effects of secreted and membrane-bound MHC class I antigens because obtaining pure molecules in sufficient quantities from crude extracts was limiting. However, recent developments in gene transfer technology have opened up new approaches to study these questions. In the present study, the potential donor-specific downregulatory immunologic effect(s) of secreted vs. membrane-bound rat MHC class I antigen will be determined by transferring DNA encoding donor-specific molecules into recipient hepatocytes in vitro. In addition, the effects of a secreted donor rat MHC class I/IgG fusion molecule (histoglobulin) will be tested. Recipient strain lymphocytes will be exposed to the different forms of donor MHC class I antigen in culture, and immunologic effects will be compared by measuring anti-donor cytotoxic and helper T-cell activity. Genetically altered hepatocytes or histoglobulin will be administered perioperatively into heart transplant recipients to determine the in vivo effects of the different forms of donor MHC antigen. Results from these experiments will contribute to the understanding of the potential for donor-soluble MHC antigens to induce and maintain MHC-specific immunologic unresponsiveness, and may eventually lead to the development of clinical therapies to induce donor-specific tolerance in transplantation.