The ultimate goal of our investigation is to treat human diabetes mellitus by means of transplantation of fetal pancreases. The immediate goal of the proposed research is to test the feasibility of this approach in a larger animal model, the genetically defined miniature swine in which tissue typing and MLC assays are available and donor-recipient pairs with desired MHC mismatch(es) can be constructed. The specific components of the proposed research program will be summarized as follows: 1. Prevention of allograft rejection. a. Determination of optimal donor tissue pretreatment for reducing tissue immunogenicity but preserving growth and maturation capabilities of fetal islets. b. Determination of the effectiveness of specific immunotherapy for the recipient, especially preexposure to donor specific class I antigens, and treatment with immunosuppressive agents, especially cyclosporin A, in conjunction with donor tissue pretreatment. c. Development of in vitro assays for the selection of the best matched graft combination. 2. Development of cryopreservation procedures for donor tissues, including pancreases and tissues which will be used for tissue typing, MLC, and recipient pretreatment. 3. Determination of a graft site with optimal surgical, physiological and immunological advantages for reversal of diabetes and graft survival. 4. Long-term monitoring of animals whose diabetes has been reversed with regards to immunological state, metabolic state, allograft survival times, and development of any complications associated with diabetes. This study will provide most critical information to demonstrate the feasibility of fetal pancreas graft for the treatment of diabetes which has clearly been demonstrated in our previous studies in rats.
