PANCREATIC ISLET ALLOGRAFT PROLONGATION

The present proposal will investigate a new approach to whole pancreas and pancreatic islet transplantation in streptozotocin diabetic rats. Selective lymphoid irradiation, using Palladium-109 hematoporphyrin, will be combined with standard immunosuppression (esp. ALG) and/or lymphoid organ ablation, and used as an acute transient method of recipient immunosuppression prior to tranplantation to permit immune recovery of the animal without graft rejection. Toxicity studies of selective lymphoid irradiation on pancreatic islet function, either as whole pancreas or as islets, will be compared by functional studies of glucose homeostasis in reconstituted diabetic animals. The efficacy of the optimal regimens and doses of Palladium-hematophorphyrin, ALG or other immunosuppressants, and/or lymphoid organ ablation, as well as the use of donor bone marrow cells in the peritransplant period, will be investigated and compared in regard to prolongation of whole pancreas and pancreatic islet allograft survival. The mechanisms involved in organ allograft prolongation will be investigated by cellular in vivo transfer experiments and in vitro studies of cellular and humoral immunological changes consequent to effective treatment and will be utilized to optimize graft prolongation. In conclusion, the goal of this proposal is to develop a peritransplant brief treatment protocol which will result in 1) donor specific prolonged graft survival; 2) reduction of, or avoidance of, standard immunosuppressants post-grafting; 3) retension of host immunocompetence to other antigens; and 4) clarification of mechanisms of immunosuppression by selective lymphoid irradiation. The proposed approaches have been tested in pilot studies in heart allografts in rats and may have major clinical applicability in whole pancreas or pancreatic islet transplantation in diabetic patients because of low toxicity of the proposed methods to the host and because of the apparent ability of this method to facilitate induction of partial tolerance in the adult host by a brief peritransplant treatment.