PANCREATIC ISLET XENOGRAFT TRANSPLANTATION

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This proposal concerns itself primarily with the possibility of using concordant xenografts of isolated pancreatic islets or crude pancreatic digests in reversing diabetes mellitus in spontaneously diabetic and streptozotocin-induced diabetic animal models. The following methods will be used to induce islet xenograft acceptance by the diabetic host: 1) direct UV irradiation of isolated islets and of crude pancreatic digests; 2) the effect of pre- and post-transplant treatment of the host with UV irradiated donor-specific blood components; 3) a combination of (1) and (2); and 4) additional peritransplant treatment of the host with a brief course of immunosuppression, particularly Cyclosporin. In the second part of this proposal the primary issue addressed is the possibility of using crude islet preparations in isografts, allografts and xenografts, rather than isolated islets, in order to avoid the problems of low yield and insufficient islet isolation that makes clinical usefulness of pancreatic islet transplantation still relatively impractical. In vitro studies of the depletion of 'stimulating cells' from the graft and the role of such cells in the xenograft model will be investigated in parallel with the above studies. The goal of this proposal is to develop a method of pretransplant treatment of the donor islet cells and of the diabetic host, which will result in 1) donor-specific prolonged xenograft survival; 2) avoidance of standard immunosuppression post-grafting; 3) retention of host immunocompetence to other antigens; and 4) clarification of mechanisms involved in the effect of UV irradiation on islet xenografts acceptance. The proposed studies are expected to demonstrate that UV irradiation will be effective in altering the immunogenicity of pancreatic islets or crude islet preparations in xenograft models. The use of the methods outlined in this proposal may have major clinical applicability to pancreatic islet transplantation in man since 1) they involve the use of xenogeneic islet tissue which could obviate the problem of supply of donor islets in clinical transplantation; 2) they involve either direct treatment of the graft or of donor type blood components, neither of which has any toxicity to the diabetic host; and 3) they may lead directly to initial trials of islet allografts and particularly concordant xenografts in man, where the methods outlined in this proposal would be readily applicable and safe, and have already been successful in induction and maintenance of islet allografts in some models of diabetes in rodents.