On the basis of our previous investigations of selective lymphoid irradiation using Palladium-hematoporphyrin in the cardiac allograft model in the rat, we propose in this competitive renewal, to analyze the toxicity and usefulness of selective lymphoid irradiation to allow successful auxiliary cardiac allotransplantation in dogs with view to the application of this method to man. The major emphasis of this proposal is on the study of the effectiveness of SLI with the use of 1) ALG; 2) thymectomy; 3) donor-specific bone marrow infusion; and 4) shortterm use of Cyclosporin A adjuvant treatment or treatments used only during the peritransplant period and therefore, avoiding long-term immunosuppression of the host and with potential practical usefulness for clinical application. Selected regimens showing highest effectiveness and least toxicity will also be tested in inbred, genetically defined, beagle donor-recipient paris. Parallel with the studies in dogs, this proposal describes experiments in cardiac allografts and xenografts in rats aimed to develop optimal immunosuppressive regimens to induce immunologic unresponsiveness by brief peritransplant treatment and immunologic manipulations. These studies include 1) the role of thymectomy in combination with SLI; 2) donor-specific bone marrow modification by UV irradiation and its use in combination with SLI; 3) the use of donor-specific blood transfusions (modified by UV irradiation) in conjunction with SLI and additional immunologic manipulation during the peritransplant period; and 4) evaluation of optimal treatment protocols using SLI on xenograft (hamster) cardiac allograft survival in rat recipients. The goal of this proposal is to develop a peritransplant treatment protocol which will result in 1) donor-specific prolonged graft survival; 2) reduction of, or avoidance of, standard immunosuppressants post-grafting; 3) retention of host immunocompetence to other antigens; and 4) clarification of mechanisms of immunosuppression and induction of unresponsiveness by selective lymphoid irradiation and adjunctive treatments. The achievement of such goals in experiments in dogs will permit the adoption of the optimal method to clinical cardiac transplantation in man, while parallel experiments in rats will lead to refinement and improvement of the use of SLI in transplantation and will lead to further experiments in dogs to optimize the method prior to its clinical use. The proposed approaches have been tested in preliminary studies in allografts and appear to have major clinical applicability in transplantation because of low toxicity to the host and their ability to facilitate induction of partial tolerance by a short-term treatment of the adult host.
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