The experiments presented in this report and proposed for the coming year are a continuation of the comprehensive investigation of problems associated with cardiac transplantation which has been continuing in this laboratory for almost two decades. The main areas of investigation are the control of the immune response in cardiac transplantation and study of the problems associated with complete heart and lung transplantation. In addition to these areas, a major goal is advanced training in cardiac transplantation immunology and physiology for postdoctoral surgical fellows. To study the control of the immune response, experiments have been performed using cyclosporin A, total lymphoid irradiation, and various antiplatelet agents. Cyclosporin A has been used alone and in combination with conventional agents (methylprednisolone, azathioprine, antithymocyte globulin) in cardiac allografts performed heterotopically and orthotopically in monkeys. Cyclosporin A alone results in extended survival with relatively few complications. When cyclosporin A was combined with other agents, allograft survival was prolonged but there were numerous infectious complications and the development of malignant lymphoma. In a rat heterotopic model, cyclosporin A was used for the control of the immune response and various antiplatelet agents were given to assess their effect on small-vessel disease. Dipyridamole was effective in completely preventing small-vessel disease at 20 and 50 days postoperatively, whereas sulfinpyrazone and cyclosporin A reduced, but did not present, the development of small-vessel disease. Complete heart and lung transplantation has been performed in small monkeys with extended survival of both autotransplants and allotransplants. This is the first demonstration of extended survival in allotransplants and due primarily to cyclosporin A immune suppression in combination with a short course of azathioprine. Survival to eight months has been achieved with transvenous biopsies of the cardiac graft showing no evidence of rejection at that time. Experiments are planned to study the physiology of cardiopulmonary denervation and its reinnervation with time.
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