INTRATESTICULAR ISLET ALLOGRAFTS IN SPONTANEOUS DIABETES

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Type 1 diabetes or insulin-dependent diabetes (IDDM) is a major health problem. Severe insulin deficiency is the hallmark of the disease and autoimmunity is considered the primary cause. The transplantation of pancreatic islets is an experimental procedure with the objective of providing patients with an endogenous source of insulin. An advantage of this method is that isolated islets can be manipulated in vitro to reduce the immunogenicity of the tissues prior to transplantation. The ultimate goal of this approach is therefore the grafting of tissues without immunosuppression. But satisfactory results have thus far been obtained only in animals with artificially-induced diabetes. Permanent allograft survival in the BB/W rat, an excellent animal model for IDDM, has not been accomplished without rigorous, and often fatal immunosuppression. Whenever immunosuppression is stopped, a prompt recurrence of the hyperglycemic syndrome takes place. It has been demonstrated convincingly that the grafted beta cells in the BB/W rat are being destroyed by an inflammatory, autoimmune, insulitis and not by a standard rejection reaction. These findings have led to skepticism concerning the feasibility of clinical islet transplantation without the use of continuous immunosuppression. Over the past 18 months we have studied several approaches to the grafting of the BB/W rat and have shown that permanent allograft survival can be accomplished: Long-term cures, exceeding 60 days, were induced in 86% of recipients of abdominal, intratesticular, islet allografts, and four injections of ALS given periodically over 30 days after transplantation. Histologic evidence of viable beta cells within the testis was found as long as 441 days after transplantation. By contrast, islets injected into the testis in its original, scrotal position, failed to reverse the diabetic syndrome in 88% of the recipients. To our knowledge our method of transplanting islets is the only one, at present, with which a permanent reversal of the hyperglycemic syndrome can be achieved in an animal model with true type 1 diabetes. The aim of this proposal is to continue with and to expand on these studies using this unique, but successful, approach to the grafting of the BB/W rat. The broad long term goals are very specific: 1) To examine the long-term effects of experimental cryptorchidism on testicular function and on the development of histologic changes in the testes of the diabetic animal and in those with intratesticular islet allografts, 2) To examine the factors that influence beta cell function in established, intratesticular, islet cell allografts, 3) To examine an immunologic mechanism for the favored survival of islet allografts in the cryptorchid testis, 4) To study the hormonal control of intratesticular islet allograft survival, and 5) to examine whether the testis can be used also for the transplantation of fetal pancreatic tissue. These studies could have practical implications for islet cell transplantation.