INTRATESTICULAR ISLET ALLOGRAFTS IN SPONTANEOUS DIABETES

1型糖尿病或胰岛素依赖型糖尿病（IDDM）是一种主要的健康问题， 问题. 严重的胰岛素缺乏是这种疾病的标志， 自身免疫被认为是主要原因。 移植 胰岛是一种实验性方法，其目的是 为患者提供内源性胰岛素来源。 的优点 该方法是可以在体外操作分离的胰岛， 移植前组织的免疫原性。 最终 因此，这种方法的目的是移植组织， 免疫抑制 但迄今为止，已取得令人满意的结果 只在人工诱发糖尿病的动物身上。 永久性同种异体移植物 BB/W大鼠是一种极好的IDDM动物模型， 没有严格的，往往是致命的免疫抑制。 每当 免疫抑制停止，高血糖的迅速复发， 综合症发生。 已经令人信服地证明， BB/W大鼠中移植的β细胞被炎症破坏， 自身免疫性胰岛炎而不是标准的排斥反应 这些 研究结果导致了对临床可行性的怀疑， 胰岛移植而不使用持续的免疫抑制。 在过去的18个月里，我们研究了几种嫁接方法， 的BB/W大鼠，并已表明，永久同种异体移植物的生存， 完成：长期治愈，超过60天，诱导86%的 腹部，睾丸内，胰岛同种异体移植物的接受者，和四个 在移植后30天内定期注射ALS。 发现睾丸内有活性β细胞的组织学证据， 移植后441天。 相比之下， 睾丸在原来的阴囊位置，未能扭转 88%的受者患有糖尿病综合征。 据我们所知， 移植胰岛是唯一的一个，目前，永久性的 可以在动物模型中实现高血糖综合征的逆转 真正的1型糖尿病 这项建议的目的是继续 并使用这种独特但成功的方法来扩展这些研究， BB/W大鼠的移植 长期目标是非常 具体：1）检查实验的长期影响 隐睾对睾丸功能和组织学发育的影响 糖尿病动物和患有糖尿病的动物的睾丸中的变化 睾丸内胰岛同种异体移植，2）检查影响 已建立的睾丸内胰岛细胞同种异体移植物中的β细胞功能， 3)探讨胰岛细胞存活的免疫学机制 4）研究隐睾的激素调控， 睾丸内胰岛移植物存活率，以及5）检查 睾丸也可用于胎儿胰腺移植 组织. 这些研究可能对胰岛细胞有实际意义。 移植

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.