INTRATESTICULAR ISLET ALLOGRAFTS IN SPONTANEOUS DIABETES

自发性糖尿病的睾丸内同种异体胰岛移植

• 批准号: 3234249
• 负责人: HELENA P SELAWRY
• 金额: $ 7.14万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-04-01 至 1989-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3234249
• 关键词: autoimmune disorder; cryptorchidism; embryo /fetus; genetic strain; homologous transplantation; hormone regulation /control mechanism; hypophysectomy; neurohormones; pancreatic islet transplantation; perfusion; pregnancy; secretion; steroid hormone; sulfonylurea; testis; tissue /organ preservation

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.

1型糖尿病或胰岛素依赖型糖尿病(IDDM)是一种主要的健康 有问题。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。人类的移植 胰岛是一种实验程序，其目的是 为患者提供内源性胰岛素来源。的优势 这种方法是可以在体外操纵孤立的胰岛来减少 移植前组织的免疫原性。终极的 因此，这种方法的目标是在没有组织的情况下移植组织 免疫抑制。但到目前为止，已经取得了令人满意的结果。 仅限于人工诱导糖尿病的动物。永久性同种异体移植 作为IDDM的优秀动物模型，BB/W大鼠的存活率尚未得到 在没有严格的，通常是致命的免疫抑制的情况下完成。什么时候都行 免疫抑制被停止，高血糖的迅速复发 综合症就会发生。事实已经令人信服地证明， BB/W大鼠体内移植的β细胞正在被一种炎症破坏， 自身免疫性，并不是由标准的排斥反应引起的。这些 这一发现引发了人们对临床试验可行性的怀疑。 不使用持续免疫抑制的胰岛移植。 在过去的18个月里，我们研究了几种嫁接方法 并表明同种异体移植物的永久存活期可以 成功：86%的患者获得了超过60天的长期治愈 腹部、睾丸内、胰岛同种异体移植受者4例 移植后30天以上定期注射肌萎缩侧索硬化。 组织学证据表明，睾丸内存在可存活的β细胞 移植后长达441天。相比之下，胰岛注射到 睾丸处于其原始的阴囊位置，未能扭转 88%的受者患有糖尿病综合征。据我们所知，我们的方法 移植胰岛是目前唯一一种永久性的 高血糖综合征的逆转可以在动物模型中实现 患有真正的1型糖尿病。这项提议的目的是继续 并使用这种独特但成功的方法来扩展这些研究 对BB/W大鼠的移植。宏大的长期目标是非常 具体：1)检查实验的长期效果 隐睾症对睾丸功能和组织学发展的影响 糖尿病动物和患有糖尿病的动物睾丸的变化 睾丸内同种异体胰岛移植，2)检查影响因素 β细胞在已建立的睾丸内同种异体胰岛细胞移植中的功能， 3)探讨胰岛有利存活的免疫学机制 同种异体隐睾腺移植，4)研究其激素调控作用。 睾丸内同种异体胰岛移植的存活率，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。