ISLET TRANSPLANTATION

这笔赠款的中心目标是开发一种技术， 胰岛可以成功地移植到大型动物模型中， 恒河猴，在免疫方面与人类同源 反应性和睾丸形态。以下是具体的 计划目标：具体目标#1：确定最佳数量 每个睾丸移植的胰岛以实现生理逆转 糖尿病病程。早期的研究表明，总共有1万人 每公斤胰岛移植到糖尿病灵长类动物睾丸导致快速 诱导正常血糖，持续100天以上。但 这些动物还表现出高胰岛素血症的证据，这表明 大量注射可能是过度的。因此雄性灵长类动物将会是 建立糖尿病模型，并对其作用进行了比较研究。 不同数量的胰岛细胞对正常血糖的诱导作用。这个 结果将与体重校正的胰岛计数相关联 移植的组织。具体目标2：确定最佳器官部位 灵长类动物的胰岛移植。胰岛移植的临床应用 移植需要将大量的胰岛移植到 睾丸。从理论上讲，这可能是不可行的，因为 人类的睾丸与人类的相比相对较小 灵长类。但早期的研究表明，将胰岛移植到 同时给予环孢素治疗的大鼠睾丸可导致 诱导寄主产生耐受性。因此，将在#年进行一项研究 雄性灵长类动物对移植到肝脏中的胰岛的存活 初次移植睾丸的动物，与完全相同的成活动物相比 从未暴露过的幼稚动物肝脏中的制剂 到小岛。具体目标#3：设计一种女性移植的方法 猴子。先前对大鼠的研究表明，分离的支持细胞 雌性大鼠肾被膜下带胰岛移植 导致同种异体胰岛移植物存活率增加。因此，一项研究将 以此启动胰岛的生存，无论有没有Sertoli 细胞，将在糖尿病患者的肾脏包膜下间隙进行检查， 雌性灵长类动物。具体目标#4：确定已建立的 睾丸内同种异体胰岛移植对血糖稳态的影响。使用标准 刺激移植的β细胞分泌胰岛素的方法 灵长类动物将接受IVGTT、OGTT和躯干刺激测试。 将测定血糖、胰岛素和C肽水平，并 与对照组以及糖尿病、非移植动物相比。 具体目标5：检查睾丸内同种异体胰岛移植的效果 在睾丸和β细胞形态上。移植的血糖正常的动物将 切除，并为光和电子准备组织 显微镜。β细胞的肉芽程度，与 从β细胞到睾丸细胞成分，存在或不存在 炎症反应，是一些特征，将是 评估过了。 这些研究的结果将提供对长期发展至关重要的知识 设计和开发技术的学期目标 人糖尿病患者的孤立胰岛移植。

The central objective of this grant is to develop a technique whereby pancreatic islets can be successfully grafted into a large animal model, the Rhesus monkey, who is homologous to the human in terms of immune responsiveness and testicular morphology. The following specific objectives are planned: Specific aim #1: Determine the optimal amount of islets grafted per testis to achieve a physiologic reversal of the diabetic process. Earlier studies have shown that a total of 10,000 islets per kg grafted into the testes of diabetic primates led to rapid induction of euglycemia which was sustained for more that 100 days. But these animals also showed evidence of hyperinsulinemia, suggesting that the mass injected may have been excessive. Male primates will thus be made diabetic and a comparative study done on the effect of specified and variable amounts of islet cells on induction of normoglycemia. The results will be correlated with weight-corrected islet counts in the grafted tissues. Specific aim #2: Determine the optimal organ site for islet transplantation in the primate. Clinical application of islet transplantation will require the grafting of a large mass of islets into the testes. Theoretically this may not be feasible because of the relatively smaller size of the testis of man compared to that of the primate. But earlier studies revealed that the grafting of islets into the testis of rats with concomitant cyclosporine therapy led to the induction of tolerance in the host. A study will thus be conducted in male primates on the survival of islets transplanted into the livers of animals with a primary testis graft, compared with survival of identical preparations in the livers of naive animals who had never been exposed to islets. Specific aim #3: Design a method for the grafting of female monkeys. Previous studies in rats have shown that isolated Sertoli cells grafted along with islets into the renal subcapsular space of female rats led to augmented islet allograft survival. Consequently a study will be initiated whereby the survival of islets, with and without Sertoli cells, will be examined in the renal, subcapsular space of diabetic, female primates. Specific Aim #4: Determine the effect of established intratesticular islet allografts on glucose homeostasis. Using standard methods for the stimulation of insulin secretion from beta cells, grafted primates will be given IVGTT, OGTT, and sustacal stimulation tests. Serum glucose, insulin and C-peptide levels will be determined and compared with control, and with diabetic, non-transplanted, animals. Specific Aim #5: Examine the effects of intratesticular islet allografts on testis and beta cell morphology. Grafted, normoglycemic animals will be orchiectomized and the tissues prepared for light and electron microscopy. The degree of granulation of beta cells, the relationship of beta cells to testicular cell components, presence or absence of inflammatory reactions, are some of the characteristics which will be assessed. The results of these studies will provide knowledge critical to the long term objective of designing and developing techniques for the transplantation of the human diabetic with isolated pancreatic islets.