PANCREATIC ISLET TRANSPLANTATION IN NOD MICE

现在几乎可以肯定，胰岛素依赖型（I型）糖尿病 糖尿病是由自身免疫过程破坏胰岛素 产生β细胞 最近的临床证据表明， 自身免疫过程可能在成功的胰腺器官移植后复发 移植 本建议的总体目标是 胰岛移植治疗自发性糖尿病研究 NOD小鼠，自身免疫性糖尿病的小鼠模型。 三个具体 提出了目标。 (I)我们将通过以下方式建立最佳方案： 其中胰岛移植物存活的最大延长是在 自身免疫性糖尿病NOD（非肥胖糖尿病）小鼠。 以下 确定恢复所需的最小胰岛数量 并维持NOD小鼠血糖正常，主要作用是 组织相容性复合体（MHC）抗原在疾病复发中作用 (MHC限制）将被分析以确定最佳的 捐助者。 用于体外移植物调节和/或 接受者治疗将被确定为实现最大的 胰岛同种异体移植物的延长。 我们将检查是否治疗 接受非糖尿病供者骨髓和免疫抑制的受者 提供了一个有效的方案， 同种异体抗原和抵抗疾病复发。 我们还将 研究多供体胰岛同种异体移植是否可以 成功应用于NOD小鼠。 (II)我们将建立方法 移植排斥和疾病导致的功能丧失 复发可以区分。 会来做这项工作 非胰岛同种异体移植物的同时移植，通过使用 体外免疫学测定，并通过表征 淋巴样细胞浸润NOD小鼠胰岛和胰岛 同种异体移植 (III)最后，我们将使用胰岛 移植，试图阐明机制 NOD小鼠中糖尿病的发展。 我们认为 这些研究结果将提供重要的 关于成功应用胰岛的信息 自身免疫性胰岛素依赖型患者的同种异体移植 糖尿病的

It is almost certain now that insulin-dependent (type I) diabetes mellitus is caused by autoimmune processes destroying the insulin producing beta cells. Recent clinical evidence indicates that the autoimmune process may recur after successful pancreas organ transplantation. The overall objective of this proposal is to study pancreatic is)et transplantation in spontaneously diabetic NOD mice, a mouse model for autoimmune diabetes. Three specific aims are proposed. (I) We will establish optimal protocol(s) by which maximal prolongation of islet graft survival is achieved in autoimmune diabetic NOD (nonobese diabetic) mice. Following determination of the minimal number of islets required to restore and maintain normoglycemia in diabetic NOD mice, role of the major histocompatibility complex (MHC) antigens in disease recurrence (MHC restriction) will be analyzed to determine optimal is)et donors. Optimal protocols for in vitro graft modulation and/or recipient treatment will be determined to achieve maximal prolongation of islet allografts. We will examine if treatment of recipients with nondiabetic donor bone marrow and immunosuppression with ALS offers an effective protocol to induce unresponsiveness to alloantigens and resistance to disease recurrence. We will also investigate if multiple donor islet allotransplantation can be successfully applied in NOD mice. (II) We will establish methods by which functional loss by graft rejection and that by disease recurrence could be differentiated. This will be done by simultaneous transplantation of non-islet allografts, by the use of in vitro immunological assays, and by characterization of lymphoid cells infiltrating islets of the NOD mouse and islet allografts. (III) Finally, we will use pancreatic islet transplantation in an attempt to elucidate the mechanism(s) underlying the development of diabetes in NOD mice. We believe that results obtain from these studies will provide important information on the successful application of islet allotransplantation in patients with autoimmune, insulin-dependent diabetes mellitus.