T CELL MEDIATED INJURY TO ISLET ALLOGRAFTS

1型糖尿病的β细胞替代疗法受到两个因素的阻碍 潜在的不同免疫障碍：（1）常规移植 排斥和（2）已建立的自身免疫发病机制的复发。 虽然各种干预战略已被证明是成功的， 在动物模型中预防自身免疫性糖尿病的发生， 胰岛移植破坏在这样的接受者已被证明是 相当有挑战性。 重要的是，胰岛的实际机制 移植损伤尚不清楚。 该提案的目标将 确定主要候选效应物的相对贡献 胰岛损伤的途径介导的定义同种异体反应性或自体 体内反应性T细胞。 我们将测试一般的工作假设 同种异体反应引起的胰岛损伤的效应机制 CD 8 T细胞不同于胰岛特异性自身免疫性CD 4 T细胞。 体内依赖于精氨酸。 干预的持续发展 胰岛移植策略，替代β细胞的设计 免疫隔离技术在1型糖尿病中的应用 糖尿病将有助于确定胰岛的机制， 由同种异体反应性T细胞和自身反应性T细胞引发的破坏。这 该提案的重点是系统地比较同种异体反应性 CD 8 T细胞与胰岛特异性CD 4 T细胞各自的 对胰岛移植造成损伤的要求。 这将通过以下具体目标来实现：（1） 确定胰岛上TNF受体表达的要求 胰岛损伤的移植;（2）确定胰岛移植的需要量 IFN γ受体表达;（3）确定胰岛细胞的需要量 Fas（CD 95）表达，以及（4）确定是否存在胰岛损伤。 对氧自由基清除敏感。

Beta-cell replacement therapy in Type 1 diabetes is hampered by two potentially distinct immune obstacles: (1) conventional transplantation rejection and, (2) recurrence of established autoimmune pathogenesis. While a variety of intervention strategies have proven successful in preventing the onset of autoimmune diabetes in animal models, prevention of islet transplant destruction in such recipients has proven to be quite challenging. Importantly, the actual mechanism(s) of islet transplant damage is (are) not clear. The goal of this proposal will be to determine the relative contribution of major candidate effector pathways in islet injury mediated by defined alloreactive or auto- reactive T cells in vivo. We will test the general working hypothesis that the effector mechanism of islet damage inflicted by alloreactive CD8 T cells is distinct from islet-specific, autoimmune CD4 T cells is cytokine-dependent in vivo. The continued development of intervention strategies for islet transplantation, design of surrogate Beta cell lines, and the application of immunoisolation technology in Type 1 diabetes will be aided by determining the mechanisms of islet destruction triggered by alloreactive versus autoreactive T cells. This proposal has the defined focus of systematically comparing alloreactive CD8 T cells with islet-specific CD4 T cells for their respective requirements for inflicting injury to pancreatic islet transplants. This will be performed through the following specific aims: (1) Determine the requirement for TNF receptor expression on islet transplants for islet injury, (2) Determine the requirement for islet IFN gamma receptor expression, (3) Determine the requirement for islet Fas (CD95) expression, and (4) Determine whether islet damage is sensitive to oxygen free radical scavenging.