T cell mediated injury to islet allografts

描述(申请人提供)：胰岛移植已显示 作为一种治疗I型糖尿病的方法，其疗效不断提高。然而，小岛 移植受到两个潜在的不同免疫障碍的影响：(1) 常规移植排斥反应和(2)已确诊的复发 自身免疫发病机制以前的研究表明，主要效应者 用于同种异体移植免疫的细胞是I类MHC限制性CD8T细胞，而 自身免疫性疾病复发的主要途径似乎需要 第二类MHC限制性的CD4T细胞。这项提议的主要目标将是 确定主要候选效应器通路的相对贡献 体内明确的同种异体或自身反应性T细胞介导的胰岛损伤。 这一建议的总前提是，胰岛的效应机制(S) 同种异体反应的CD8 T细胞造成的损伤与胰岛特异性不同， 体内自身免疫(胰岛特异性)CD4T细胞。特别是，我们将测试 CD8T细胞介导的胰岛排斥反应工作假说的意义 需要与目标胰岛细胞进行直接的同源交互，而 CD4胰岛特异性T细胞的发病机制涉及间接识别 MHC-II类抗原呈递的胰岛相关抗原 细胞(APC)。解剖这两类移植物反应性T细胞的作用 需要一种模型，在该模型中，每条途径都可以被独立研究。至 要做到这一点，我们建议继续使用定义的T细胞受体进行研究 (TCR)-具有同种异体反应性CD8 T特异性的转基因小鼠 细胞(2C)或胰岛特异性CD4T细胞(BDC2.5)。这项建议的重点是 系统地比较这两种类型的胰岛破坏性T细胞 他们各自对胰岛损伤的要求 移植。特别是，我们建议确定相对要求 用于胰岛损伤的细胞溶解机制和炎症机制。终极的 这些成果的应用将是发展战略组合 将减弱同种异体反应和同种异体反应限速通路的治疗 移植物损伤的自身免疫途径。

DESCRIPTION (provided by applicant): Pancreatic islet transplantation has shown increasing efficacy as a therapy for Type I diabetes. However, islet transplants are subject to two potentially distinct immune obstacles: (1) Conventional transplantation rejection and, (2) Recurrence of established autoimmune pathogenesis Previous studies suggest that the predominant effector cell for allograft immunity is the class I MHC-restricted CD8 T cell while the predominant pathway for autoimmune disease recurrence appears to require the class II MHC-restricted CD4 T cell. The chief goal of this proposal will be to determine the relative contribution of major candidate effector pathways of islet injury mediated by defined alloreactive or autoreactive T cells in vivo. The general premise of this proposal is that the effector mechanism(s) of islet damage inflicted by alloreactive CD8 T cells is distinct from islet-specific, autoimmune (islet-specific) CD4 T cells in vivo. In particular, we will test implications of the working hypothesis that CD8 T cell-mediated islet rejection requires a direct, cognate interaction with the target islet cell while the pathogenesis of CD4 islet-specific T cells involves the indirect recognition of islet-associated antigens presented by MHC class II-bearing antigen-presenting cells (APCs). Dissecting the role of these two types of graft-reactive T cells requires a model in which each pathway can be studied independently. To accomplish this, we propose to continue studies using defined T cell receptor (TcR)-transgenic mice with specificities representative of alloreactive CD8 T cells (2C) or islet-specific CD4 T cells (BDC2.5). This proposal has the focus of systematically comparing these two types of islet-destructive T cells for their respective requirements for inflicting injury to pancreatic islet transplants. In particular, we proposed to determine the relative requirement for cytolytic versus inflammatory mechanisms of islet damage. The ultimate application of such results will be to develop strategic combinational therapies that will attenuate rate-limiting pathways of both alloreactive and autoimmune pathways of graft damage.