Islet transplantation in autoimmune diabetes

描述(由申请人提供)：尽管20多年来关于同种异体反应性T细胞和自身反应性T细胞在同种异体胰岛移植破坏中的相对贡献的争论 在自身免疫性1型糖尿病(T1D)患者中，直接询问在自身免疫环境中实际渗透和损伤胰岛移植物的T细胞的类型和特异性的基础研究令人惊讶地缺乏。这一问题本身构成了关于自身免疫受者胰岛移植排斥反应发病机制的最新信息的一个明显空白。因此，该项目的总体目标是确定在非肥胖糖尿病(NOD)临床前T1D模型中负责同种异体胰岛移植物破坏的T细胞的性质。此外，虽然NOD小鼠对同种异体移植耐受有明显的抵抗力，但完全不清楚是什么T细胞的TPEs导致了这种耐受的移植物排斥反应。许多先前的研究强调了记忆T细胞、炎症、病原体感染和遗传抵抗作为诱导移植耐受的一般障碍的作用。这项建议旨在探索自发性自身免疫作为另一种与同种异体移植耐受相关的内源性障碍的本质。也就是说，该项目还将确定负责识别同种异体胰岛移植物的T细胞的性质(自体反应和/或同种异体反应)，更重要的是，确定抵抗的T细胞的性质 促进耐受性的疗法对小鼠没有影响。这些一般目标将通过以下具体目标来实现：具体目标1：确定主要T细胞识别途径(S)，以区分同种和同种异体胰岛移植在自身免疫NOD小鼠中的破坏。这一初步目标将检验具有自身免疫(胰岛反应)特异性的CD4T细胞是靶向MHC无关同种异体胰岛移植物的主要细胞成分的假设。这一目的将试图支持或驳斥这一主要假设。具体目的2：确定NOD小鼠胰岛移植的抗原特异性和T细胞靶向性。这一目的将试图支持或驳斥双重自体/异体反应性‘异种’T细胞在同种异体胰岛移植物中特异富含的假设。特异性IM 3：确定NOD小鼠同种异体胰岛移植排斥反应的耐受性T细胞的性质。这一目标解决了在自身免疫性糖尿病的背景下确定T细胞反应性的实际/翻译问题，该T细胞反应性对于促进耐受的治疗是困难的。迫切需要开发新的有效的治疗方法来提高糖尿病受者同种异体胰岛移植物的存活率。然而，我们认为，该项目的结果通过澄清构成当前治疗策略的关键限速障碍的T细胞的实际类型，形成了指导此类治疗设计的主要和必要的基础。

DESCRIPTION (provided by applicant): Despite debate for more than two decades on the relative contribution of alloreactive versus autoreactive T cells in islet allograft destruction in autoimmune Type 1 diabetic (T1D) recipients, there has been a surprising paucity of basic studies that directly interrogate the types and specificities of T cells that actually infiltrate ad injure islet grafts in the autoimmune setting. This issue itself constitutes a glaring gap in curret information regarding the pathogenesis of islet transplant rejection in autoimmune recipients. Therefore, the general goal of this project is to determine the nature of T cells responsible for islet allograft destruction in the non-obese diabetic (NOD) pre-clinical model of T1D. Moreover, while it is clear that NOD mice are resistant to allograft tolerance, it is not at all clear what tpes of T cells are actually responsible for such tolerance-resistant graft rejection. Many previous studies have highlighted the role of memory T cells, inflammation, pathogen infection, and genetic resistance as general barriers to transplantation tolerance induction. This proposal sets out to explore the nature of spontaneous autoimmunity as another related endogenous barrier to allograft tolerance. That is, this project will also determine the nature of T cells (autoreactie and/or alloreactive) responsible for islet allograft recognition and, importantly, thos that resist tolerance-promoting therapies NOD mice. These general goals will be addressed through the following Specific Aims: Specific Aim 1: Determine primary T cell recognition pathway(s) that distinguish between the destruction of syngeneic versus allogeneic islet transplants in autoimmune NOD mice. This initial aim will test the hypothesis that CD4 T cells with autoimmune (islet-reactive) specificity comprise the primary component of cells targeting even MHC-unrelated islet allografts. This aim will attempt to either support or refute this primary hypothesis. Specific Aim 2: Determine the actual antigen specificity and T cells targeting islet transplants in NOD mice. This aim will attempt to support or refute the hypothesis that dual auto-/allo-reactive 'heterologous' T cells are specifically enriched in islet allografts. Specific im 3: Determine the nature of T cells responsible for 'tolerance resistant' islet allograft rejection n NOD mice. This Aim addresses the practical/translational issue of determining the nature of T cell reactivity that is refractory to tolerance-promoting therapies in the setting of autoimmune diabetes. There is a pressing need to develop novel and effective therapies to promote islet allograft survival in diabetic recipients. However, we believe that results from this project form primary and essential foundation for guiding such therapeutic design by clarifying the actual types of T cells that form key rate-limiting barriers to current treatment strategies.