Islet transplantation in autoimmune diabetes

胰岛移植治疗自身免疫性糖尿病

• 批准号: 8697580
• 负责人: Ronald G Gill
• 金额: $ 30.34万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697580
• 关键词: Address; Alloantigen; Allogenic; Allograft Tolerance; Allografting; Animals; Antigens; Autoantigens; Autoimmune Diabetes; Autoimmune Process; Autoimmunity; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Cellular Structures; Clinical; Development; Disease; Failure; Foundations; Future; Genetic; Glare; Goals; Graft Rejection; Immune; Immunity; Inbred NOD Mice; Infection; Inflammation; Insulin; Intervention; Islets of Langerhans Transplantation; Isogenic transplantation; Knowledge; Lead; MHC Class I Genes; Mediating; Memory; Memory B-Lymphocyte; Nature; Non obese; Organ Transplantation; Pathogenesis; Pathology; Pathway interactions; Population; Pre-Clinical Model; Recurrence; Refractory; Relative (related person); Resistance; Role; Source; Specificity; T memory cell; T-Cell Immunologic Specificity; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transplantation; Transplantation Tolerance; allograft rejection; autoreactive T cell; autoreactivity; combat; cross reactivity; design; diabetic; effective therapy; experience; injured; islet; islet allograft; novel; pathogen; pre-clinical; public health relevance; response; success; treatment strategy; type I diabetic

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.

描述（由申请人提供）：尽管关于同种异体反应性T细胞与自身反应性T细胞在胰岛移植物破坏中的相对作用争论了二十多年， 在自身免疫性1型糖尿病（T1 D）接受者中，直接询问在自身免疫性环境中实际浸润并损伤胰岛移植物的T细胞的类型和特异性的基础研究令人惊讶地缺乏。这个问题本身构成了一个明显的差距，目前的信息有关胰岛移植排斥反应的发病机制，在自身免疫受体。因此，本项目的总体目标是确定在T1 D的非肥胖糖尿病（NOD）临床前模型中负责胰岛同种异体移植物破坏的T细胞的性质。此外，虽然很明显NOD小鼠对同种异体移植物耐受有抗性，但根本不清楚什么类型的T细胞实际上负责这种耐受性移植物排斥。许多先前的研究已经强调了记忆T细胞、炎症、病原体感染和遗传抗性作为移植耐受诱导的一般障碍的作用。本研究旨在探讨自发性自身免疫作为同种异体移植耐受的另一个内源性屏障的本质。也就是说，该项目还将确定负责胰岛移植物识别的T细胞的性质（自身反应性和/或同种异体反应性），重要的是， 耐受性促进疗法NOD小鼠。这些一般目标将通过以下具体目标来解决：具体目标1：确定区分自身免疫NOD小鼠中同基因胰岛移植物与同种异体胰岛移植物的破坏的主要T细胞识别途径。这一最初的目标将检验这样的假设，即具有自身免疫（胰岛反应性）特异性的CD 4 T细胞包括靶向甚至MHC无关的胰岛同种异体移植物的细胞的主要成分。这个目标将试图支持或反驳这一主要假设。具体目标2：确定NOD小鼠中胰岛移植物的实际抗原特异性和靶向T细胞。这一目标将试图支持或反驳双重自体/同种异体反应性“异源”T细胞特异性富集于胰岛同种异体移植物的假设。特异性im 3：确定NOD小鼠中负责“耐受性抵抗”胰岛同种异体移植排斥的T细胞的性质。该目标解决了确定自身免疫性糖尿病背景下耐受促进疗法难治的T细胞反应性的性质的实际/翻译问题。 目前迫切需要开发新的和有效的治疗方法来促进糖尿病受者的胰岛移植物存活。然而，我们认为，该项目的结果通过澄清形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基础。