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）：尽管在胰岛同种异体移植物破坏中，关于同种异体反应性与自动反应性T细胞的相对贡献进行了二十年以上的争论。 自身免疫性1型糖尿病患者（T1D）接受者，基本研究一直很少，这些研究直接审问了在自身免疫环境中实际浸润的T细胞的类型和特异性。这个问题本身构成了有关自身免疫接收者胰岛移植排斥的发病机理的库雷斯信息中的明显差距。因此，该项目的一般目标是确定导致T1D非肥胖糖尿病（NOD）临床前模型中胰岛同种异体移植破坏的T细胞的性质。此外，虽然很明显，点头小鼠对同种异体移植的耐受性具有抵抗力，但根本不清楚哪些T细胞的TPE实际上是造成这种耐受性移植的抑制的原因。以前的许多研究强调了记忆T细胞，炎症，病原体感染和遗传耐药性作为移植耐受性诱导的一般障碍的作用。该提议着手探索自发自身免疫的性质，作为同种异体耐受性的另一个相关的内源性障碍。也就是说，该项目还将确定负责胰岛移植识别的T细胞（自动反应和/或同种异体反应性）的性质，并且重要的是，抗拒的THOS 促耐受性疗法点头小鼠。这些一般目标将通过以下特定目的来解决：具体目标1：确定原发性T细胞识别途径，以区分自身免疫性小鼠中的合同性胰岛移植的破坏与同种异体胰岛移植。最初的目标将检验以下假设：具有自身免疫性（胰岛反应性）特异性的CD4 T细胞构成了靶向MHC无关胰岛的细胞的主要成分。这个目标将试图支持或反驳这一主要假设。具体目标2：确定靶向NOD小鼠胰岛移植的实际抗原特异性和T细胞。该目标将试图支持或反驳这一假设，即双重自动/异源性反应“异源” T细胞被特异性地富集在同种异体移植物中。特异性IM 3：确定负责“耐受性”胰岛同种异体移植抑制的T细胞的性质。这个目的解决了确定T细胞反应性的性质的实用/翻译问题，T细胞反应性的性质对自身免疫性糖尿病的耐受性促进疗法难治性。 迫切需要开发新颖有效的疗法，以促进糖尿病患者中的同种异体移植生存。但是，我们认为，该项目的结果构成了指导这种治疗设计的主要基础，通过阐明构成当前治疗策略的关键限制障碍的T细胞的实际类型。