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 细胞在胰岛同种异体移植物破坏中的相对贡献争论了二十多年。 对于自身免疫性 1 型糖尿病 (T1D) 受体，令人惊讶的是，直接询问在自身免疫环境中实际渗透并损伤胰岛移植物的 T 细胞的类型和特异性的基础研究非常少。这个问题本身就构成了有关自身免疫受者胰岛移植排斥的发病机制的当前信息的明显差距。因此，该项目的总体目标是确定在 T1D 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具有抵抗力，但根本不清楚哪种类型的 T 细胞实际上负责这种耐受抵抗性移植物排斥。之前的许多研究都强调了记忆 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。该提案旨在探索自发性自身免疫的本质，作为同种异体移植耐受的另一个相关内源性障碍。也就是说，该项目还将确定负责胰岛同种异体移植物识别的 T 细胞（自身反应性和/或同种异体反应性）的性质，更重要的是，确定那些抵抗胰岛移植物的 T 细胞的性质。 NOD小鼠的耐受促进疗法。这些总体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，以区分自身免疫 NOD 小鼠中同基因与同种异体胰岛移植的破坏。这一初步目标将检验以下假设：具有自身免疫（胰岛反应性）特异性的 CD4 T 细胞构成了靶向 MHC 无关胰岛同种异体移植物的细胞的主要成分。这一目标将试图支持或反驳这一主要假设。具体目标 2：确定 NOD 小鼠的实际抗原特异性和靶向胰岛移植的 T 细胞。这一目标将试图支持或反驳双重自身/同种异体反应性“异源”T 细胞在胰岛同种异体移植物中特异性富集的假设。具体im 3：确定负责NOD 小鼠“耐受性抗性”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 T 细胞反应性性质的实际/转化问题，在自身免疫性糖尿病的情况下，T 细胞反应性对于促进耐受性的疗法是难治的。 迫切需要开发新颖且有效的疗法来促进糖尿病受体的同种异体胰岛移植物的存活。然而，我们相信，该项目的结果通过阐明构成当前治疗策略关键限速障碍的 T 细胞的实际类型，为指导此类治疗设计奠定了主要和重要的基础。