Human islet-derived, islet-reactive T cells from subjects with Type 1 diabetes

项目概要/摘要 了解人类1型糖尿病（T1 D）的自身免疫反应对于设计 成功的免疫疗法对那些有风险的疾病以及那些已确定的疾病。 虽然啮齿类动物模型的研究极大地指导了我们的自身免疫过程，翻译的 从啮齿动物模型到人类临床试验的成功治疗和预防研究还远远不够 成功虽然我们知道很多关于啮齿动物模型和胰岛浸润T细胞的信息， 通过组织学和免疫组织化学，我们以前没有发现T1 D患者的浸润， 有机会直接从患有T1 D的人中分离淋巴细胞浸润物用于库分析， 功能能力。我们从7名T1 D患者中分离出胰岛，并进行了培养或分选， 直接从胰岛中取出95个CD 4和CD* T细胞系。我们已经证明了反应性和HLA限制 4种CD 4 + T细胞系和3种CD 8 + T细胞系（显示了多种反应性）。这样做的目的 建议是测定每个T细胞系对整个正常胰岛、整个胰岛蛋白、已知的胰岛- 自身反应性T细胞的相关肽靶向，至衍生自携带后 翻译修饰，以定义其HLA限制并定义其效应子功能。这些小岛- 浸润性T细胞将是该领域研究人员研究胰岛浸润性T细胞功能的重要工具/试剂。 T1 D人源化小鼠模型中的T细胞，T细胞受体库，以保留自身反应性T细胞受体 对于未来的研究，在自身反应性T细胞与T调节细胞、B细胞、抗原相互作用的功能测定中， 呈递细胞和先天免疫系统。最后，这些研究将为研究者设计 成功的免疫疗法对于那些有T1 D风险的人，特别是对于那些已经确诊的T1 D患者。

PROJECT SUMMARY/ABSTRACT Understanding the autoimmune response in human type 1 diabetes (T1D) is crucial for the design of successful immunotherapies for those at-risk for the disease as well as for those with established disease. While studies of rodent models of have greatly instructed us on the autoimmune process, the translation of successful therapies and prevention studies in the rodent models to human clinical trials has been far less successful. While we know much information concerning islet infiltrating T cells in the rodent models and islet infiltrates in humans with T1D by histology and immunohistochemistry, we previously have not had the opportunity to isolate directly the lymphocytic infiltrate from human with T1D for repertoire analysis and functional capacity. We have received islet isolations from 7 individuals with T1D and have grown or sorted directly out of the islets, 95 CD4 and CD* T cell lines. We have demonstrated the reactivity and HLA restriction of 4 CD4+ T cell lines and 3 CD8+ T cells lines (multiple reactivities are represented). The purpose of this proposal is to assay each T cell line for reactivity to whole normal islets, whole islet proteins, known islet- associated peptide targets of autoreactive T cells, to peptides derived from islet proteins that bear post- translational modifications, to define their HLA restriction, and define their effector functions. These islet- infiltrating T cells will be vital tools/reagents for investigators in the field to study the function of islet-infiltrating T cells in humanized mouse models of T1D, T cell receptor repertoire, to preserve autoreactive T cell receptors for future studies, in functional assays of autoreactive T cell interactions with T regulatory cells, B cell, antigen presenting cells and the innate immune system. Finally, these studies will inform investigators in the design of successful immunotherapies for those at-risk for T1D and especially for those with established T1D.