Mechanisms of immune tolerance in autoimmune diabetes

描述（由申请人提供）：1型糖尿病（T1 D）由自身免疫T淋巴细胞介导的胰腺中产生胰岛素的β细胞的破坏引起。每天多次注射胰岛素是糖尿病患者的救命疗法，但不能治愈。为了治愈T1 D，我们必须首先识别出自身反应性T细胞，其次我们必须去除它们。直到最近，识别细胞一直是一项非常困难的任务。然而，肽-MHC四聚体技术的最新进展使我们能够识别、跟踪和询问1型糖尿病小鼠模型和人类中的单个CD 4 + T淋巴细胞克隆。通过拥有研究疾病期间抗原特异性T细胞的工具和技术，我们将能够评估外周耐受性的破坏，并检查治疗效果，以选择性地去除或沉默这些自身反应性T细胞作为靶向治疗。我们最近采用了一种敏感的四聚体富集方案，允许识别和表型非常罕见的CD 4 + T细胞的特定肽：MHCII复合物。我们假设，II类MHC：肽四聚体和富集技术将提供一种灵敏和可靠的方法，用于确定胰岛Ag特异性CD 4 + T细胞的数量和活化状态， T1 D患者的可行样本。我们进一步假设使用这种方法表征胰岛Ag特异性CD 4 T细胞将为T1 D诊断和疾病分期提供有用的生物标志物试剂。使用这项技术，我们将确定糖尿病患者外周耐受性是否丧失，胰岛β细胞肽表位是否成为免疫系统的主要靶点。我们预测，新发T1 D患者将比非糖尿病患者具有更多的β细胞肽：MHCII特异性CD 4 + T细胞活化表型。随着对β细胞靶点的更好理解，我们将能够开发抗原特异性方法来选择性消除自我破坏性T细胞以治愈糖尿病。

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) results from the autoimmune T lymphocyte mediated destruction of the insulin producing beta cells in the pancreas. Multiple daily insulin injections are a lifesaving therapy for diabetic patients, they are not a cure. In orer to cure T1D we must first identify the self-reactive T cells, and secondly we must remove them. Until recently identifying the cells has been a very difficult task. However, recent advances in peptide-MHC tetramer technology have allowed us to identify, track and interrogate individual CD4+ T lymphocyte clones in both mouse models and humans with type 1 diabetes. By having the tools and technology to study antigen specific T cells during disease, we will be able to assess the breakdown in peripheral tolerance and examine therapeutic efficacy to selectively remove or silence these self-reactive T cells as a targeted cure. We have recently adapted a sensitive tetramer enrichment protocol allowing the identification and phenotyping of exceedingly rare CD4+ T cells of a specific peptide:MHCII complex. We hypothesize that class II MHC:peptide tetramer and enrichment techniques will provide a sensitive and robust method for determining the number and activation status of islet Ag-specific CD4+ T cells using clinically feasible samples from T1D patients. We further hypothesize that characterization of islet Ag-specific CD4 T cells using this approach will provide a useful biomarker reagent for T1D diagnosis and disease staging. Using this technology we will determine if peripheral tolerance is lost in diabetic patients and islet beta cell peptide epitopes become major targets of the immune system. We predict that individuals with new onset T1D will have more beta cell peptide:MHCII specific CD4+ T cells with an activated phenotype than non-diabetic individuals. With a better understanding of beta cell targets, we will be able to develop antigen specific approaches to selectively eliminate self-destructive T cells to cure diabetes.