Disruption of T cell tolerance in type 1 diabetes

项目总结/摘要 自身免疫性疾病，如1型糖尿病，是通过免疫耐受性的破坏而产生的。我们现在已经 逐渐了解到免疫耐受由一个多层网络组成， 回应检查。在这个项目中，三个互补的团队将共同努力， 进一步阐明这些检查点如何运作，以提高我们对自身免疫的理解，并最终 改善其待遇。该计划项目将有三个高度协作和互动的项目领导 由Mark安德森博士（项目1）、Jeff Bluestone博士（项目2）和John Kappler博士（项目3）沿着， 科学核心（动物核心和分子核心）。赠款的主要主题是： 1.中枢胸腺耐受对T1 D患者T效应细胞和Treg库的影响 2.胰岛素作为T1 D中T效应细胞和T调节细胞的关键自身抗原特异性。 3. T1 D中T调节细胞的肽特异性 4.利用胰岛抗原的肽结合特性改进生物测定和耐受性方法。 这项工作的长期目标是提高我们对T细胞耐受性如何控制的理解， 进一步改善1型糖尿病中自身反应性T细胞应答的特异性。调查人员将 在动物模型和患有1型糖尿病的人类受试者中使用最先进的工具。结果 这些研究将有助于进一步完善我们对自身免疫的理解， 治疗和诊断。

Project Summary/Abstract Autoimmune diseases like type 1 diabetes arise through a breakdown in immune tolerance. We have now come to understand that immune tolerance consists of a multi-layered network that keeps such untoward responses in check. In this program project grant, three complementary teams will be working together to further unravel how these checkpoints operate to improve our understanding of autoimmunity and ultimately improve its treatment. This program project will have three highly collaborative and interactive projects headed by Drs. Mark Anderson (Project 1), Jeff Bluestone (Project 2) and John Kappler (Project 3) along with two scientific cores (Animal core and Molecular core). The major themes of the grant are: 1. The impact of central thymic tolerance on the T effector and Treg repertoire in T1D.. 2. Insulin as a critical self-antigen specificity for both T effectors and T regulatory cells in T1D. 3. Peptide specificity of Tregulatory cells in T1D 4. Using peptide binding characteristics of islet antigens to improve bioassays and tolerance methods. The long term objectives of this work is to improve our understanding of how T cell tolerance is controlled and the further refining the specificity of the autoreactive T cell response in type 1 diabetes. The investigators will be using state of the art tools in both animal models and in human subjects with type 1 diabetes. Results of these studies will help further refine our understanding of autoimmunity and help improve methods for its treatment and diagnosis.