Checkpoints and Autoimmune Homeostasis in T1D

T1D 中的检查点和自身免疫稳态

• 批准号: 7686453
• 负责人: GERALD T NEPOM
• 金额: $ 68.9万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686453
• 关键词: Animal Model; Antigens; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmunity; Avidity; Blood specimen; CD4 Positive T Lymphocytes; Cells; Characteristics; Class; Clinical; Clinical Research; Core Facility; Disease; Disease Progression; Disease susceptibility; Elements; Epitopes; Equilibrium; Evaluation; Flow Cytometry; Frequencies; Histocompatibility Antigens Class I; Homeostasis; Homing; Human; Immune response; Insulin; Insulin-Dependent Diabetes Mellitus; MHC Class II Genes; Mediating; Modeling; Monitor; Mus; National Institute of Allergy and Infectious Disease; Pathway interactions; Patients; Peripheral; Phase; Phenotype; Prevention; Progressive Disease; Proinsulin; Property; Purpose; Recurrence; Regulation; Regulatory Element; Research Personnel; Research Technics; Resources; Risk; Screening procedure; Site; Specificity; T-Lymphocyte; Techniques; Technology; Testing; Transgenes; Translating; Translations; autoreactive T cell; clinical phenotype; design; diabetes risk; disorder prevention; human study; human subject; in vivo; islet; islet amyloid polypeptide; mouse model; new technology; peripheral blood; programs; response; tool

Autoreactive CD4+ T cells are present at low frequency in peripheral blood, often with low antigen avidity, and show reactivity to multiple autoantigens. Nevertheless, they are central determinants of autoimmunity, guiding not only specificity and magnitude of immune responses, but also critically involved in the balance between disease progression and regulation. We propose to exploit recent advances in several areas¿ multimer technology, T1D prediction, cellular microarrays, and humanized mouse models¿in order to develop profiles for islet antigen-reactive T cells associated with T1D susceptibility, disease, and protection. In Aim 1, HLA class II tetramers (for six islet antigens) and class I tetramers (for two islet antigens) will be used together with flow cytometry techniques to compare T cell characteristics among well-characterized human subjects at risk for T1D or with progressive disease; In Aim 2, we will analyze the functional properties of one of the important phenotypes associated with T1D¿namely, the low avidity autoreactive CD4+ T cells. A partially humanized mouse model created for this purpose will enable a detailed evaluation of the activation and homing properties. In Aim 3, new technologies designed to translate research techniques into more sensitive and rapid clinical tests will be developed, in order to advance T cell profiling into a more useful clinical research tool. These studies will be closely integrated with other elements of the Autoimmunity Cooperative Group, both at UCHSC and at other sites, and the resources derived in this project will be disseminated to the other sites, as well.

自身反应性CD 4 + T细胞以低频率存在于外周血中，通常具有低抗原亲合力， 并显示出对多种自身抗原的反应性。然而，它们是自身免疫的中心决定因素， 不仅指导免疫反应的特异性和强度，而且还关键地参与平衡， 疾病进展和调节之间的联系我们建议利用几个领域的最新进展。 多聚体技术、T1 D预测、细胞微阵列和人源化小鼠模型， 开发与T1 D易感性、疾病和保护相关的胰岛抗原反应性T细胞谱。 在目标1中，将HLA II类四聚体（对于六种胰岛抗原）和I类四聚体（对于两种胰岛抗原）进行免疫组化。 与流式细胞术技术一起使用，以比较充分表征的 处于T1 D风险或患有进展性疾病的人类受试者;在目标2中，我们将分析功能性 与T1 D相关的重要表型之一的性质，即低亲和力自身反应性 CD 4 + T淋巴细胞。为此目的建立的部分人源化小鼠模型将能够进行详细的评估 激活和归航的特性在目标3中，旨在将研究成果转化为 将开发更灵敏、更快速的临床检测技术，以推进T细胞分析 变成一个更有用的临床研究工具这些研究将与《公约》的其他内容密切结合， 自身免疫合作组，无论是在UCHSC和其他网站，和资源来源于此 该项目也将传播到其他地点。