Treg and Antigen Presentation in Autoimmunity

自身免疫中的 Treg 和抗原呈现

• 批准号: 7006618
• 负责人: FEI F SHIH
• 金额: $ 11.28万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-10 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7006618
• 关键词: B lymphocyte; CD4 molecule; T cell receptor; T lymphocyte; antigen presentation; antigen presenting cell; autoimmune disorder; autoimmunity; cell cell interaction; cell differentiation; cell growth regulation; cell migration; cell proliferation; cytokine; flow cytometry; gene expression; genetically modified animals; glucose 6 phosphate isomerase; immunoglobulins; immunopathology; immunoregulation; laboratory mouse; protein structure function; rheumatoid arthritis; toll like receptor

DESCRIPTION (provided by applicant): The candidate, Dr. Fei F. Shih, is a faculty member in the Rheumatology Division, Department of Pediatrics at Washington University. Dr. Shih has a long standing interest in autoimmune diseases. Her ultimate goal is to become an independent investigator in the field of autoimmunity and engage in translational research to apply her bench research to patient care. To achieve this goal she is examining T cell autoimmunity in KRN mice, a murine model of rheumatoid arthritis. Thymic deletion is the major mechanism whereby autoreactive T cells are eliminated from the functional cell repertoire. In KRN mice, incomplete deletion of KRN T cells with specificity for the ubiquitous self-antigen glucose-6-phosphate-isomerase (GPI) resulted in their activation and arthritis through provision of T cell help to anti-GPI B cells. Transgenic expression of a KRN TCR agonist under the MHC II promoter resulted in thymic deletion with loss of anti-GPI T and B cell responses and attenuated arthritis course. However, double transgenic mice succumbed to systemic autoimmunity with multi-organ inflammation and autoantibody production. Extensive thymic deletion resulted in lymphopenia and elimination of CD4+CD25+ regulatory T cells (Tregs), but spared some CD4+ T cells expressing endogenous TCR which oligoclonally expanded in the periphery. Disease was transferred by these T cells and prevented by co-transfer of CD4+CD25+ Tregs. This proposal employs a two-prong approach to elucidate the mechanisms whereby systemic T cell autoreactivity can result in diverse disease phenotype from joint centered synovitis to a fulminant multi-organ inflammation. Specific Aim 1 investigates the role of Tregs in the trafficking, growth, and the acquisition of effector function by pathogenic T cells. Specific Aim 2 interrogates the capacity of different antigen presenting cells (under steady state and during inflammation) to present GPI and how this will affect the initiation and propagation of disease in KRN mice.

描述(由申请人提供)： 这位候选人施飞飞博士是华盛顿大学儿科风湿科的一名教员。施博士对自身免疫性疾病的研究由来已久。她的最终目标是成为自身免疫领域的一名独立研究员，并从事转译研究，将她的长凳研究应用于患者护理。为了实现这一目标，她正在检测KRN小鼠的T细胞自身免疫，KRN小鼠是类风湿性关节炎的小鼠模型。胸腺缺失是自身反应性T细胞从功能细胞库中被消除的主要机制。在KRN小鼠中，对普遍存在的自身抗原葡萄糖-6-磷酸异构酶(GPI)具有特异性的KRN T细胞的不完全缺失通过向抗GPI B细胞提供T细胞帮助而导致其激活和关节炎。在MHC II启动子下转基因表达KRN TCR激动剂导致胸腺缺失，抗GPI T和B细胞反应丧失，关节炎病程减轻。然而，双转基因小鼠死于全身自身免疫，伴随着多器官炎症和自身抗体的产生。胸腺的广泛缺失导致淋巴细胞减少和CD4+CD25+调节性T细胞(Tregs)的消除，但保留了一些表达内源性TCR的CD4+T细胞，这些TCR在外周呈寡克隆性扩张。疾病通过这些T细胞转移，并通过CD4+CD25+Tregs的共同转移来预防。这项建议采用双管齐下的方法来阐明系统性T细胞自身反应可导致从关节中心性滑膜炎到暴发性多器官炎症的不同疾病表型的机制。具体目的1研究Tregs在致病T细胞的运输、生长和获得效应功能中的作用。特定目标2质问的能力 不同的抗原提呈细胞(在稳定状态下和在炎症期间)呈现GPI，以及这将如何影响KRN小鼠疾病的启动和传播。