T CELL RECOGNITION & REPERTOIRE--AUTOIMMUNE THYROIDITIS

T细胞识别

• 批准号: 2145192
• 负责人: YI-CHI M. KONG
• 金额: $ 15.99万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1997-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2145192
• 关键词: CELL; RECOGNITION; REPERTOIRE; AUTOIMMUNE; THYROIDITIS

The overall goal is to use murine experimental autoimmune thyroiditis (EAT) as a model to probe the recognitory and pathogenic mechanisms leading to thyroid lesions in Hashimoto's thyroiditis (HT). The early finding of H-2 linkage to thyroid damage has led to the recognition of MHC association with HT and other autoimmune diseases. In recent years, observations from human T cell studies have paralleled those found in the mouse. These include the proliferation of primed T cells to homologous and heterologous thyroglobulin (Tg), their subset composition in the thyroid, and cytotoxicity for thyroid target cells. In the mouse, we have further examined the role of shared and unique Tg epitopes in thyroiditogenicity, the infiltration kinetics of TCRalpha/beta+ T cell subsets, the efficacy of immunotherapy, as well as the regulatory mechanisms in EAT. Our recent gene transfer studies have demonstrated susceptibility to EAT mediated by H-2A molecules and resistance by H-2E molecules, as well as modulation of diseases by antibodies (Abs) to H-2A alpha,beta chain- specific synthetic peptides. The new relationship between MHC influence and T cell subset pathogenesis lays the groundwork for a study of the trimolecular interactions among MHC/self antigen/TCR vbeta gene usage in EAT. The self antigen (Ag) link of Tg epitopes may be within the four primary hormonogenic sites on Tg, which are highly conserved among mammalian species; recent report has shown one site to serve as a T cell epitope. We wish to test the pathogenicity of these thyroxine (T4-)- containing Tg epitopes in EAT. Postulating that these conserved epitopes are prime candidates for autoepitopes, we propose to: 1. Examine and identify thyroiditogenic epitopes on mouse Tg recognized by T cells--with particular emphasis on T4-containing synthetic peptides shared with human Tg. 2. Examine the T cell repertoire and TCR vbeta gene usage for shared and conserved epitopes--with emphasis on thyroiditogenic T cells. 3. Examine the MHC class II gene influence on TCR repertoire and autoreactivity--comparing the effects of H-2A/E genes and antibodies to their synthetic peptides, and vbeta gene deletion in two EAT-susceptible haplotypes. 4. Examine the MHC class I gene influence on EAT pathogenesis-- regarding the role of D genes and modulation by Abs to synthetic peptides.

总体目标是使用小鼠实验自身免疫性甲状腺炎