T CELL RECOGNITION--REPERTOIRE IN AUTOIMMUNE THYROIDITIS

T 细胞识别——自身免疫性甲状腺炎的全部内容

• 批准号: 2468037
• 负责人: YI-CHI M. KONG
• 金额: $ 21.23万
• 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 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2468037
• 关键词: MHC class II antigen; T cell receptor; T lymphocyte; animal genetic material tag; autoantigens; autoimmune thyroiditis; autoimmunity; genetic polymorphism; genetic susceptibility; genetically modified animals; hormone receptor; human tissue; immunogenetics; laboratory mouse; leukocyte activation /transformation; lymphocyte proliferation; thyroglobulin; thyroid gland; thyroxine; tissue /cell culture

The overall goal is to use murine experimental autoimmune thyroiditis (eat) as a model to probe the recognitory and pathogenic mechanisms leading to thyroid damage in Hashimoto's thyroititis (HT), the hypothyroid syndrome. A major thrust in this renewal application is the emphasis on the use of HLA class II transgenic mice and human thyroid antigens because of new findings culminated with the last 2 years. The new findings include: 1) HLA-DR3 transgene confers susceptibility to EAT-resistant, as well as class II-deficient mice, permitting EAT induction by either thyroglobulin (HTg) or mouse (M) Tg. 2) Similar to H2A polymorphism determining EAT susceptibility, HLA-DRB1 polymorphism is a determinant, since HLA-DR2 transgenic mice are resistant to MTg-induced EAT. 3) Preliminary data show that HLA-DQ polymorphism can also be demonstrated, with distinct responses to HTg or MTg, implicating HTg-unique, as well as MTg-unique, epitopes associated with each species. 4) The identification of certain conserved, thyroiditogenic thyroxine (T4)-containing peptides, which are not dependent on the variable iodine residues on Tg for immunogenicity, can now be studied in conjunction with unique epitopes. We propose to: 1. Determine the role of HLA class II genes in autoimmune thyroiditis by examining HLA-DRB1 and HLA-DQ polymorphism--potential for HLA association with HT. 2. Determine the mutual influence of HLA-DR and HLA-DQ genes in double transgenic mice on EAT susceptibility and resistance--with emphasis on gene complementation and down-regulation (protection). 3. Identify thyroiditogenic epitopes unique to MTg and HTg--examining T cell repertoire and function. 4. Determine if HLA association with Tg correlates with other major thyroid antigens--using recombinant thyroperoxidase (rTPO) and thyroid- stimulating hormone receptor (rTSHR).

总体目标是使用小鼠实验自身免疫性甲状腺炎