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: 2856762
• 负责人: YI-CHI M. KONG
• 金额: $ 20.44万
• 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/2856762
• 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).

总体目标是利用小鼠实验性自身免疫性甲状腺炎 (eat)作为探讨其致病机理的模型 导致桥本甲状腺炎（HT）中的甲状腺损伤，甲状腺功能减退 综合征在这个更新应用程序的一个主要推力是强调 使用HLA II类转基因小鼠和人甲状腺抗原， 在过去的两年里，新的发现达到了顶峰。这些新发现 包括：1）HLA-DR 3转基因赋予EAT抗性易感性， 以及II类缺陷小鼠，允许EAT诱导， 甲状腺球蛋白（HTg）或小鼠（M）Tg。2)H2 A多态性 决定EAT易感性，HLA-DRB 1多态性是决定因素， 因为HLA-DR 2转基因小鼠对MTg诱导的EAT具有抗性。第三章 初步数据表明，HLA-DQ多态性也可以证明， 对HTg或MTg有不同的反应，暗示HTg独特，以及 MTg-独特的，与每个物种相关的表位。4)识别 某些保守的，促甲状腺素（T4）的含有肽， 其不依赖于Tg上的可变碘残基， 免疫原性，现在可以结合独特的表位进行研究。 我们建议： 1.确定HLA II类基因在自身免疫性甲状腺炎中的作用 检测HLA-DRB 1和HLA-DQ多态性--HLA关联的可能性 与HT。 2.确定HLA-DR和HLA-DQ基因在双重免疫中的相互影响 转基因小鼠对EAT易感性和抗性的研究 基因互补和下调（保护）。 3.鉴定MTg和HTg独特的促甲状腺激素表位--检查T 细胞库和功能。 4.确定HLA与Tg的相关性是否与其他主要 甲状腺抗原-使用重组甲状腺过氧化物酶（rTPO）和甲状腺- 刺激激素受体（rTSHR）。