T Cell Recognition & Repertoire in Autoimmune Thyroditis

描述(由申请人提供)：总体目标是以小鼠实验性自身免疫性甲状腺炎(EAT)为模型，探索桥本甲状腺炎(HT)即甲状腺功能减退综合征中促进和抑制甲状腺损害的识别、致病和调节机制。由于前些年的新发现，这一新的应用重点是强调使用特定的HLA单、双II类转基因小鼠和主要的人类甲状腺抗原和一种新的H2E转基因模型。1)人类甲状腺球蛋白(HTG)或小鼠(M)TG诱导的EAT易感性和抗性相关基因的鉴定，从而显示了EAT易感性和抗性的多态。2)在存在II类抗性等位基因的情况下，EAT的发育受到下调；DQ8转基因调节DR3介导的敏感性就是一个例子。3)与传统的敏感菌株不同，不寻常的H2E模型只允许HTG诱导，而不允许MTG诱导。4)对于人类白细胞抗原和H_2E转基因模型，由计算机模拟得到的特定的甘油三酯表位已被证明是甲状腺机能亢进的，揭示了HTG特有的表位。最近DNA基因免疫的成功为将我们的模型扩展到另外两种主要的甲状腺抗原提供了新的动力。我们建议： 1.表征对HTG具有明显渗透性的新型H_2AE转基因模型。 2.检测在保护性II类等位基因和环境因素的影响下，转基因小鼠对甘油三酯和促甲状腺激素表位的反应。 3.确定人类白细胞抗原与甘油三酯的相关性是否与其他主要甲状腺抗原--甲状腺过氧化物酶(HTPO)和促甲状腺激素受体(HTSHR)基因免疫相关。 4.探讨T细胞在MTG诱导耐药中的调控机制。

DESCRIPTION (provided by applicant): The overall goal is to use murine experimental autoimmune thyroiditis (EAT) as a model to probe the recognitory, pathogenic, and regulatory mechanisms, both promoting and inhibiting thyroid damage in Hashimoto's thyroiditis (HT), the hypothyroid syndrome. A major thrust in this renewal application is the emphasis on the use of specific HLA single and double class II transgenic mice and major human thyroid antigens and a novel H2E transgenic model because of new findings in the previous years. These include: 1) Identification of HLA-DRB1 and DQ transgenes responsible for susceptibility and resistance to EAT induced with either human thyroglobulin (hTg) or mouse (m) Tg, thereby demonstrating polymorphism in EAT susceptibility and resistance. 2) In the presence of resistant class II alleles, EAT development is down-modulated; an example is DQ8 transgene moderating DR3-mediated susceptibility. 3) The unusual H2E model is permissive only for hTg, but not mTg, induction, unlike conventional, susceptible strains. 4) For both HLA and H2E transgenic models, specific Tg epitopes derived from computer modeling have proven thyroiditogenic, revealing hTg-unique epitopes. The recent success in genetic immunization with DNA has provided renewed impetus to extend our models to two other major thyroid antigens. We propose to: 1. Characterize the novel H2AE+ transgenic model with distinct permissiveness for hTg. 2. Examine the response of HLA-DR3 transgenic mice to Tg and thyroiditogenic epitopes under the influence of protective class II alleles and environmental factors. 3. Determine if HLA association with Tg correlates with other major thyroid antigens-genetic immunization with thyroid peroxidase (hTPO) and thyroid-stimulating hormone receptor (hTSHR). 4. Characterize the mechanisms of T cell regulation in mTg-induced resistance.