T Cell Recognition & Repertoire in Autoimmune Thyroditis

描述（由申请人提供）：总体目标是使用小鼠实验性自身免疫性甲状腺炎（EAT）作为模型，以探索促进和抑制桥本甲状腺炎（HT）（甲状腺功能减退综合征）中甲状腺损伤的免疫、致病和调节机制。由于前几年的新发现，该更新申请的一个主要重点是强调使用特定的HLA单和双II类转基因小鼠和主要的人类甲状腺抗原以及新型H2 E转基因模型。其中包括：1）鉴定HLA-DRB 1和DQ转基因，其负责对用人甲状腺球蛋白（hTg）或小鼠（m）Tg诱导的EAT的易感性和抗性，从而证明EAT易感性和抗性的多态性。2)在耐药II类等位基因的存在下，EAT的发展被下调;一个例子是DQ 8转基因调节DR 3介导的易感性。3)不寻常的H2 E模型仅允许hTg诱导，但不允许mTg诱导，这与常规的敏感菌株不同。4)对于HLA和H2 E转基因模型，来自计算机建模的特异性Tg表位已被证明是致甲状腺的，揭示了hTg独特的表位。最近在DNA基因免疫方面的成功为将我们的模型扩展到其他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具有不同容许性的新型H2 AE+转基因模型。 2.检测HLA-DR 3转基因小鼠在保护性II类等位基因和环境因素影响下对Tg和促甲状腺激素表位的反应。 3.确定与Tg相关的HLA是否与其他主要甲状腺抗原相关-甲状腺过氧化物酶（hTPO）和促甲状腺激素受体（hTSHR）的遗传免疫。 4.描述mTg诱导的抗性中T细胞调节的机制。

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.