T Cell Recognition & Repertoire in Autoimmune Thyroditis

T细胞识别

• 批准号: 6901008
• 负责人: YI-CHI M. KONG
• 金额: $ 23.98万
• 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 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6901008
• 关键词: MHC class II antigen; NOD mouse; T lymphocyte; antigens; autoimmune thyroiditis; cytokine; dietary trace element; disease /disorder model; epitope mapping; flow cytometry; genetic polymorphism; genetic susceptibility; genetically modified animals; hormone receptor; immunogenetics; iodide peroxidase; iodine; model design /development; nutrition related tag; thyroglobulin; thyrotropin; transfection; transforming growth factors; vector vaccine

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.

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，探索桥本甲状腺炎（HT）（甲状腺功能减退综合征）中促进和抑制甲状腺损伤的识别、致病和调节机制。由于前几年的新发现，这一更新应用的一个主要推力是强调使用特异性HLA单类和双类转基因小鼠和主要的人类甲状腺抗原，以及一种新的H2E转基因模型。其中包括：1)鉴定人甲状腺球蛋白（hTg）或小鼠(m) Tg诱导的EAT易感和耐药的HLA-DRB1和DQ转基因，从而证明EAT易感和耐药的多态性。2)抗性II类等位基因存在时，EAT发育下调；一个例子是DQ8转基因调节dr3介导的易感性。3)不寻常的H2E模型只允许hTg诱导，而不允许mTg诱导，这与传统的易感菌株不同。4)对于HLA和H2E转基因模型，从计算机模型中获得的特异性Tg表位已被证明具有甲状腺促甲状腺性，揭示了htg独有的表位。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：

项目成果

Thyroglobulin peptides of specific primary hormonogenic sites can generate cytotoxic T cells and serve as target autoantigens in experimental autoimmune thyroiditis.

• DOI: 10.1006/clin.1997.4487
• 发表时间: 1998
• 期刊: Clinical immunology and immunopathology
• 作者: Q. Wan;D. Mccormick;C. David;Y. Kong

Tumor regression following DNA vaccination and regulatory T cell depletion in neu transgenic mice leads to an increased risk for autoimmunity.

• DOI: 10.4049/jimmunol.0804074
• 发表时间: 2009-05-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Jacob JB;Kong YC;Nalbantoglu I;Snower DP;Wei WZ
• 通讯作者: Wei WZ

Enhancing or suppressive effects of antibodies on processing of a pathogenic T cell epitope in thyroglobulin.

抗体对甲状腺球蛋白中致病性 T 细胞表位加工的增强或抑制作用。

• 发表时间: 1999
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Dai,Y;Carayanniotis,KA;Eliades,P;Lymberi,P;Shepherd,P;Kong,Yc;Carayanniotis,G
• 通讯作者: Carayanniotis,G

Coexpression of susceptible and resistant HLA class II transgenes in murine experimental autoimmune thyroiditis: DQ8 molecules downregulate DR3-mediated thyroiditis.

小鼠实验性自身免疫性甲状腺炎中易感和耐药 HLA II 类转基因的共表达：DQ8 分子下调 DR3 介导的甲状腺炎。

• DOI: 10.1006/jaut.2002.0587
• 发表时间: 2002
• 期刊: Journal of autoimmunity
• 影响因子: 12.8
• 作者: Flynn,JeffreyC;Wan,Qiang;Panos,JohnC;McCormick,DanielJ;Giraldo,AlvaroA;David,ChellaS;Kong,Yi-chiM
• 通讯作者: Kong,Yi-chiM

Autoimmune thyroiditis as an indicator of autoimmune sequelae during cancer immunotherapy.

自身免疫性甲状腺炎作为癌症免疫治疗期间自身免疫后遗症的指标。

• DOI: 10.1016/j.autrev.2009.02.034
• 发表时间: 2009
• 期刊: Autoimmunity reviews
• 影响因子: 13.6
• 作者: Kong,Yi-chiM;Jacob,JenniferB;Flynn,JeffreyC;Elliott,BruceE;Wei,Wei-Zen
• 通讯作者: Wei,Wei-Zen