PATHOGENSIS AND THERAPY OF AUTOIMMUNE THYROID DISEASE

自身免疫性甲状腺疾病的发病机制和治疗

• 批准号: 6476127
• 负责人: LESLIE J DE GROOT
• 金额: $ 25.22万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-07-01 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6476127
• 关键词: African American; Graves disease; MHC class II antigen; T lymphocyte; apoptosis; autoimmune disorder; caucasian American; cell proliferation; cytotoxic T lymphocyte; epitope mapping; family genetics; flow cytometry; gene expression; hormone receptor; human subject; interleukin 2; iodide peroxidase; major histocompatibility complex; racial /ethnic difference; receptor expression; thyroid disorder; thyrotropin; tissue /cell culture

Autoimmune thyroid disease (AITD) affects at least 6 percent of all women in their lifetime, and more than 10 percent of older women. The broad aim of our research program is to understand the causes of human autoimmune thyroid disease, the mechanisms involved in controlling the immune response, and, if possible, to develop preventive or therapeutic measures based on the immunology of the disease. Genetic factors including inheritance of MHC genes and specific CTLA4 alleles have been shown by many investigators to play a role in predisposing to Graves' disease. Responses to specific TSH receptor (TSH-R), and thyroid peroxidase (TPO) epitopes, have been demonstrated for T cells, T cell lines, and T cell clones in patients with Graves' disease. We will study the mechanism through which HLA-DRbeta1*03 and DQalpha1*05 are associated with Graves' disease, by purifying these molecules and studying the affinity of TSH-R and TPO peptides for binding. We will ask whether the binding affinity corresponds with the ability of the epitopes to stimulate T cells. We will also determine whether specific subgroups of DRbeta1*03 are primarily associated with Graves' disease, and why the DRbeta1*03 molecule found in Black Americans is not associated with Graves' disease, while the molecule found in Caucasians is associated with Graves' disease. We will also analyze the relative binding affinity of TSH-R and TPO epitopes for DRbeta1*07 and DQalpha1*02, which appear to be protective factors and, in theory, might not bind the epitopes. We will assess the function of CTLA4 in patients and control subjects in relation to inheritance of a specific allele associated with development of Graves' disease. Expression of the gene will be studied by FACs analysis and resting in stimulated cells, and function will be studied by use of anti-CTLA4 antibodies during in vitro culture of lymphocytes with antigen and nonspecific T cell stimulating molecules. Secretion of IL-2 during proliferation with/without anti-CTLA4, and apoptosis after withdrawal of IL-2, will also be studied as markers for CTLA4 action. CTLA4 function will be evaluated in T cell subsets. The studies planned have direct bearing on development of AITD in humans, and also apply to other autoimmune disease such as Diabetes.

自身免疫性甲状腺疾病（AITD）在其一生中至少有6％的女性，而超过10％的老年妇女会影响。 我们的研究计划的广泛目的是了解人类自身免疫性甲状腺疾病的原因，控制免疫反应的机制，并在可能的情况下制定基于疾病免疫学的预防或治疗措施。 许多研究者已经证明了包括MHC基因遗传和特定CTLA4等位基因在内的遗传因素在诱发坟墓疾病中发挥作用。对于特异性TSH受体（TSH-R）和甲状腺过氧化物酶（TPO）表位的反应已在坟墓疾病患者的T细胞，T细胞系和T细胞克隆中得到证明。我们将研究HLA-DRBETA1*03和DQALPHA1*05通过净化这些分子并研究TSH-R和TPO肽的亲和力来结合结合的机制。 我们将询问结合亲和力是否与表位刺激T细胞的能力相对应。 我们还将确定drbeta1*03的特定亚组是否主要与坟墓的疾病有关，以及为什么在黑人美国人中发现的drbeta1*03分子与坟墓疾病无关，而在高加索人中发现的分子与坟墓疾病有关。 我们还将分析drbeta1*07和dqalpha1*02的TSH-R和TPO表位的相对结合亲和力，它们似乎是保护因素，从理论上讲，它们可能不会结合表位。 我们将评估CTLA4在患者和对照受试者中的功能与遗传与坟墓疾病发展有关的特定等位基因的功能。 基因的表达将通过FACS分析和刺激细胞中的静止性研究，并在用抗原和非特异性T细胞刺激分子的淋巴细胞体外培养过程中使用抗CTLA4抗体来研究功能。 IL-2在具有/没有抗CTLA4的增殖过程中的分泌以及撤回IL-2后的凋亡，也将作为CTLA4作用的标记。 CTLA4功能将在T细胞子集中评估。 计划的研究直接与人类AITD的发展有关，也适用于其他自身免疫性疾病，例如糖尿病。