PATHOGENESIS 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: 3228271
• 负责人: LESLIE J DE GROOT
• 金额: $ 17.86万
• 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 1994-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3228271
• 关键词: B lymphocyte; Graves disease; T cell receptor; T lymphocyte; antibody formation; antibody receptor; antigens; antiidiotype antibody; autoimmune disorder; autoimmune thyroiditis; cell mediated cytotoxicity; clone cells; gene expression; gene rearrangement; genetic disorder; helper T lymphocyte; human subject; immune response genes; immunogenetics; immunoglobulin idiotypes; laboratory mouse; laboratory rabbit; microsomes; molecular cloning; monoclonal antibody; myxedemas; synthetic peptide; thyroid disorder

Autoimmune thyroid disease (Graves' disease, thyroiditis, myxedema) affects 6% of women during their life span. The cause is probably multifactorial involving abnormal presentation of antigen, aberrant DR expression, and abnormalities in T cell suppressor circuits. We hypothesize that T cell immunization to thyroid microsomal antigen is a major factor in autoimmune thyroid disease, and we will analyze carefully the interaction of T cells and microsomal antigen. Antigen specific T cell clones derived from thyroid tissue would be investigated for their ability to control B cell specific antibody production, cytotoxicity directed to thyroid cells, and induction of immunoregulatory responses. A dominant epitope will be sought in microsomal antigen-thyroid preoxidase by defining immunoreactivity of T cell clones to purified microsomal antigen, peptide fragments, and synthetic peptides. The T cell receptor variable V alpha and V beta segments will be cloned and sequenced to determine whether one V segment is favored in gene rearrangement forming T cell receptors. An idiotypic monoclonal antibody directed to the T cell receptor of microsomal antigen specific T cell clones will be developed. Release of microsomal antigen-thyroid peroxidase from thyroid cells cultured in vitro will be analyzed, in an effort to determine how the immune system is exposed to the antigen. The studies should define the epitope(s) on thyroid microsomal antigen recognized by T cells, and the specific responses of the T cells to the antigen. If there is a dominant microsomal antigen epitope, or limited epitopes, monoclonal antibodies to the T cell receptor for the antigen could allow development of specific immunosuppressive therapy. Our analysis of the V alpha and B beta gene segments may define the use of favored segments in T cell receptor gene rearrangement, and thus identify a hereditable factor which could be important in the development of these diseases.

自身免疫性甲状腺疾病（Graves疾病，甲状腺炎，粘液性水肿） 在寿命中影响6％的妇女。 原因可能是 多因素涉及抗原异常表现，异常DR T细胞抑制电路的表达和异常。 我们 假设T细胞对甲状腺微粒体抗原的免疫是一种 自身免疫性甲状腺疾病的主要因素，我们将分析 小心T细胞和微粒体抗原的相互作用。 抗原 将研究源自甲状腺组织的特定T细胞克隆 为了控制B细胞特异性抗体产生的能力， 针对甲状腺细胞的细胞毒性，并诱导 免疫调节反应。 将寻求主要的表位 微粒体抗原 - 甲状腺前氧化酶通过定义T的免疫反应性 细胞克隆纯化的微粒体抗原，肽片段和 合成肽。 T细胞受体变量V alpha和V beta 段将被克隆并测序以确定一个v段是否 在形成T细胞受体的基因重排中受到青睐。 白痴 针对微粒体T细胞受体的单克隆抗体 将开发抗原特异性T细胞克隆。 微粒体的释放 来自体外培养的甲状腺细胞的抗原 - 甲状腺过氧化物酶将是 分析，以确定免疫系统如何暴露 抗原。 研究应定义甲状腺上的表位 T细胞识别的微粒体抗原，以及 T细胞到抗原。 如果有主要的微粒体抗原 表位或有限的表位，对T细胞的单克隆抗体 抗原的受体可以允许开发特定 免疫抑制疗法。 我们对V alpha和Bβ基因段的分析可能定义使用 在T细胞受体基因重排中有利的段，因此 确定一个可遗传的因素，这可能很重要 这些疾病的发展。