PATHOGENESIS AND THERAPY OF AUTOIMMUNE THYROID DISEASE

描述（由申请人提供）：格雷夫斯病是一种常见的甲状腺疾病，由自身免疫引起，可产生严重的并发症，包括心脏问题和眼病。环境因素起一定作用，但疾病的发展受到遗传因素的强烈制约，包括特定HLA II类基因的遗传和CTLA-4基因的特定版本。我们先前已经研究了II类MHC基因在格雷夫斯病中的作用，通过它们将来自抗原呈递细胞上的TSH受体的T细胞表位呈递给T细胞，从而发展免疫力。我们已经证明，某些经常刺激格雷夫斯病患者T细胞的TSH受体表位以中等亲和力与HLA-DRbetal*0301结合。我们将研究TSH受体表位，HLA蛋白和T细胞的相互作用，以更好地了解疾病的发展和可能抑制免疫过程的方法。TSH受体表位与Graves'患者中常见的所有DR和DQ蛋白的结合将被详细描述，并与患者的基因型和来自具有相同基因型的患者的T细胞的反应性相关。利用计算机算法、亲和力研究和T细胞应答，以及从DR蛋白的洗脱表位测序获得的信息，我们将建立重要的或免疫显性的TSH受体T细胞表位。有了这些信息在手，我们将试图获得突变的TSH受体序列，抑制患者的T细胞对TSH受体表位的反应。我们还将使用结合在DR或DQ分子或四聚体中的TSH受体表位，从体外患者血液样本中去除反应性T细胞，以确定是否可以找到降低免疫反应性的方法。在TSH-R免疫小鼠的Graves病模型中，我们将开发可能抑制疾病过程的表位，包括眼病的发展。这些表位将来可能同样用于患者。我们的研究将与A博士合作进行。Godkin博士将用计算机算法分析TSH-R表位。Phelps博士将分析我们从DR 3分子中分离出来的TSH-R表位。Kwok博士将提供DR 3四聚体。Ludgate的Graves病模型。

DESCRIPTION (provided by applicant): Graves' disease is a common disease of the thyroid caused by autoimmunity and can produce serious complications including cardiac problems and eye disease. Environmental factors play some role, but development of disease is strongly conditioned by genetic factors including inheritance of specific HLA Class II genes, and a specific version of the CTLA-4 gene. We have previously investigated the role of Class II MHC genes in Graves' disease through their presentation of T cell epitopes derived from the TSH receptor on antigen presenting cells, to T cells, in the development of immunity. We have shown that certain TSH receptor epitopes, which frequently stimulate T cells from patients with Graves' disease, bind with moderate affinity to HLA-DRbetal*0301. We will study the interaction of TSH receptor epitopes, HLA proteins, and T cells to better understand the development of disease and methods for possible inhibition of the immune process. Binding of TSH receptor epitopes to all of the DR and DQ proteins commonly found in our Graves' patients will be detailed and related to the genotype of the patient and reactivity of T cells from patients with the same genotype. Using computer algorithms, affinity studies, and T cell responses, as well as information gained from sequencing eluted epitopes from DR protein, we will establish the important or immunodominant TSH receptor T cell epitopes. With this information in hand, we will attempt to derive mutated TSH receptor sequences which inhibit the response of patients' T cells to TSH receptor epitopes. We will also use TSH receptor epitopes bound in DR or DQ molecules, or in tetramers, to remove reactive T cells from patient blood samples in vitro to determine whether a method can be found to reduce immunoreactivity. In a model of Graves' disease in TSH-R-immunized mice, we will develop epitopes that may inhibit the disease process, including the development of ophthalmopathy. Such epitopes might similarly be used in patients in the future. Our studies will be done in collaboration with Dr. A. Godkin, who will analyze TSH-R epitopes in a computer algorithm, Dr. R .G. Phelps, who will analyze TSH-R epitopes which we elute from DR3 molecules, Dr. W. Kwok, who will provide DR3 tetramers, and with Dr. M. Ludgate on the model of Graves' disease.