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: 2414774
• 负责人: LESLIE J DE GROOT
• 金额: $ 20.51万
• 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 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2414774
• 关键词: African American; Graves disease; MHC class II antigen; SCID mouse; T lymphocyte; anergy; autoantigens; autosomal dominant trait; caucasian American; disease /disorder model; disease /disorder proneness /risk; epitope mapping; family genetics; genotype; hormone receptor; human subject; immunomodulators; immunotherapy; leukocyte count; linkage mapping; major histocompatibility complex; nonhuman therapy evaluation; oligonucleotides; polymerase chain reaction; thyrotropin

The aim of our research program is to understand the causes of autoimmune thyroid disease, the mechanism of the immune response and, if possible, to develop preventative or therapeutic immunomodulatory measures. We will identify dominant and pathogenic epitopes of TSH receptor (hTSH-R), determine genetic factors promoting the disease, determine the relationship of epitope recognition to MHG genotypes, and study potential immunotherapeutic measures in vitro and in vivo in a SCID mouse model. Epitopes will be identified using recombinant antigen and synthetic peptides reacting with PBMG, T cell lines and T cell clones derived from patients with GD and controls. We will study populations, families with a high incidence of GD, especially homozygous HLA-DQA1 *0501 patients, and young individuals in such families in the early phase of disease. To establish biologic importance of the epitopes we will consider 1) differential reactivity comparing patients with GD and controls, 2) concordance of reactivity by PBMC, and derived T cell lines and clones, 3) correlation of epitope recognition with disease and MHC genotype within families, 4) recognition of epitopes in young family members genetically at risk for GD, 5) changes in lymphocyte reactivity following antigen deprivation, and 6) relation of specific epitopes to MHG genes. Epitope reactivity will be analyzed following mutation of the peptide. Peptides which may be able to act as antagonists to the natural epitope, or to induce anergy in T cell lines or clones in vitro will be investigated. We will study, in SCID mice, the ability of T cell lines, reacting to specific epitopes, to reconstitute thyroiditis and produce thyroid stimulating antibodies in animals also xeno- transplanted with isologous thyroid tissue. In this model we can also test peptide antagonists, epitope induced T cell anergy, and induction of tolerance by antigen. Class II MHC genotypes will be determined by a PCR/site specific oligonucleotide methodology in Caucasian populations, Black populations, and Caucasian and Black family groups, to determine linkage of HLA with disease. Since it is clear that HLA associations explain only part of the genetic influence, we will proceed to type, in specific highly informative families, a group of at least eight candidate immune-associated genes for linkage to GD.

我们的研究计划的目的是了解自身免疫的原因 甲状腺疾病，免疫反应的机制，如果可能的话 制定预防或治疗性免疫调节措施。我们将 确定TSH受体（HTSH-R）的显性和致病表位， 确定促进该疾病的遗传因素，确定 表位识别与MHG基因型的关系并研究潜力 SCID小鼠模型中的体外和体内免疫治疗量。 将使用重组抗原和合成鉴定表位 与PBMG，T细胞系和T细胞克隆反应的肽 具有GD和对照的患者。我们将研究人群，有 GD的高发病率，尤其是纯合HLA-DQA1 *0501患者，以及 在疾病早期，此类家庭中的年轻人。到 确定我们将考虑的表位的生物学重要性1） 比较GD和对照患者的差异反应性，2） PBMC的反应性以及衍生的T细胞系和克隆的一致性，3） 表位识别与疾病和MHC基因型的相关性 家庭，4）在遗传上认识年轻家庭成员的表位 有GD的风险，5）抗原后淋巴细胞反应性的变化 剥夺和6）特定表位与MHG基因的关系。表位 在肽突变后，将分析反应性。肽 可能能够充当自然表位的对手，或 将研究在体外诱导T细胞系或克隆中的Anergy。我们 将在SCID小鼠中研究T细胞系的能力，对 特定表位，重建甲状腺炎并产生甲状腺 刺激动物中的抗体也被异种移植 甲状腺组织。在此模型中，我们还可以测试肽拮抗剂， 表位诱导T细胞消极，并通过抗原诱导耐受性。 II类MHC基因型将由PCR/位点特异性确定 高加索人群，黑人人群，黑人种群的寡核苷酸方法论 以及高加索人和黑人家庭团体，以确定HLA与 疾病。由于很明显，HLA关联仅解释 遗传影响，我们将继续输入特定信息丰富的信息 家庭，至少八组候选免疫相关基因 链接到GD。