MODULATION OF AN ANIMAL MODEL OF HYPERTHYROIDISM

甲亢动物模型的调节

• 批准号: 6138084
• 负责人: Sandra M McLachlan
• 金额: $ 32.58万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-15 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6138084
• 关键词: Graves disease; T lymphocyte; antibody specificity; autoantibody; disease /disorder model; enzyme linked immunosorbent assay; fibroblasts; flow cytometry; gender difference; hormone receptor; hyperthyroidism; iodide peroxidase; iodine; laboratory mouse; lymphocyte proliferation; pathologic process; protein structure; thyrotropin

Graves' hyperthyroidism, a very common autoimmune disorder affecting primarily women, is caused by TSH receptor (TSHR) autoantibodies that mimic the action of TSH. Very recently, the first animal model has been developed with the hallmarks of Graves' hyperthyroidism. We now propose to use this "Chiba" model to investigate several critical issues in Graves' disease, including exploration of approaches for immune intervention. 1. Addressing critical issues in Graves' disease:- The Chiba mouse model will be used to study the role of thyroid peroxidase (TPO) antibodies (common in Graves' disease), TSHR intramolecular cleavage, gender and iodide ingestion on development and course of hyperthyroidism 2. TSHR Antibody characterization:- TSHR antibodies arising in the Chiba mouse model will be characterized by approaches used for human TSHR autoantibodies, including:- (i) functional assays for TSH binding inhibition (TBI), thyroid stimulating immunoglobulin (TSI) and antibodies that block the biological action of TSH (TSBAb), (ii) epitopes and (iii) flow cytometry with intact cells to examine binding of non-functional TSHR antibodies. 3. TPO antibody characterization:- We will determine whether TPO antibodies in the Chiba model resemble human autoantibodies in terms of their:- (i) affinities, (ii) preferential recognition of native TPO and, (iii) preferential interaction with epitopes in the immunodominant region recognized by human TPO autoantibodies. 4. T Cell responses to TSHR antigen:- With the Chiba model of Graves' disease, we will:- (i) study the role of T cells in providing help in the generation of functional TSHR antibodies, (ii) determine the cytokines secreted by TSHR-specific T cells and, (iii) determine if the proliferative response of TSHR-specific T cell clones will vary depending on the antigen presenting cell (macrophages, B cells or syngeneic TSHR-expressing fibroblasts) 5. Intervention in the immune response in the Chiba model:- The Chiba model now makes feasible studies on the immunotherapy of hyperthyroidism in these animals, a long road that may ultimately provide the basis for immune intervention in human disease. We propose to examine the effect of second signal blockade (anti-CD40L) as a means to:- (i) Prevent the induction of disease and reverse the course of established disease and, (ii) Target a specific antigen (TSHR), rather than employing blanket suppression of the immune response.

坟墓的甲状腺功能亢进，一种非常常见的自身免疫性疾病，影响 主要是女性，是由TSH受体（TSHR）自身抗体引起的 模仿TSH的作用。 最近，第一个动物模型是 以坟墓甲状腺功能亢进症的标志发展。 我们现在建议 使用这种“千叶”模型来研究 坟墓疾病，包括探索免疫方法 干涉。 1。解决坟墓疾病中的关键问题： - Chiba小鼠模型将用于研究甲状腺过氧化物酶的作用 （TPO）抗体（在Graves疾病中常见），TSHR分子内分子 关于发展和过程的分裂，性别和碘摄入 甲状腺功能亢进2。TSHR抗体表征：-TSHR抗体 在Chiba小鼠模型中产生的将以方法为特征 用于人类TSHR自身抗体，包括：（i）功能测定 对于TSH结合抑制（TBI），甲状腺刺激免疫球蛋白 （TSI）和阻断TSH（TSBAB）生物学作用的抗体， （ii）与完整细胞的表位和（iii）流式细胞仪检查 非功能性TSHR抗体的结合。 3。TPO抗体 表征： - 我们将确定千叶中的TPO抗体是否 模型与人类自身抗体相似： - （i）亲和力， （ii）对天然TPO和（iii）优先识别的优先识别 与免疫区域的表位相互作用，由 人类TPO自身抗体。 4。t细胞对TSHR抗原的反应： - 与 我们将： - （i）研究T的作用 细胞为产生功能性TSHR抗体提供帮助， （ii）确定由TSHR特异性T细胞分泌的细胞因子，以及 （iii）确定TSHR特异性T细胞的增殖反应是否 克隆会根据抗原呈递细胞（巨噬细胞，， B细胞或表达tshr的合成性TSHR的成纤维细胞）5。 Chiba模型中的免疫反应： - 千叶模型现在 可行研究这些 动物，一条最终可能为免疫提供基础的漫长道路 干预人类疾病。 我们建议检查 第二个信号封锁（抗CD40L）作为： - （i）防止 诱导疾病并扭转已建立疾病的进程， （ii）靶向特定的抗原（TSHR），而不是使用毯子 抑制免疫反应。