MODULATION OF AN ANIMAL MODEL OF HYPERTHYROIDISM

格雷夫斯甲亢，一种非常常见的自身免疫性疾病，影响 主要是女性，由促甲状腺激素受体(TSHR)自身抗体引起 模仿促甲状腺激素的作用。最近，第一个动物模型已经被 带有格雷夫斯甲状腺机能亢进症的特征。我们现在提议 使用这个“千叶”模型来研究几个关键问题 格雷夫斯病，包括探索免疫方法 干预。1.解决格雷夫斯病的关键问题： 将千叶小鼠模型用于研究甲状腺过氧化物酶的作用 (TPO)抗体(Graves病常见)，TSHR分子内 乳沟、性别和碘摄入量对发育和病程的影响 甲状腺功能亢进症2.TSHR抗体特征：-TSHR抗体 在千叶小鼠模型中产生的特征将通过方法 用于人类TSHR自身抗体，包括：(I)功能分析 用于TSH结合抑制(TBI)、甲状腺刺激性免疫球蛋白 (TSI)和阻断TSH生物学作用的抗体(TSBAb)， (Ii)表位和(Iii)完整细胞的流式细胞术检测 结合不起作用的TSHR抗体。3.TPO抗体 特征：-我们将确定千叶脑中的TPO抗体 该模型在以下方面类似于人类自身抗体：-(I)亲和力， (2)优先承认土著TPO和，(3)优先 与免疫优势区识别的表位相互作用 人类TPO自身抗体。4.T细胞对TSHR抗原的反应：-with Graves病的千叶模型，我们将：(I)研究T 细胞在产生功能性TSHR抗体方面提供帮助， (Ii)测定TSHR特异性T细胞分泌的细胞因子， (Iii)确定TSHR特异性T细胞的增殖反应 克隆将根据抗原提呈细胞(巨噬细胞， B细胞或表达同基因TSHR的成纤维细胞)5.干预 千叶模型中的免疫反应：-千叶模型现在使 甲状腺功能亢进症免疫治疗的可行性研究 动物，一条漫长的道路，最终可能提供免疫的基础 对人类疾病的干预。我们建议研究以下措施的影响 第二信号阻断(抗CD40L)作为一种手段：-(I)防止 诱发疾病，逆转既定疾病的进程， (2)针对特定抗原(TSHR)，而不是使用毯子 抑制免疫反应。

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.