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Study on mechanisms of induction of anti-thyrotropin receptor antibodies in murine experimental Graves'disease.

小鼠实验性格雷夫斯病抗促甲状腺素受体抗体诱导机制研究。

基本信息

批准号：
09670468
负责人：
KOHNO Yoichi
金额：
$ 1.86万
依托单位：
Chiba University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

In order to investigate the mechanisms of induction of anti-thyrotropin receptor antibodies in Graves' disease, we established a new mouse model presenting stimulating anti-thyrotropin receptor-mediated hyperthyroidism with similar features of Graves' disease in human in which fibroblasts transfected with human thyrotropin receptor gene as an immunogen, The study showed that stimulating anti- thyrotropin receptor antibodies is exclusively dependent on the expression of class IT MHC molecule on the thyrotropin receptor-expressing fibroblasts used for immunization although total level of anti- thyrotropin receptor antibodies is influenced by some gene(s) other than MHC.These results strongly suggest that aberrant expression of class II MHC molecule on target organ (in this case, thyroid follicular cells) is quite important for initiation or progression of autoimmunity. By use of fibroblasts transfected with chimera receptors between human thyrotropin receptor and rat lutenizing hormone/chorionic gonadotropin receptor, we further demonstrated that N-terminal portion of the thyrotropin is crucial in induction of anti-thyrotropin receptor. Finally, we introduced CD86 gene into murine fibroblasts and immunized mice with thyrotropin receptor-positive fibroblasts which as higher costimulatory capacity for T cells. The results indicated in this system that CD86 has no additive effect on induction of anti-thyrotropin receptor antibodies.

为了探讨格雷夫斯病中抗促甲状腺素受体抗体的诱导机制，我们建立了一种新的小鼠模型，该模型呈现刺激抗促甲状腺素受体介导的甲状腺功能亢进症，其特征与人类格雷夫斯病相似，其中成纤维细胞转染人促甲状腺素受体基因作为免疫原。尽管抗促甲状腺素受体抗体的总水平受MHC以外的某些基因的影响，但抗促甲状腺素受体抗体完全依赖于用于免疫接种的表达促甲状腺素受体的成纤维细胞上IT类MHC分子的表达。这些结果强烈表明，靶器官（在本例中为甲状腺）上II类MHC分子的异常表达滤泡细胞）对于自身免疫的启动或进展非常重要。通过使用转染人促甲状腺素受体和大鼠促黄体激素/绒毛膜促性腺激素受体之间的嵌合受体的成纤维细胞，我们进一步证明促甲状腺素的N末端部分在抗促甲状腺素受体的诱导中至关重要。最后，我们将CD86基因导入小鼠成纤维细胞，并用促甲状腺素受体阳性成纤维细胞免疫小鼠，以提高T细胞的共刺激能力。结果表明，在该系统中CD86对于抗促甲状腺激素受体抗体的诱导没有加和作用。