HLA class II transgenic mice as experimental model of MS

多发性硬化（MS）是一种常见的中枢神经系统炎性脱髓鞘疾病，其特征是局部T细胞和巨噬细胞浸润到白色物质中。MS的病因仍然未知，但遗传和环境因素在疾病的发展中都很重要。MS的易感性与某些MHC II类等位基因有关，尽管对其确切功能的分析仍然很复杂。在这个建议中，我们将调查不同的人类MHC II类分子在MS的发病机制的贡献。为了测试这一点，我们已经产生了转基因小鼠表达几个HLA-DR和-DQ基因的小鼠内源性II类基因已被敲除。此外，为了进一步使我们的转基因小鼠人源化，我们已经用人CD4基因替换了小鼠CD4。我们的目的是：1）通过诱导转基因小鼠实验性变态反应性脑脊髓炎（EAE），建立MS的实验模型。该分析将揭示HLA II类分子在疾病易感性/抗性中的作用。2)分析HLA Ⅱ类分子在细胞因子表达和T细胞选择中的作用。3)目的：研究受HLA II类分子限制的CNS自身抗原T细胞表位的加工和呈递。HLA II类限制性实验模型的开发将有助于了解HLA II类分子在MS发病机制和免疫干预措施中的确切作用。

Multiple sclerosis (MS) is a common inflammatory demyelinating disease of the central nervous system characterized by local infiltration of T cells and macrophages into the white matter. The etiology of MS remains unknown, but both genetic and environmental factors are important in the development of disease. Susceptibility to MS has been linked to certain MHC class II alleles, although analysis of their exact function remains complicated. In this proposal, we will investigate the contribution of different human MHC class II molecules in the pathogenesis of MS. To test this, e have generated transgenic mice expressing several HLA-DR and -DQ genes in mice where the endogenous class II genes have been knocked out. In addition, to further humanize our transgenic mice, we have replaced the mouse CD4 with human CD4 gene. Our objectives are: 1) To generate experimental models of MS via induction of experimental allergic encephalomyelitis (EAE) in the transgenic lines. This analysis will shed light into the role of HLA class II molecules in susceptibility/resistance of disease. 2) To analyze the role of HLA class II molecules in cytokine expression and T cell selection. 3) To examine processing and presentation of T cell epitopes derived from CNS autoantigens, restricted by the HLA class II molecules. The development of HLA class II restricted experimental models will aid towards understanding the exact role of HLA class II molecules in MS pathogenesis and in the formulation of immunotherapeutic interventions.