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症性脱髓鞘疾病，其特征是T细胞和巨噬细胞局部浸润到白质中。MS的病因尚不清楚，但遗传和环境因素在疾病的发展中都很重要。对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。在本提案中，我们将研究不同的人类MHC II类分子在ms发病机制中的作用。为了验证这一点，我们在敲除内源性II类基因的小鼠中产生了表达几种HLA-DR和-DQ基因的转基因小鼠。此外，为了进一步使我们的转基因小鼠人源化，我们将小鼠CD4替换为人类CD4基因。我们的目标是：1)通过在转基因系中诱导实验性过敏性脑脊髓炎（EAE）来建立MS的实验模型。这一分析将揭示HLA II类分子在疾病易感性/抗性中的作用。2)分析HLAⅱ类分子在细胞因子表达和T细胞选择中的作用。3)检测受HLAⅱ类分子限制的中枢神经系统自身抗原衍生的T细胞表位的加工和提呈。HLA II类限制性实验模型的建立将有助于了解HLA II类分子在MS发病机制和免疫治疗干预制定中的确切作用。

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.