多发性硬化症（MS）是由自身反应性T细胞介导对髓鞘抗原免疫耐受破坏所致的自身免疫病。诱导长期抗原特异性耐受，清除或抑制自身反应性T细胞，可有效防止MS发生。但胸腺功能随年龄依赖逐渐退化和其内自身抗原的不稳定表达限制了治疗效果。我们前期实验证实，胚胎干细胞来源的胸腺上皮祖细胞（ESC-TEPs）移植到体内，可分化为胸腺上皮细胞（TECs），重建胸腺结构，促进T细胞发育。本课题拟在此基础上建立MS动物模型，将引起MS的关键致病性抗原（髓鞘少突胶质细胞糖蛋白，MOG）表达在mESC-TEPs内，胸腺内移植，研究其能否在分化为TECs改善微环境的同时，实现胸腺内MOG长期表达，诱导耐受，实现自身反应性T细胞清除或抑制,达到治疗MS的目的；并探讨该治疗机制是与中枢耐受或/和外周耐受有关，及TECs是否直接提呈抗原，介导自身耐受发生。这对通过诱导自身免疫耐受，去治疗MS类的自身免疫病具有重要意义。

Multiple sclerosis（MS） is a devastating autoimmunity disease. Myelin antigen is attacked by self-reactive T cells in MS. The most logical way for preventing MS would be to induce self-antigen-specific tolerance and delete or suppress functionally self-reactive T cells, which is followed by the same mechanism that the immune system uses to maintain self-tolerance throughout life. However, it is well known that the thymus profoundly undergoes age-dependent involution, and its functions are seriously compromised in the elderly. Thymic epithelial cells (TECs) are the major component of the thymic microenvironment for T cell development. Our preliminary results show that embryonic stem cells (ESCs) can be induced in vitro to generate thymic epithelial progenitors(TEPs) that further develop into functional TECs in vivo. We will investigate whether transplantation of mESC-TEPs expressing disease-causative self-antigen myelin oligodendrocyte glycoprotein (MOG) in mice results in enhanced T cell regeneration, long-term expression of MOG in the thymus, prevention of MS development, and remission of established MS in mice. We will also investigate the underlying mechanisms and determine whether the treatment is related to central (self-reactive T cells deleted) or/and peripheral(inhibitory effect of regulatory T cell ) tolerance and whether or not the tolerance is mediated by TECs directly. Our findings may suggest that transplantation of ESC-TEPs expressing disease-causative self-antigen(s) may provide an effective approach for the prevention and treatment of autoimmune disease.