异源性mESC-TEPs胸腺内移植诱导耐受改善NOD小鼠T1D相关机制研究

1型糖尿病(T1D)是自身反应性T细胞攻击胰岛引起β细胞损害的自身免疫病。其发病机制是由于主要组织相容性复合体II(MHCII)分子的特异性单倍型位点，引起胸腺上皮细胞(TECs)对胰岛自身抗原表达和提呈障碍，导致免疫耐受缺陷所致。前期工作表明，小鼠胚胎干细胞源性胸腺上皮祖细胞(mESC-TEPs)在体内可分化为功能性的TECs，促进免疫耐受。由此我们提出，异源性的TECs具有与T1D小鼠TECs不同的MHCII分子，可正常表达胰岛自身抗原，诱导免疫耐受，达到阻止T1D的目的。因此，本课题拟用NOD小鼠T1D模型，研究异源性mESC-TEPs胸腺内移植后，分化为TECs，改善T1D的发生和发展；探讨相关机制是否与异源性TECs上MHCII分子和胰岛自身抗原表达和提呈有关，以及异源性TECs是否介导了抗原特异性中枢耐受和外周耐受。研究结果将为严重的T1D类自身免疫病治疗提供新的研究途径。

Type 1 diabetes(T1D) is an autoimmune disease results from the destruction of insulin-secreting islet β-cells by autoreactive T cells. The pathogenesis is associated with particular major histocompatibility complex (MHC) haplotype loci and impaired islet autoantigen expression and/or presentation in the thymus, which results in defects in both central and peripheral tolerance. We have reported that mouse embryonic stem cells (mESCs) can be selectively induced in vitro to generate thymic epithelial progenitors (TEPs) that further develop into functional thymic epithelial cells (TECs) in vivo to induce tolerance. Therefore, we propose that allogeneic TECs with MHC II molecule which is different from that of T1D mice can express the islet self-antigen to promote tolerance and prevent T1D functionally. We will investigate here that the allogeneic TECs derived from transplanted mESC-TEPs can ameliorate T1D in NOD mice in vivo, which is associated with the expression of allogeneic mis-mismatched MHC II molecule and islet self-antigen on TECs. Furthermore, we will demonstrate whether the allogeneic TECs can be induced to produce central and peripheral tolerance. Our findings will suggest that ESC-derived TEPs may offer a new approach to control T1D.