胚胎滋养细胞诱导母-胎免疫耐受维持正常妊娠的分子机制

正常妊娠的建立和维持依赖母体对胚胎抗原的免疫耐受，协调的母-胎对话是母-胎免疫耐受的核心，我们前期研究发现：携带父系抗原的胚胎滋养细胞通过募集与训导母体免疫细胞，形成有利于胚胎发育的免疫耐受微环境。本项目以蜕膜免疫细胞的来源与驻留、表型训导与功能调节为切入点，利用人体标本与小鼠模型，通过组学技术、细胞共培养与免疫细胞亚群定向分化体系、体内外沉默或过表达关键基因、荧光标记过继转输等，解析胚胎滋养细胞对蜕膜免疫细胞亚群的募集、分化与功能调控等过程；进一步利用四倍体胚胎补偿技术，构建外胎层和胚胎组织呈现不同基因型的胚胎，特异性修饰和更改滋养细胞基因表达，探讨滋养细胞介导母-胎免疫耐受的重要分子机制；从生理与病理两方面阐明母-胎免疫耐受与正常妊娠建立和维持机制，为反复自然流产等母-胎免疫调节紊乱性疾患的防治提供新的策略，对提高同种异体移植物成活率及抗肿瘤免疫亦将产生重要贡献。

Establishing and maintaining a normal pregnancy depend on the maternal immune tolerance to the embryonic antigen. Maternal fetal dialogue is the core of maternal fetal immune tolerance. Our previous studies have found that: the embryonic trophoblast cells carrying the paternal antigens are critical in the formation of a unique microenvironment of immune tolerance through the recruitment and instruction of maternal immune cells. This project is to investigate the roles of embryonic trophoblasts in the enrichment, development and functional regulation of decidual immune cells by using human samples and mouse model via genomics/proteomics, cell coculture, immune cell subset direct differentiation, gene silence or overexpression, fluorescent labeling and adoptive transfer, ect. We then explore the molecular mechanism of trophoblast cells mediating maternal fetal immune tolerance by establishing tetraploid embryo complementation via constructing the embryo with the cover layer and embryo tissue showing different genotype. Thus, we will clarify the physiological and pathological mechanisms of maternal fetal immune tolerance and the normal pregnancy establishment. Our study might provide a new strategy for prevention and treatment of maternal-fetal immune regulation disorders including recurrent spontaneous abortion, which may also improve the graft survival rate and anti-tumor immunity.