血吸虫感染所致胸腺萎缩对虫卵肉芽肿及纤维化发生的作用机制研究

Thymus is the main immune organ of T cell differentiation, development and mature. Previously we have found that infection of Schistosoma Japonicum can cause atrophy of thymus，induce aging of T cells in the peripheral immune organs. Meanwhile, we found S. japonicum infection induce significantly high level expression of CD8+CD28− Tregs in liver and peripheral blood. In vitro experiments revealed that CD8+CD28− Tregs inhibit the proliferation of naive CD4+ T cells of spleen mononuclear cells. Tracing and adoptive immunotherapy experiment confirmed that CD8+CD28− Tregs were specifically recruited to egg granuloma in liver, and they could increase the IL-10 secretion and reduce host immune responses, thereby weaken granulomatous inflammatory reaction and the levels of liver fibrosis in chronic phase during S. japonicum infection. These data demonstrate the roles of CD8+CD28− Tregs in regulation of immune response during liver granuloma formation induced by S. japonicum egg. However, the mechanism is still unknown. Thus, surrounding the hypothesis that” Strengthen of Treg subgroups caused by thymus atrophy after infection of S.Japonicum is an important reason of granuloma and liver fibrosis”, we want to recognize the change features of Treg subgroups related to the pathogenesis of Schistosomiasis and the function of thymus atrophy in the strengthen of Treg subpopulation, and finally investigate the mechanism related to the improvement of pathogenesis after regeneration of thymus function These work will useful for reveal the precise mechanisms of liver granuloma and fibrosis during S. japonicum infection and supply new for immunotherapy in schistosomiasis japonica.

胸腺为机体重要中枢免疫器官，是T淋巴细胞分化，发育和成熟的重要场所。我们发现血吸虫感染会引起胸腺发生萎缩、外周T细胞出现老化，特别是CD8+CD28-Treg数量明显增加，并且这种改变不会因吡喹酮治疗而恢复；过继实验发现CD8+CD28-Treg会特异性募集在虫卵肉芽肿周围，肉芽肿炎性反应及肝脏纤维化程度明显减轻，提示胸腺及其完整性与虫卵肉芽肿和肝纤维化的发生存在密切联系，其作用机制值得深入研究。为此，本项目围绕“血吸虫感染所致胸腺萎缩引起输出Treg细胞亚群功能的强化是介导虫卵肉芽肿和肝纤维化发生的重要原因” 这一假说，研究血吸虫感染后与病程相关的输出Treg细胞亚群的变化特征，探讨胸腺萎缩在强化这些特征性Treg亚群中的作用，以及胸腺功能重构对虫卵肉芽肿和肝脏纤维化的延缓作用及其机制，进一步揭示机体免疫系统对虫卵肉芽肿和肝脏纤维化发生及其调控的精确机制，为晚期血吸虫病防治提供新的思路。

胸腺为机体重要中枢免疫器官，是T淋巴细胞分化，发育和成熟的重要场所。本项目根据项目书的研究目标展开研究工作，目前完成了：①通过检测小鼠在感染日本血吸虫后不同时间点其胸腺、脾脏、肝脏虫卵肉芽肿炎症及肝纤维化的动态病理变化情况，提示了血吸虫感染所致的胸腺萎缩与肝脏肉芽肿炎症与肝纤维化的发生密切相关。②通过观察小鼠在感染日本血吸虫后体内不同Treg细胞亚群（CD4+CD25+Foxp3+、CD8+CD28-、naïve Treg和am Tregs)的动态变化情况，提示了血吸虫感染所致的胸腺萎缩、Treg细胞亚群的输出与肝脏虫卵肉芽肿和肝脏纤维化发生的相关性。③通过将感染小鼠脾脏中分离的CD8+CD28-Treg细胞过继转移至感染小鼠体内，明确了CD8+CD28-Treg细胞亚群在肝脏虫卵肉芽肿及纤维化发生发展中的作用，即CD8+CD28-Treg细胞通过募集至虫卵周围从而明显改善感染小鼠肝脏中的肉芽肿炎症及肝纤维化。④利用抗炎分子（Sj16重组蛋白）及药物（黄连素）重构胸腺功能后观察血吸虫感染后效应性 Treg 细胞亚群的变化特征，以及虫卵肉芽肿和肝纤维化进程变化情况，明确了重构胸腺功能可显著缓解血吸虫感染引起的虫卵肉芽肿和肝脏纤维化程度，其机制可能与重构胸腺功能后Treg细胞的输出减少有关。⑥探讨了活化T细胞核因子(NFAT)在调控血吸虫感染所致的胸腺萎缩引起输出Treg 细胞亚群功能强化介导虫卵肉芽肿和肝纤维化发生中的作用。本研究进一步揭示了胸腺在血吸虫感染诱导病理损害中的效应性作用，进一步阐明了虫卵肉芽肿和肝脏纤维化发生与Treg细胞亚群的关系及其作用机制，深化了对血吸虫病致病机制的认识，为血吸虫病的防治提供了新的思路和对策。