日本血吸虫SEA诱导外周移植免疫耐受的机制研究

Donor-specific immune tolerance is the goal that every practitioner pursues in organ transplantation. Recently, the progress in understanding of regulatory cells makes it possible for achieving peripheral immune tolerance in transplantation. Helminth is the master of immune regulation, and could regulate the immune response of the host in many aspects, including the induction of regulatory cells. Moreover, it shows “bystander effects” when suppressing the immunoreaction, which induces immune tolerance for bystander antigens. Thus, it becomes a novel method for induction of immune tolerance in transplantation with helminth and its secretes. We found that the recipient receiving a liver from a donor with Schistosoma japonicum showed a certain extent of immune tolerance in clinic, which revealed that the eggs of Schistosoma japonicum could regulate the immune system. Based on these facts, we successfully prepared the soluble egg antigens (SEA) from Schistosoma japonicum eggs. In this research, we would like to 1) evaluate the effects of SEA on the immune system and renal graft in the kidney transplantation model of rats; 2) explore the strategy of donor-specific immune tolerance induced by SEA together with donor B lymphocytes; 3) research the mechanism in which SEA works on dendritic cells. The results of this research would help clarify the regulatory mechanism of SEA, and provide a novel method for donor-specific immune tolerance induction. It would highlight the value in clinic and scientific research.

诱导供者特异性免疫耐受是每位器官移植医师梦寐以求的目标。近年来对调节性细胞的深入研究，为实现外周移植免疫耐受提供了可能。蠕虫类寄生虫是免疫调节的大师，可以从多方面调节宿主的免疫反应，包括诱导调节性细胞的生成。更重要的是，其免疫调节作用具有“旁观效应”，能够使宿主对旁观抗原形成免疫耐受。利用蠕虫及其分泌物诱导移植免疫耐受成为新的研究方向。我们在临床上发现接受日本血吸虫供肝肝移植的患者出现了一定程度的免疫耐受，提示血吸虫虫卵具有免疫调节作用。因此，我们成功制备了日本血吸虫可溶性虫卵抗原（soluble egg antigen, SEA）,将在大鼠肾移植模型中评估其对免疫系统和移植物的影响，探索SEA联合供者B淋巴细胞诱导特异性免疫耐受，研究SEA作用于树突状细胞的机制。该研究将有助于阐明SEA的免疫调节机制，提供新的诱导特异性免疫耐受的途径，有很强的临床和科学价值。

诱导供者特异性免疫耐受是每位器官移植医师梦寐以求的目标。近年来对调节性细胞的深入研究，为实现外周移植免疫耐受提供了可能。蠕虫类寄生虫是免疫调节的大师，可以从多方面调节宿主的免疫反应，包括诱导调节性细胞的生成。更重要的是，其免疫调节作用具有“旁观效应”，能够使宿主对旁观抗原形成免疫耐受。利用蠕虫及其分泌物诱导移植免疫耐受成为新的研究方向。我们在临床上发现接受日本血吸虫供肝肝移植的患者出现了一定程度的免疫耐受，提示血吸虫虫卵具有免疫调节作用。因此，我们成功制备了日本血吸虫可溶性虫卵抗原（soluble egg antigen, SEA）,以小鼠皮肤移植模型为研究对象，通过流式细胞术、mRNA seq 等技术，发现日本血吸虫SEA可以抑制排斥和延长皮肤移植物的存活，且生信分析提示SEA减轻排斥反应可能与调节细胞对IFN-γ的反应，IL - 17信号通路和趋化因子信号通路以及细胞因子与细胞因子受体的相互作用信号通路的激活有关。此外，课题组还利用单细胞测序等技术搭建了临床器官移植免疫监测平台和血吸虫病外周与肝脏免疫图谱，取得了较好的社会和经济效益。上述研究将为的抗排斥甚至诱导免疫耐受的提供新的治疗策略。