控制关键的炎性细胞因子IL-6、IL-21信号通路促进致敏移植免疫耐受诱导

Tolerance induction is still one of key questions of organ transplantation. Inflammation plays a critical role in transplant tolerance but its underlying mechanism is not well-defined. IL-6 and IL-21 an important proinflammatory cytokines and function as third signaling pathway, affecting immune responses and inflammation events. Their signaling pathways are critical in causing delayed graft function and affecting transplant tolerance. Our group firstly revealed that transplant immune balance would be tilted into tolerance as IL-6 deficient donor and IL-21 receptor deficient recipient are used in a presensitized transplant model. We hypothesize control of proinflammatory microenvironment can result in transplant tolerance. Therefore, our present study will test whether dual blockade of IL-6 and IL-21 signaling pathways can enhance tolerance induction in the sensitized transplant model through a couple of scientific experiments including survival analysis, administration of neutralizing monoclonal antibodies in vivo, adoptive transfer of immune cells, PAMP intervention experiments, test of third-party tolerance, gene differentiation analysis. The study in targeting IL-6 and IL-21 signaling pathways would provide new therapeutic strategy for sensitized transplant patients.

炎症在移植耐受诱导中至关重要但机制尚不明。文献和我们研究发现表明：IL-6 、IL-21是重要炎性细胞因子、特异性免疫第三信号，能影响免疫反应和炎症诸多功能，其信号通路在移植耐受分别起关键作用。本课题首次证明在无任何其它免疫抑制剂使用下单纯供体缺失IL-6 和受体缺失IL-21 能使MHC I 和II 完全不匹配的移植心脏长期存活，供、受体分别阻断IL-6、IL-21 诱导移植耐受国内外尚无报导， 其机制尚未阐明。我们推测"控制炎性微环境促进移植物耐受"。本课题将通过利用基因敲除小鼠、活体抗体中和实验、移植心脏存活活体实验、免疫细胞过继实验、PAMP干扰、第三方耐受测试、基因表达分析等，来深入探讨控制关键的炎性细胞因子IL-6、IL-21促进致敏移植耐受的作用机制，揭示对耐受诱导增效作用，为致敏移植耐受诱导提供新思路、药物作用新靶点。

炎症在移植耐受诱导中至关重要但机制尚不明。本研究课题研究白介素-6（IL-6）和白介素-21（IL-21）信号通路对致敏移植耐受诱导产生的影响，重点研究了供体IL-6缺失后对致敏移植心脏耐受诱导的影响和其它移植耐受诱导试剂对移植受体内先天性免疫细胞和后天性免疫细胞的影响。研究发现供体缺失IL-6后能显著延长移植物存活，改变了移植受体内外周血的CD4+和CD8+记忆T细胞的形成。另外，在小鼠预致敏心脏移植模型中，给予Tregs消除性单抗PC61或雷帕霉素，移植心脏内Gr1+中性粒细胞数都会增加，而过继输入Tregs给移植受体后，移植心脏内的Gr1+中性粒细胞数不会发生变化。然而，不论何种处理，都一致性导致了移植心脏内F4/80+巨噬细胞数明显增高。尽管雷帕霉素和过继输入Tregs不能影响NK1.1+细胞，但是，PC61摄入后能显著增加移植心脏内NK1.1+细胞数。本研究结果为今后临床改善致敏移植受体的耐受诱导提供了新的思路和策略。