ECDI结合供体脾细胞通过IDO途径活化AhR诱导小鼠移植肾免疫耐受

Our previous study have shown that ECDI fixed donor splenic cells(ECDI-SP) can prolong survival time of mice kidney allografts and induce Tregs and secretion of IL-10. This situation is similar to activation of Aryl hydrocarbon Receptor (AhR) in na?ve T cells and DC cells. In addition, if we used 1-MT to inhibit IDO, the immune tolerance induced by ECDI-SP was also blocked. Therefore, we postulate the mechanism that ECDI-SP may induce Tregs and tolerogenic DC cells by activation of AhR via IDO pathway, and promote long-term survival of kidney allografts. In order to confirm this hypothesis, we plan to observe whether ECDI-SP can induce Tregs and tolerogenic DC cells and promote long-term survival of allografts in mice kidney transplant model. Confirm the roles of IDO and AhR on inducing immune tolerance by using 1-MT to inhibit IDO and using AhR-/- mice as recipient mice. Elucidate the mechanism that ECDI-SP inducing Tregs and tolerogenic DC cells via IDO-kynurenine-AhR pathway. The aim of this study is to elucidate the mechanisms that ECDI-SP inducing immune tolerance in mice kidney transplantation and provide new methods for inducing immune tolerance in clinic.

我们前期研究表明ECDI结合供体脾细胞（ECDI-SP）能够延长小鼠移植肾存活时间，诱导Tregs产生和IL-10分泌，与幼稚T细胞和DC细胞内芳香烃受体（AhR）活化后结果相似；并且应用1-MT阻断IDO后，ECDI-SP诱导免疫耐受也被阻断。因此我们提出"ECDI-SP可能通过IDO途径活化AhR，诱导Tregs和耐受性DC细胞产生，促进移植肾长期存活"的机制假说。为验证上述假说，我们拟在小鼠肾移植模型中，观察ECDI-SP能否诱导Tregs和耐受性DC细胞的产生，促进移植肾长期存活；应用1-MT阻断IDO，以及以AhR-/-小鼠为受体小鼠，验证IDO和AhR在诱导免疫耐受中的作用。在体外MLR实验中，阐明ECDI-SP通过IDO-犬尿氨酸-AhR途径，诱导Tregs和耐受性DC细胞产生的机制。本研究旨在阐明ECDI-SP诱导小鼠移植肾免疫耐受的机制，为临床诱导免疫耐受提供新的思路。

诱导移植肾免疫耐受可以使肾移植患者避免长期服用免疫抑制剂带来感染和肿瘤等副作用。我们的研究结果表明，ECDI结合供体脾细胞（ECDI-SP）能够显著延长小鼠移植心脏存活时间，诱导Tregs和IL-10+DC细胞产生，提高DC细胞内IDO表达水平，活化幼稚T细胞和DC细胞内芳香烃受体（AhR）。应用1-MT阻断IDO后，或在AhR-/-小鼠为受体小鼠中，ECDI-SP诱导免疫耐受被阻断，提示IDO和AhR在ECDI-SP诱导移植免疫耐受中起关键作用。在体外MLR实验中，我们进一步阐明了ECDI-SP通过IDO—犬尿氨酸—AhR途径，诱导Tregs和耐受性DC细胞产生的分子机制。本研究在小鼠心脏移植模型中阐明ECDI-SP诱导小鼠移植物免疫耐受的新机制，为临床诱导移植肾免疫耐受提供新的思路。