联合α-1抗胰蛋白酶和ECDI结合供体脾细胞诱导小鼠肾移植免疫耐受

Our previous study have shown that ECDI fixed donor splenocytes(ECDI-SP) could prolong the kidney graft survival in mice kidney transplantation model, and induction of regulatory T cells(Tregs) play a key role in this process. However, proinflammatory factors secreting in perioperative period are important obstacles for Tregs induction.α-1 antitrypsin have been reported to effectively reduce the secretion of proinflammatory fators, therefore we postulate that using α-1 antitrypsin in perioperative period may enhance the effect of ECDI-SP on induction of Tregs and immune tolerance. In the present study, we will investigate whether α-1 antitrypsin combined with ECDI-SP can prolong kidney graft survival in mice kidney transplantation model. We will also investigate whether α-1 antitrypsin can inhibit the secretion of proinflammatory factors and promote ECDI-SP inducing Tregs and inhibiting effector T cells. We will further illustrate the possible molecular mechanisms that α-1 antitrypsin inhibit proinflammatory factor secretion and promote ECDI inducing immune tolerance in MLR study in vitro. The aims of the present study are to demonstrate that α-1 antitrypsin and ECDI-SP have coordinated effect on inducing immune tolerance in mice kidney transplantation model, to illustrate the possible mechanisms, and to provide a new method for inducing immune tolerance on transplantation field.

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，诱导调节性T细胞（Tregs）产生在其中起关键作用，但是在围手术期前炎症因子的释放是诱导Tregs产生的重要障碍。α-1抗胰蛋白酶已被证实可以有效减少前炎症因子释放，因此我们假设在围手术期联合应用α-1抗胰蛋白酶可能增强ECDI-SP诱导Tregs和移植肾免疫耐受的效果。本课题拟在小鼠肾移植模型中，验证联合应用α-1抗胰蛋白酶能否促进ECDI-SP诱导小鼠移植肾的长期存活；探讨α-1抗胰蛋白酶能否抑制前炎症因子释放，促进ECDI-SP 诱导Tregs产生和抑制效应性T细胞。在体外MLR实验中，进一步阐明α-1抗胰蛋白酶通过抑制前炎症因子释放，促进ECDI-SP诱导免疫耐受的分子机制。本课题旨在阐明α-1抗胰蛋白酶和ECDI-SP在诱导小鼠移植肾免疫耐受中的协同作用和机制，为诱导移植免疫耐受提供新的方法。

我们的前期研究表明ECDI结合供体脾细胞（ECDI-SP）能够延长小鼠移植心脏的存活时间，诱导调节性T细胞（Tregs）产生在其中起关键作用，但是在围手术期前炎症因子的释放是诱导Tregs产生的重要障碍。α-1抗胰蛋白酶已被证实可以有效减少前炎症因子释放，因此我们假设在围手术期联合应用α-1抗胰蛋白酶可能增强ECDI-SP诱导Tregs和移植心脏免疫耐受的效果。本课题在小鼠心脏移植模型中，证实联合应用α-1抗胰蛋白酶和ECDI-SP能够诱导小鼠移植心脏的长期存活。α-1抗胰蛋白酶可以抑制前炎症因子释放，增加抗炎症因子释放，从而促进ECDI-SP 诱导Tregs产生和抑制Th17细胞和CD8+T细胞增殖，同时抑制供体特异性的抗体分泌。在体外MLR实验中，我们证实α-1抗胰蛋白酶可以促进ECDI-SP抑制受体小鼠脾T细胞增殖。本课题阐明了联合α-1抗胰蛋白酶和ECDI-SP诱导小鼠移植心脏免疫耐受的作用和机制，为临床诱导移植免疫耐受提供新的方法。