ECDI结合供体脾细胞联合阻断OX40/OX40L通路诱导预致敏小鼠肾移植免疫耐受

如何诱导预致敏移植受者免疫耐受是当前器官移植领域的难题。我们的前期研究证实ECDI结合供体脾细胞（ECDI-SP）能够延长大鼠和小鼠移植肾存活时间，诱导调节性T细胞（Treg）产生在其中起关键作用，但ECDI-SP未能够延长预致敏小鼠移植肾存活时间。预致敏受者体内产生的记忆性T细胞（Tm）是促进排斥反应发生的重要因素，而OX40/OX40L共刺激分子是调控Tm和Treg的关键通路，阻断该通路可抑制Tm，促进Treg产生。本课题拟在前期研究基础上，采用预致敏小鼠肾移植模型，验证ECDI-SP联合阻断OX40/OX40L通路能否协同诱导小鼠移植肾长期存活，探讨阻断OX40/OX40L通路能否抑制Tm、促进ECDI-SP诱导Treg产生，并采用体外MLR实验进一步阐明阻断OX40/OX40L通路协同ECDI-SP诱导免疫耐受的分子机制，为临床诱导预致敏移植受者免疫耐受提供新的方法。

It is a tough problem that how to induce immune tolerance in presensitized transplant recipients. Our previous studies have shown that ECDI-fixed donor splenocytes (ECDI-SP) could prolong the kidney allograft survival in rats and mice kidney transplant models, and induction of regulatory T cells (Treg) play a key role in this process, whereas ECDI-SP fail to prolong survival of the kidney allograft in presensitized recipients. Memory T cells (Tm) generated in presensitized recipients have been reported to play important roles in promoting rejection. OX40/OX40L costimulation pathway plays a key role in controlling Tm and Treg, and blockage of this pathway could inhibit Tm while promote Treg expansion. Based on the previous studies, we will investigate whether ECDI-SP combined with blockage of OX40/OX40L pathway can prolong kidney allograft survival in presensitized mice kidney transplant model. We will also investigate whether blockage of OX40/OX40L pathway can inhibit Tm and promote ECDI-SP inducing Treg expansion. In the mixed lymphocytes reaction experiment in vitro, we will further illustrate the possible molecular mechanisms that blockage of OX40/OX40L pathway synergize with ECDI-SP in inducing immune tolerance. The aim of the present study is to explore new methods for clinical application of inducing immune tolerance in presensitized transplant recipients.