受体肠源性肥大细胞在肝移植抗体介导排斥反应中促进肝窦内皮细胞损伤并进而损伤移植肝的机制

项目名称： 受体肠源性肥大细胞在肝移植抗体介导排斥反应中促进肝窦内皮细胞损伤并进而损伤移植肝的机制

项目编号： No.81470897

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李济宇

作者单位： 同济大学

项目金额： 73万元

中文摘要： 肝移植术后的抗体介导的排斥损伤（AMR）一直未受重视，其首发效应是移植物血管内皮细胞的损伤，机制不明。肥大细胞在移植免疫中的作用正被深入认识，课题组前期阐明了供肝肥大细胞介导免疫耐受在移植物保护中的重要作用，进而发现术后受体肠管富集的肥大细胞发生脱颗粒且跟供肝损伤严重程度正相关，提示受体肥大细胞可能参与AMR。其机制可能是：移植后激活补体系统释放活性片段C3a、C5a，经体循环到肠管，结合肠管肥大细胞表面G蛋白偶联受体引起脱颗粒；释放的胰蛋白酶经门静脉汇至肝脏，与肝窦内皮细胞表面蛋白酶受体结合，上调内皮细胞粘附分子等表达，促进白细胞浸润和微血栓形成；上调MHCI类抗原表达，最终促进AMR损伤移植肝。该研究从受体内功能联系密切的肝和肠联合考虑的全新视角，探讨肠管肥大细胞参与AMR对移植物损伤作用的机制，以期阐明肥大细胞介导免疫排异损伤的重要作用，为减轻移植物损伤寻找新的靶点提供理论依据。

中文关键词： 肝移植；肠源性肥大细胞；抗体介导的排斥反应；肝窦内皮细胞；胰蛋白酶

英文摘要： Primarily caused by endothelial cell damage,Antibody mediated rejection (AMR) after liver transplantation is agnored until recently. The exact mechanism is still unkown. The role of mast cell (MC) in immunology has been futherly recognized recent years. Our previous work showed that resident MC in donor liver plays as a protector by inducing immune tolerance.In the meanwhile, we found that MCs in the bowels of recipients not only degranulate but also the degree of the degranulation correlates with the severity of damage in the transplanted livers.The result may reveal that MCs play a role in AMR. We hypotheize the mechanism of MCs in AMR as follows: C3a and C5a which are released by complement system activation in AMR,arrive to bowel through circulation and conjugate with their G protein coupled receptors to trigger MC degranulation; mast cell tryptase (MCT) released by MC degranulation is confluent and arrives to liver through portal vein,and then activate proteinase on the surface of liver sinusoidal epithelial cells (LSEC) to upregulate adhesive molecules of LSECs and so on;These molecules can cause leukocyte inflitration and microthrombus formation;Upregulation of major histocompatabile complex (MHC)I antigen expression promoting the damage of liver by AMR.From the view of close relationship between liver and bowel, We aim to discover the mechanism of MC degranulation in promoting liver damage in AMR and find a new method to alleviate the damage of transplanted liver.

英文关键词： Liver transplantation;Bowel mast cell;Antibody mediated rejection;Liver sinusoidal epithelial cell;Trypsin