自体抗原Col I通过IL-17介导肝移植术后慢性排斥反应的机制研究

Immunosuppressive drugs significantly increased the survival of transplant patients. However it is not functional in preventing chronic rejection. Previous reports have demonstrated that immune responses especially Abs to self-Ags through IL17 has significant pro-fibrotic properties leading to chronic allograft failure (heart, lung and kidney). However few reports about the mechanism of chronic rejection (CR) after liver transplantation were published. The aim of this project is to investigate the role of Collagen I (ColⅠ) in the pathogenesis of CR. Rat liver transplantation chronic rejection model was established to investigate the Collagen expression during CR. Collagen immunized Rat was used to reveal the mechanism of IL-17 expression and Th17 differentiation during rejection. And IL-17A -/- Rat was used to determine the mechanism of IL-17 in Liver fibrosis and regeration. The project will be great value for understanding pathogenesis of CR and provide the novel target spot in CR prevention after liver transplantation.

器官移植术后患者需要长期服用免疫抑制药物预防排斥；虽然免疫抑制剂在很大程度上降低了急性排斥发生率，但对慢性排斥反应仍然无能为力。探求慢性排斥的发病机制并加快临床转化在供体器官匮乏的今天尤为迫切。目前有关肝脏慢性排斥的研究极少，现阶段的研究发现，自身抗原而不是同种异体抗原参与了器官移植（心脏、肺和肾脏）的慢性排斥反应，其机制与IL-17密切相关。本组现有研究显示肝移植慢性排斥患者自身抗原（Col I）明显增高，体外Col I能够明显诱导CD4+ T细胞分泌IL-17。本课题拟通过大鼠肝脏移植慢性排斥模型，分析自身抗原（ColⅠ）是否通过诱导IL-17参与肝脏移植慢性排斥反应及具体作用机制。本项目的实施有利于明确自身抗原在诱导器官移植慢性排斥中的作用，了解肝脏移植慢性排斥反应中IL-17A的产生及其作用的机制，以期寻求合适的干预靶点和时机，为临床治疗提供实验基础和理论依据。

器官移植术后患者需要长期服用免疫抑制药物预防排斥；虽然免疫抑制剂在很大程度上降低了急性排斥发生率，但对慢性排斥反应仍然无能为力。探求慢性排斥的发病机制并加快临床转化在供体器官匮乏的今天尤为迫切。目前有关肝脏慢性排斥的研究极少，现阶段的研究发现，自身抗原而不是同种异体抗原参与了器官移植（心脏、肺和肾脏）的慢性排斥反应，其机制与IL-17密切相关。本组现有研究显示肝移植慢性排斥患者自身抗原（Col I）明显增高，体外Col I能够明显诱导CD4+ T细胞分泌IL-17。本课题通过大鼠肝脏移植慢性排斥模型，围绕肝移植排斥过程中Treg和IL-17参与肝脏移植慢性排斥反应及具体作用机制开展多项基础研究。发表SCI论文13篇，包括NAV REV IMMUNOL, HAPATOLOGY, BLOOD，CELL MOL IMMUNOL等国际一流期刊。研究成果获江苏省科学技术奖一等奖，南京市科技进步奖一等奖，二等奖各1项。相关工作有效为寻求合适的干预靶点和时机，开展免疫相关临床治疗提供实验基础和理论依据。