凋亡细胞诱导的多反应性自然抗体介导大鼠移植肾排斥反应及损伤的机制

Antibody has been a major limitation to rejection of kidney graft and a significant factor to allograft long-term survival. Besides donor specific antibodies (DSA), the role of non-donor specific antibodies (NDSA) in the field of organ transplantation has being attracted more and more attention in recent years. However, the exact cause for the development of NDSA it still obscure thus far. In our preliminary studies, we found a kind of special antibody-polyreactive antibodies, which correlated with HLA reactivity significantly. We found and reported the first time that polyreactive antibodies in kidney transplant patients could affect the long-term survival of the transplanted kidney allograft. Under the National Natural youth fund project, the applicant confirmed polyreactive antibodies is an important cause of NDSA from monoclonal antibody level as well as serum level, thus provided a new evidence for the cause of NDSA besides the theory of cross reactivity. However, the mechanism of polyreactive antibodise mediated graft rejection and injury is still unclear. Based on previous important findings, we plan to explore the mechanism of polyreactivity antibody mediated renal allograft rejection through the research on the model of kidney transplantation in rats as well as serological and pathological specimens of renal transplant patients. We anticipate to provide evidence for finding new targets and formulating new strategies for clinical treatment. Our study is expected to be of great value in the treatment of rejection after renal transplantation and for the improvement of long-term renal allograft survival.

抗体是移植肾排异反应的主要原因，也是影响移植肾存活的关键因素。除了供体特异性抗体（DSA），近年非供体特异性抗体（NDSA）在移植领域的作用渐受到关注。然而NDSA产生的原因尚不明确。我们在前期研究中发现一种特殊的抗体—多反应性抗体，与HLA反应性密切相关。且首次发现并报道肾移植患者多反应性抗体可影响移植肾长期存活。申请人在国自然青年基金项目资助下，分别从单克隆抗体及血清学水平证实多反应性抗体是NDSA产生的重要原因，从而开创性的在交叉反应理论之外，为移植患者NDSA产生原因提供了新的证据。然而多反应性抗体介导移植肾排斥反应及损伤的机制尚不明确。本研究在前期重要发现的基础上，拟结合大鼠肾移植模型及临床肾移植患者血清学、病理学研究探索多反应性抗体介导移植肾排斥反应及损伤的机制，为临床治疗发现新靶点及制定新策略提供依据，在肾移植术后排斥反应治疗及提高移植肾长期存活方面具有重要应用价值。

抗体是移植肾排异反应的主要原因，也是影响移植肾存活的关键因素。我们在前期研究中发现一种特殊的抗体—多反应性抗体，与HLA反应性密切相关。且首次发现并报道肾移植患者多反应性抗体可影响移植肾长期存活。研究者分别从单克隆抗体及血清学水平证实多反应性抗体是NDSA产生的重要原因，为移植患者NDSA产生原因提供了新的证据。然而多反应性抗体介导移植肾排斥反应及损伤的机制尚不明确。本研究在前期重要发现的基础上，结合大鼠肾移植模型及临床肾移植患者血清学、病理学研究探索多反应性抗体介导移植肾排斥反应及损伤的机制。研究通过建立大鼠肾移植排斥模型，观察凋亡细胞处理对移植肾亚急性排斥反应的影响。移植术后1天、7天和14天，检测血肌酐尿素氮、炎症因子水平、脾脏淋巴细胞分类及计数、组织病理、免疫组化和移植物存活率等，分析不同处理对移植肾病理的影响。结果发现凋亡细胞预处理可以诱导多反应性B淋巴细胞分泌的抗体升高，受体大鼠体内的血清多反应性抗体活性影响了移植排斥反应，抑制性T细胞对移植排斥反应的作用。本研究结果证实，凋亡细胞注射可通过促进多反应性抗体水平减少移植肾的急性炎症程度，其机制与凋亡细胞处理通过多反应性抗体水平升高抑制炎症细胞功能相关。基于未来对以上问题的解决，凋亡细胞诱导法为临床器官移植领域中产生安全而有效的预防或治疗移植排斥策略提供了实验基础。