移植肾内定向爆破负载NO的C4d靶向微泡对抗体介导排斥的防治作用及其作用机制研究

Antibody mediated rejection (AMR) is the major cause of renal allograft dysfunction. However, the current therapeutic approaches are systemically and the effect is barely satisfactory. C4d is the specific marker of AMR. Thrombosis, B cells, T cells and macrophages are involved in the process of AMR. NO has a strong antithrombotic function, and can inhibit the activation and proliferation of B cells, T cells and macrophages through a variety of pathways and is expected to become a new strategy for AMR prevention. We have previously established a rat model of AMR, successfully produced C4d targeted microbubbles and used them to realize noninvasively C4d detection. This study will be performed to explore the effects of intra-renal allograft local destruction of C4d targeted microbubbles loaded with NO in management of antibody-mediated rejection based on previous research results. The mechanisms of the effect of NO for AMR will be further investigated from aspects of thrombosis, cellular immunity, transcription factors, cytokines, antibody production and complement activation. This study will realize the targeted and precise treatment of AMR for the first time and prolong the renal allograft survival.

抗体介导的排斥（AMR）是导致移植肾失功的首要原因，现有的治疗手段都是全身性处理和用药且效果尚不理想。C4d为AMR的特异性标记分子，血栓形成、B细胞、T细胞和巨噬细胞都参与了AMR的进程。NO具有很强的抗血栓功能，且可以通过多种途径抑制B细胞、T细胞和巨噬细胞的活化和增殖，有望成为AMR防治新策略。我们前期已经建立了大鼠AMR模型和制作了C4d靶向微泡造影剂并利用其实现了C4d的无创超声检测。本项目将在现有研究基础上，进一步探讨移植肾内定向爆破负载NO的C4d靶向微泡对AMR的防治效果，并从血栓形成、细胞免疫、转录因子、细胞因子、抗体产生、补体激活等方面入手，深入探索NO减轻AMR的具体机制。该研究将首次实现AMR的靶向精准治疗，延长移植肾存活。

抗体介导的排斥（AMR）是导致移植物失功的重要原因，现有的治疗手段都是全身性处理和用药且效果尚不理想。小动物疾病模型是开展AMR相关研究的必要工具，我们建立了大鼠和小鼠AMR模型，并在此基础上进一步深入研究取得了一系列原创性成果，包括：设计成功合成了负载NO的C4d靶向微泡（NO-MBC4d），利用该微泡实现了急性AMR的靶向精准治疗；证实阻断IL-6/IL-6R信号通路可以显著减轻急性AMR并延长移植物存活；发现雷公藤甲素可以通过抑制多种免疫细胞活性减轻慢性移植动脉病；发现青蒿素可以减轻大鼠心脏移植急性排斥反应并延长受体存活。因为IL-6R阻断剂托珠单抗、雷公藤和青蒿素为临床上的常用药物，因此本项目研究发现可以快速在临床得到转化应用。临床移植术后发生AMR的患者将多了多个有效的治疗策略，这有助于改善移植物预后，具备极其重要的社会和现实意义。上述研究成果发表学术论文6篇，其中SCI论文4篇，包括1篇发表于移植领域TOP期刊 J Heart Lung Transplant (IF 10.247)，3篇发表于杂志Front Immunol (IF 7.561)，申请国内发明专利1项（申请中），在中华医学会器官移植年会分组会议报告1次。