Circulation:延长心脏移植生存的新型策略

　　意大利一项研究表明，靶向离子通道嘌呤受体P2X7（P2X7R）是一种新型的延长心脏移植生存率的临床相关策略。该研究12月18日在线发表于《循环》（Circulation）杂志。

　　心脏移植对于终末期心力衰竭患者是一种挽救生命的方法。除了该领域的诸多进展，目前的免疫移植方案仍旧与长期不良心脏移植物转归及发生并发症包括感染和肿瘤等相关。发明新型、短期和有效的免疫调节疗法或可取得重要收获。细胞破坏或活化时释放的嘌呤腺苷5’-三磷酸（ATP）可被淋巴细胞上的P2X7R识别并调控T细胞活化。目前已有新型的临床级别的P2X7R抑制剂，使得靶向P2X7R成为心脏移植的潜在治疗。

　　研究者分析了小鼠和人体内P2X7R的表达，并在小鼠心脏移植受者中进行靶向P2X7R治疗。数据显示，P2X7R在人体和小鼠中移植物浸润的淋巴细胞中P2X7R可特异性上调。使用高碘酸氧化ATP（oATP）短期靶向P2X7R可在80%的小鼠中提高完全错配的同种异体心脏移植长期生存率。心脏移植的长期生存率与T细胞活化、Th1/Th17分化和T细胞的STAT3磷酸化减少有关，从而导致移植物浸润和冠状动脉病。体外P2X7R通路的基因学上调也显示可刺激Th1/Th17细胞分裂。另外，在鼠类慢性排斥模型中靶向P2X7R还阻止了冠状动脉病的进展。

与心脏移植相关的拓展阅读：

• 延长心脏移植生存的新型策略
• JACC：未来十年心脏移植研究方向
• Eur Heart J：线粒体多态性或影响心脏移植预后
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Long-Term Heart Transplant Survival by Targeting the Ionotropic Purinergic Receptor P2X7

Background

Heart transplantation is a lifesaving procedure for patients with end-stage heart failure. Despite much effort and advances in the field, current immunosuppressive regimens are still associated with poor long-term cardiac allograft outcomes as well as with the development of complications including infections and malignancies. The development of a novel, short-term and effective immunomodulatory protocol will thus be an important achievement. The purine adenosine 5'-triphosphate (ATP), released during cell damage/activation, is sensed by the ionotropic purinergic receptor P2X7 (P2X7R) on lymphocytes and regulates T cell activation. Novel clinical-grade P2X7R inhibitors are available, rendering the targeting of P2X7R a potential therapy in cardiac transplantation.

Methods and Results

We analyzed P2X7R expression in patients and mice and P2X7R targeting in murine recipients in the context of cardiac transplantation. Our data demonstrate that P2X7R is specifically upregulated in graft-infiltrating lymphocytes in cardiac-transplanted humans and mice. Short-term P2X7R targeting with periodate-oxidized ATP (oATP) promotes long-term cardiac transplant survival in 80% of murine recipients of a fully mismatched allograft. Long-term survival of cardiac transplants was associated with reduced T cell activation, Th1/Th17 differentiation and inhibition of STAT3 phosphorylation in T cells, thus leading to a reduced transplant infiltrate and coronaropathy. In vitro genetic upregulation of the P2X7R pathway was also shown to stimulate Th1/Th17 cell generation. Finally, P2X7R targeting halted the progression of coronaropathy in a murine model of chronic rejection as well.

Conclusions

P2X7R targeting is a novel clinically relevant strategy to prolong cardiac transplant survival.