Transplantation Research Center, Boston Children's Hospital, Harvard Medical School, Enders Building 5th floor, Rm EN530, 300 Longwood Ave, Boston, MA 02115, USA.
Circulation. 2013 Jan 29;127(4):463-75. doi: 10.1161/CIRCULATIONAHA.112.123653. Epub 2012 Dec 18.
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, and with the development of complications, including infections and malignancies, as well. The development of a novel, short-term, and effective immunomodulatory protocol will thus be an important achievement. The purine 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.
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 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, T-helper cell 1/T-helper cell 17 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 T-helper cell 1/T-helper cell 17 cell generation. Finally, P2X7R targeting halted the progression of coronaropathy in a murine model of chronic rejection as well.
P2X7R targeting is a novel clinically relevant strategy to prolong cardiac transplant survival.
心脏移植是治疗终末期心力衰竭患者的一种救生程序。尽管在该领域付出了巨大努力并取得了进展，但目前的免疫抑制方案仍与心脏移植物的不良长期预后相关，并伴有并发症的发展，包括感染和恶性肿瘤等。因此，开发一种新的、短期的、有效的免疫调节方案将是一项重要的成就。嘌呤 ATP 在细胞损伤/激活时释放，被淋巴细胞上的离子型嘌呤能受体 P2X7（P2X7R）感知，并调节 T 细胞激活。新型临床级 P2X7R 抑制剂已可获得，使 P2X7R 成为心脏移植的潜在治疗靶点。
我们分析了心脏移植患者和小鼠中的 P2X7R 表达，并在心脏移植背景下分析了小鼠受者中的 P2X7R 靶向作用。我们的数据表明，P2X7R 在心脏移植的人类和小鼠中的浸润淋巴细胞中特异性地上调。用 periodate-oxidized ATP 进行短期 P2X7R 靶向作用可促进 80%的完全不匹配同种异体移植物小鼠受者的长期心脏移植存活。心脏移植物的长期存活与 T 细胞活化、辅助性 T 细胞 1/辅助性 T 细胞 17 分化以及 T 细胞中 STAT3 磷酸化的抑制有关，从而导致移植浸润减少和冠状病变。体外遗传上调 P2X7R 途径也被证明可刺激辅助性 T 细胞 1/辅助性 T 细胞 17 细胞的生成。最后，P2X7R 靶向作用也阻止了慢性排斥反应小鼠模型中冠状病变的进展。
P2X7R 靶向作用是一种延长心脏移植存活的新的临床相关策略。
