Department of Microbiology and Immunology, Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA.
J Immunol. 2010 Dec 1;185(11):7007-13. doi: 10.4049/jimmunol.1001504. Epub 2010 Oct 20.
Ischemia reperfusion injury (IRI) is an unavoidable event during solid organ transplantation and is a major contributor to early graft dysfunction and subsequent graft immunogenicity. In a therapeutic paradigm using targeted complement inhibitors, we investigated the role of complement, and specifically the alternative pathway of complement, in IRI to heart isografts. Mouse heterotopic isograft heart transplants were performed in C57BL/6 mice treated with a single injection of either CR2-Crry (inhibits all complement pathways) or CR2-fH (inhibits alternative complement pathway) immediately posttransplantation. Transplanted hearts were harvested at 12 and 48 h for analysis. Both inhibitors resulted in a significant reduction in myocardial IRI, as measured by histology and serum cardiac troponin I levels. Furthermore, compared with untreated controls, both inhibitors reduced graft complement deposition, neutrophil and macrophage infiltration, adhesion molecule expression (P-selectin, E-selectin, and I-CAM-1), and proinflammatory cytokine expression (TNF-α, IL-1β, KC, and MCP-1). The reduction in myocardial damage and cellular infiltration was not significantly different between CR2-Crry- and CR2-fH-treated mice, although adhesion molecule and cytokine levels were significantly lower in CR2-Crry-treated mice compared with CR2-fH-treated mice. In conclusion, the alternative complement pathway plays a major contributing role in myocardial IRI after heart transplantation, and local (targeted) complement inhibition has the potential to provide an effective and safe therapeutic strategy to reduce graft injury. Although total complement blockade may be somewhat more efficacious in terms of reducing inflammation, specific blockade of the alternative pathway is likely to be less immunosuppressive in an already immunocompromised recipient.
缺血再灌注损伤（IRI）是实体器官移植过程中不可避免的事件，也是导致早期移植物功能障碍和随后移植物免疫原性的主要因素。在使用靶向补体抑制剂的治疗范例中，我们研究了补体，特别是补体替代途径，在心脏同种异体移植物 IRI 中的作用。在 C57BL/6 小鼠中进行了小鼠异位同种异体心脏移植，在移植后立即给予单次注射 CR2-Crry（抑制所有补体途径）或 CR2-fH（抑制替代补体途径）。在 12 和 48 小时收获移植心脏进行分析。两种抑制剂均导致心肌 IRI 显著减少，如组织学和血清心肌肌钙蛋白 I 水平所示。此外，与未治疗的对照组相比，两种抑制剂均减少了移植物补体沉积、中性粒细胞和巨噬细胞浸润、粘附分子表达（P 选择素、E 选择素和 I-CAM-1）和促炎细胞因子表达（TNF-α、IL-1β、KC 和 MCP-1）。虽然 CR2-Crry 治疗组与 CR2-fH 治疗组相比，粘附分子和细胞因子水平明显降低，但与 CR2-Crry 治疗组相比，心肌损伤和细胞浸润的减少并无显著差异。结论：补体替代途径在心脏移植后心肌 IRI 中起主要作用，局部（靶向）补体抑制具有提供有效和安全治疗策略以减少移植物损伤的潜力。尽管从减少炎症的角度来看，完全阻断补体可能更有效，但在已经免疫抑制的受者中，特异性阻断替代途径可能不太具有免疫抑制作用。
