Targeted Complement Inhibitors Protect against Posttransplant Cardiac Ischemia and Reperfusion Injury and Reveal an Important Role for the Alternative Pathway of Complement Activation
Targeted Complement Inhibitors Protect against Posttransplant Cardiac Ischemia and Reperfusion Injury and Reveal an Important Role for the Alternative Pathway of Complement Activation
复制标题
靶向补体抑制剂可预防移植后心脏缺血和再灌注损伤，并揭示补体激活替代途径的重要作用
DOI：
10.4049/jimmunol.1001504
复制
发表时间：
2010-12-01
影响因子：
4.4
通讯作者：
Tomlinson, Stephen
中科院分区：
文献类型：
--
作者：
Atkinson, Carl;He, Songqing;Tomlinson, Stephen
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，是早期移植物功能障碍和随后移植物免疫原性的主要原因。在使用靶向补体抑制剂的治疗范例中，我们研究了补体的作用，特别是补体的替代途径，在IRI心脏同种移植物中。在移植后立即用CR2-Crry（抑制所有补体途径）或CR2-fH（抑制旁路补体途径）单次注射处理的C57 BL/6小鼠中进行小鼠异位同种移植心脏移植。在12和48小时收获移植心脏用于分析。通过组织学和血清心肌肌钙蛋白I水平测定，两种抑制剂均导致心肌IRI显著降低。此外，与未处理的对照组相比，两种抑制剂均降低了移植物补体沉积、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）。CR2-Crry和CR2-fH处理的小鼠之间心肌损伤和细胞浸润的减少没有显著差异，尽管与CR2-fH处理的小鼠相比，CR2-Crry处理的小鼠中的粘附分子和细胞因子水平显著较低。总之，旁路补体途径在心脏移植后心肌IRI中起着重要作用，局部（靶向）补体抑制有可能提供一种有效和安全的治疗策略，以减少移植物损伤。尽管完全补体阻断在减轻炎症方面可能更有效，但是旁路途径的特异性阻断在已经免疫受损的接受者中可能具有较少的免疫抑制作用。
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.