Targeting pathogenic postischemic self-recognition by natural IgM to protect against posttransplantation cardiac reperfusion injury.
Targeting pathogenic postischemic self-recognition by natural IgM to protect against posttransplantation cardiac reperfusion injury.
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DOI：
10.1161/circulationaha.114.010482
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发表时间：
2015-03-31
期刊：
影响因子：
37.8
通讯作者：
Tomlinson S
中科院分区：
文献类型：
--
作者：
Atkinson C;Qiao F;Yang X;Zhu P;Reaves N;Kulik L;Goddard M;Holers VM;Tomlinson S
天然IgM抗体代表一类先天模式识别受体，其识别在应激或垂死细胞上表达的危险相关分子模式。它们通过处理坏死前细胞和抑制炎症在组织稳态中起重要作用。然而，缺血性损伤导致致病水平的IgM结合和补体激活，导致炎症和损伤。我们研究了自身反应性IgM在移植的独特环境中的作用，其中供体器官经历了冷缺血和热缺血，以及全球缺血性损伤。通过将野生型供体小鼠的心脏移植到用特异性自身反应性IgM mAb重建的抗体缺陷小鼠中，我们鉴定了移植后表达的新表位，并证明了IgM识别这些表位在移植物损伤中的关键作用。有了这些信息，我们开发并表征了一种利用天然抗体的缺血后识别系统的治疗策略。基于新表位鉴定，我们构建了抗annexin-IV单链抗体（scFv）和与C3活化抑制剂Crry连接的scFv（scFv-Crry）。在同种异体移植模型中，其中受体含有完整的天然抗体库，两种构建体都阻断了移植物IgM结合和补体激活，并显著降低了移植物炎症和损伤。此外，scFv-Crry特异性靶向移植心脏，与补体缺乏不同，不会影响对感染的免疫力，这是免疫抑制移植受体的一个重要考虑因素。我们确定了移植后心脏内表达的病理生理学上重要的表位，并描述了一种新的靶向补体抑制的可翻译策略，该策略与目前可用的方法相比具有几个优点。
Natural IgM antibodies represent a class of innate pattern recognition receptors that recognize danger associated molecular patterns expressed on stressed or dying cells. They play important roles in tissue homeostasis by disposing of pre-necrotic cells and suppressing inflammation. However, ischemic insult leads to a pathogenic level of IgM binding and complement activation, resulting in inflammation and injury. We investigate the role of self-reactive IgM in the unique setting of transplantation, where the donor organ undergoes both cold and warm ischemia, and global ischemic insult. By transplanting hearts from wild-type donor mice into antibody-deficient mice reconstituted with specific self-reactive IgM mAbs, we identified neoepitopes expressed post-transplant, and demonstrated a key role for IgM recognition of these epitopes in graft injury. With this information, we developed and characterized a therapeutic strategy that exploited the post-ischemia recognition system of natural antibodies. Based on neoepitope identification, we constructed an anti-annexin-IV single chain antibody (scFv) and an scFv linked to Crry, an inhibitor of C3 activation (scFv-Crry). In an allograft transplant model, in which recipients contain a full natural antibody repertoire, both constructs blocked graft IgM binding and complement activation, and significantly reduced graft inflammation and injury. Furthermore, scFv-Crry specifically targeted to the transplanted heart and, unlike complement deficiency, did not affect immunity to infection, an important consideration for immunosuppressed transplant recipients. We identified pathophysiologically important epitopes expressed within the heart post-transplant, and describe a novel translatable strategy for targeted complement inhibition that has several advantages over currently available approaches.