Targeting Pathogenic Postischemic Self-Recognition by Natural IgM to Protect Against Posttransplantation Cardiac Reperfusion Injury | |
Article | |
关键词: EPSTEIN-BARR-VIRUS; COMPLEMENT INHIBITION; ISCHEMIA/REPERFUSION INJURY; MYOCARDIAL-ISCHEMIA; ENDOTHELIAL-CELLS; RECEPTOR; ACTIVATION; ANTIBODIES; MICE; DISEASE; | |
DOI : 10.1161/CIRCULATIONAHA.114.010482 | |
来源: SCIE |
【 摘 要 】
Background-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 prenecrotic 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. Methods and Results-By transplanting hearts from wild-type donor mice into antibody-deficient mice reconstituted with specific self-reactive IgM monoclonal antibodies, we identified neoepitopes expressed after transplantation 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 postischemia recognition system of natural antibodies. On the basis of 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 transplantation 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. Conclusions-We identified pathophysiologically important epitopes expressed within the heart after transplantation and described a novel translatable strategy for targeted complement inhibition that has several advantages over currently available approaches.
【 授权许可】
Free