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Chun, N.; Fairchild, R. L.; Li, Y.; Liu, J.; Zhang, M.; Baldwin, W. M.; Heeger, P. S.
American journal of transplantation, November 2017, Volume: 17, Issue: 11Journal Article
Building on studies showing that ischemia–reperfusion‐(I/R)‐injury is complement dependent, we tested links among complement activation, transplantation‐associated I/R injury, and murine cardiac allograft rejection. We transplanted BALB/c hearts subjected to 8‐h cold ischemic storage (CIS) into cytotoxic T‐lymphocyte associated protein 4 (CTLA4)Ig‐treated wild‐type (WT) or c3−/− B6 recipients. Whereas allografts subjected to 8‐h CIS rejected in WT recipients with a median survival time (MST) of 37 days, identically treated hearts survived >60 days in c3−/− mice (p < 0.05, n = 4–6/group). Mechanistic studies showed recipient C3 deficiency prevented induction of intragraft and serum chemokines/cytokines and blunted the priming, expansion, and graft infiltration of interferon‐γ–producing, donor‐reactive T cells. MST of hearts subjected to 8‐h CIS was >60 days in mannose binding lectin (mbl1−/−mbl2−/−) recipients and 42 days in factor B (cfb−/−) recipients (n = 4–6/group, p < 0.05, mbl1−/−mbl2−/− vs. cfb−/−), implicating the MBL (not alternative) pathway. To pharmacologically target MBL‐initiated complement activation, we transplanted BALB/c hearts subjected to 8‐h CIS into CTLA4Ig‐treated WT B6 recipients with or without C1 inhibitor (C1‐INH). Remarkably, peritransplantation administration of C1‐INH prolonged graft survival (MST >60 days, p < 0.05 vs. controls, n = 6) and prevented CI‐induced increases in donor‐reactive, IFNγ‐producing spleen cells (p < 0.05). These new findings link donor I/R injury to T cell–mediated rejection through MBL‐initiated, complement activation and support testing C1‐INH administration to prevent CTLA4Ig‐resistant rejection of deceased donor allografts in human transplant patients. Recipient complement deficiency or peritransplant administration of a C1‐inhibitor blocks inflammation and T cell activation induced by prolonged donor cold storage and overcomes abatacept‐resistant murine heart transplant rejection.
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