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Complement Dependence of Murine Costimulatory Blockade‐Resistant Cellular Cardiac Allograft Rejection
Author(s) -
Chun N.,
Fairchild R. L.,
Li Y.,
Liu J.,
Zhang M.,
Baldwin W. M.,
Heeger P. S.
Publication year - 2017
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.14328
Subject(s) - medicine , complement system , immunology , transplantation , alloimmunity , cytotoxic t cell , priming (agriculture) , spleen , heart transplantation , inflammation , pharmacology , immune system , biology , biochemistry , botany , germination , in vitro
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 (CTLA 4)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 CTLA 4Ig‐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, IFN γ‐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 CTLA 4Ig‐resistant rejection of deceased donor allografts in human transplant patients.