Complement Dependence of Murine Costimulatory Blockade-Resistant Cellular Cardiac Allograft Rejection

N. Chun, R. L. Fairchild, Y. Li, J. Liu, M. Zhang, W. M. Baldwin, P. S. Heeger

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2810-2819
Number of pages10
JournalAmerican Journal of Transplantation
Volume17
Issue number11
DOIs
StatePublished - Nov 2017

Keywords

  • animal models: murine
  • basic (laboratory) research/science
  • complement biology
  • costimulation
  • immunobiology
  • immunosuppression/immune modulation

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