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

Am J Transplant. 2017 Nov;17(11):2810-2819. doi: 10.1111/ajt.14328. Epub 2017 May 30.


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.

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

MeSH terms

  • Abatacept / pharmacology*
  • Allografts
  • Animals
  • CTLA-4 Antigen / immunology*
  • Complement System Proteins / immunology*
  • Graft Rejection / etiology
  • Graft Rejection / prevention & control*
  • Graft Survival / drug effects
  • Graft Survival / immunology*
  • Heart Transplantation / adverse effects*
  • Immunosuppressive Agents / pharmacology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Tissue Donors


  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Immunosuppressive Agents
  • Abatacept
  • Complement System Proteins