Complement Dependence of Murine Costimulatory Blockade-Resistant Cellular Cardiac Allograft Rejection.
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.
['Chun|N|N|', 'Fairchild|R L|RL|', 'Li|Y|Y|', 'Liu|J|J|', 'Zhang|M|M|', 'Baldwin|W M|WM|', 'Heeger|P S|PS|']
D000069594:Abatacept D064591:Allografts D000818:Animals D060908:CTLA-4 Antigen D003165:Complement System Proteins D006084:Graft Rejection D006085:Graft Survival D016027:Heart Transplantation D007166:Immunosuppressive Agents D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D008810:Mice, Inbred C57BL D013601:T-Lymphocytes D014019:Tissue Donors
animal models: murine basic (laboratory) research/science complement biology costimulation immunobiology immunosuppression/immune modulation