C1-inhibitor attenuates hyperacute rejection and inhibits complement, leukocyte and platelet activation in an ex vivo pig-to-human perfusion model.
Xenotransplantation may be a future alternative due to increased shortage of organs. Classical complement activation is central in hyperacute rejection in pig-to-human combinations. We investigated the effects of C1-inhibitor (C1-INH), a regulator of the complement and contact systems, on hyperacute rejection. Pig kidneys were perfused with fresh human blood to which either C1-INH (n = 6) or human serum albumin (n = 6) was added. The survival of the C1-INH perfused kidneys (mean 327 min) was significantly longer (p < 0.00001) than the controls (79 min). C1-INH substantially inhibited complement activation (C1rs-C1-INH complexes, C4bc, C3bc and terminal complement complex) (p < 0.001 for all) compared with the marked complement activation in the controls. No contact activation was found. Leukocytes and platelets were substantially activated (counts, myeloperoxidase, beta-thromboglobulin, thrombospondin, soluble P-selectin) in the control group, and this activation was markedly reduced by C1-INH (p < 0.02 for all). Immunohistochemistry showed less C1q, C3, TCC, IgG and fibrin deposition in the C1-INH group. C1-INH may be useful to attenuate hyperacute rejection, probably through inhibition of complement. The reduced activation of neutrophils and platelets may mainly be secondary to inhibition of complement.
Fiane
A E
AE
Department of Surgery A, University of Oslo, The National Hospital, Norway. a.e.fiane@klinmed.uio.no
Videm
V
V
Johansen
H T
HT
Mellbye
O J
OJ
Nielsen
E W
EW
Mollnes
T E
TE
D000818:Animals; D000941:Antigens / Q000276:immunology; D003172:Complement C1 / Q000276:immunology; D003174:Complement C1 Inactivator Proteins / Q000276:immunology / Q000627:therapeutic use*; D003179:Complement C3b / Q000378:metabolism; D003171:Complement Pathway, Classical / Q000276:immunology*; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007668:Kidney / Q000098:blood supply / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016030:Kidney Transplantation / Q000276:immunology*; D007704:Kininogens / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D018375:Neutrophil Activation / Q000276:immunology; D010477:Perfusion; D015539:Platelet Activation / Q000276:immunology*; D011288:Prekallikrein / Q000378:metabolism; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
D000941:Antigens; D003172:Complement C1; D003174:Complement C1 Inactivator Proteins; D007704:Kininogens; D003179:Complement C3b; D011288:Prekallikrein