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.
Department of Surgery A, University of Oslo, The National Hospital, Norway. a.e.fiane@klinmed.uio.no
A E
AE
Fiane
V
V
Videm
H T
HT
Johansen
O J
OJ
Mellbye
E W
EW
Nielsen
T E
TE
Mollnes
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