Reaction of complement with endothelial cells in a model of xenotransplantation.
We review our studies on the role of complement (C) as mediator of xenograft hyperacute rejection using an in vitro model consisting of porcine endothelial cells as target and human serum as source of natural antibodies and C. Cytotoxicity of endothelial cells required IgM antibodies to porcine endothelial cells, and the classical pathway and membrane attack complex of C. These findings correlated with in vivo results of porcine organs transplanted into rhesus monkeys, which showed a) co-deposition of IgM, C3, C4 and C9, along blood vessels of rejecting organs, with trace deposits of factors B or P, and b) minimal deposition of IgM and C components in transplants with prolonged survival that were performed in rhesus monkeys depleted of natural antibodies but with normal C levels. Human serum causes activation of porcine endothelial cells manifested by release of heparan sulfate proteoglycan. Heparan sulfate release was induced by C5a alone. A new approach to avert xenograft hyperacute rejection was tested. To inhibit cytotoxicity of porcine endothelial cells by human C, the membrane-associated C inhibitor decay-accelerating factor (DAF) of human origin was incorporated into endothelial cells. Human DAF was able to efficiently inhibit C-mediated killing of porcine endothelial cells, suggesting that the use of DAF and other C inhibitors could be used to interfere with C-mediated xenograft hyperacute rejection.
Dalmasso
A P
AP
VA Medical Center, Minneapolis, MN.
Platt
J L
JL
Bach
F H
FH
D000818:Animals; D000937:Antigen-Antibody Reactions; D018958:CD55 Antigens; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D003167:Complement Activation; D003165:Complement System Proteins / Q000502:physiology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004730:Endothelium, Vascular / Q000276:immunology*; D006084:Graft Rejection; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000494:pharmacology; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
D018958:CD55 Antigens; D011508:Chondroitin Sulfate Proteoglycans; D003165:Complement System Proteins; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D008565:Membrane Proteins