Enzymatic remodelling of the carbohydrate surface of a xenogenic cell substantially reduces human antibody binding and complement-mediated cytolysis.
The major obstacle to successful discordant xenotransplantation is the phenomenon of hyperacute rejection (HAR). In the pig-to-primate discordant transplant setting, HAR results from the deposition of high-titre anti-alpha-galactosyl antibodies and complement activation leading to endothelial cell destruction and rapid graft failure. To overcome HAR, we developed an enzymatic carbohydrate remodelling strategy designed to replace expression of the Gal alpha-1,3-Gal xenoepitope on the surface of porcine cells with the non-antigenic universal donor human blood group O antigen, the alpha-1,2-fucosyl lactosamine moiety (H-epitope). Xenogenic cells expressing the human alpha-1,2-fucosyltransferase expressed high levels of the H-epitope and significantly reduced Gal alpha-1,3-Gal expression. As a result, these cells were shown to be resistant to human natural antibody binding and complement-mediated cytolysis.
D000818:Animals; D001483:Base Sequence; D001667:Binding, Competitive; D002460:Cell Line; D003167:Complement Activation; D017931:DNA Primers; D004187:Disaccharides / Q000378:metabolism*; D005647:Fucosyltransferases / Q000235:genetics / Q000378:metabolism*; D005700:Galactosyltransferases / Q000235:genetics / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000378:metabolism*; D014162:Transfection; D014183:Transplantation, Heterologous / Q000276:immunology; D014407:Tumor Cells, Cultured; D000097631:Galactoside 2-alpha-L-fucosyltransferase
D017931:DNA Primers; D004187:Disaccharides; D005647:Fucosyltransferases; D005700:Galactosyltransferases; D012333:RNA, Messenger; D000097631:Galactoside 2-alpha-L-fucosyltransferase; C055075:galactosyl-(1-3)galactose; C038887:N-acetyllactosamine alpha-D-galactosyltransferase