Enzymatic remodelling of the carbohydrate surface of a xenogenic cell substantially reduces human antibody binding and complement-mediated cytolysis

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 d...

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Bibliographic Details
Published in:Nature medicine Vol. 1; no. 12; pp. 1261 - 1267
Main Authors: Sandrin, Mauro S, Fodor, William L, Mouthtouris, Effie, Osman, Narin, Cohney, Shlomo, Rollins, Scott A, Guilmette, Edward R, Setter, Eva, Squinto, Stephen P, Mckenzie, Ian F.C
Format: Journal Article
Language:English
Published: United States 01-12-1995
Subjects:
Animals
Base Sequence
Binding, Competitive
Cell Line
Complement Activation
Disaccharides - metabolism
DNA Primers
Fucosyltransferases - genetics
Fucosyltransferases - metabolism
Galactoside 2-alpha-L-fucosyltransferase
Galactosyltransferases - genetics
Galactosyltransferases - metabolism
Graft Rejection - immunology
Humans
Mice
Mice, Transgenic
Molecular Sequence Data
RNA, Messenger - metabolism
Transfection
Transplantation, Heterologous - immunology
Tumor Cells, Cultured
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Summary: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.
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ISSN:1078-8956
1546-170X
DOI:10.1038/nm1295-1261