The anti-nonGal xenoantibody response to alpha1,3-galactosyltransferase gene knockout pig xenografts.
OBJECTIVE
Anti-nonGal xenoantibodies are a major barrier to the survival of genetically modified porcine xenografts. This review summarizes the contribution of anti-nonGal xenoantibodies to the activation of porcine endothelial cells and graft rejection, and further provides an update on recent advancements in defining the unique features of anti-nonGal xenoantibody structure.


RESULTS
Anti-nonGal xenoantibodies pre-exist at low levels in humans and nonhuman primates, and are notably absent in neonates. Exposure of nonhuman primates to alpha1,3-galactosyltransferase gene knockout endothelial cells initiates an induced xenoantibody response that is restricted and encoded by the germline immunoglobulin heavy chain gene IGHV3-21. The target xenoantigen remains undetermined, but several candidate targets have been proposed, including carbohydrate xenoantigens. New advancements in molecular modeling provide insight on the mechanism by which xenoantibodies bind to structurally related carbohydrates.


CONCLUSIONS
Genetic manipulation of porcine donors has significantly prolonged the survival of grafts placed into nonhuman primate recipients, but anti-nonGal xenoantibodies and thrombosis limit the ability of these grafts to function on a long-term basis. Recent developments defining pre-existing anti-nonGal xenoantibody levels, the restriction in the anti-nonGal xenoantibody response and the identification of key sites defining xenoantibody-carbohydrate interactions now provide the information necessary to develop new approaches to preventing xenoantibody-mediated rejection.
Harnden
Ivan
I
Department of Cardiothoracic Surgery, Saban Research Institute, Childrens Hospital Los Angeles, Keck School of Medicine of the University of Southern California, Los Angeles, California 90027, USA.
Kiernan
Kathleen
K
Kearns-Jonker
Mary
M
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D000910:Antibodies, Heterophile / Q000737:chemistry / Q000276:immunology*; D015478:Antigens, Heterophile / Q000276:immunology; D042783:Endothelial Cells / Q000276:immunology*; D005700:Galactosyltransferases / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D055786:Gene Knockout Techniques; D050438:Genes, Immunoglobulin Heavy Chain; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival / Q000235:genetics; D056724:Immunity, Humoral; D008969:Molecular Sequence Data; D013045:Species Specificity; D013552:Swine; D023001:Transplantation Tolerance / Q000235:genetics; D014183:Transplantation, Heterologous / Q000276:immunology*; D014312:Trisaccharides / Q000276:immunology
D000910:Antibodies, Heterophile; D015478:Antigens, Heterophile; D014312:Trisaccharides; C076569:alpha-galactosyl epitope; D005700:Galactosyltransferases; C530267:alpha-1,3-galactosyltransferase 1, porcine