TY - JOUR
T1 - The Anti-nonGal xenoantibody response to α1,3-galactosyltransferase gene knockout pig xenografts
AU - Harnden, Ivan
AU - Kiernan, Kathleen
AU - Kearns-Jonker, Mary
PY - 2010/4
Y1 - 2010/4
N2 - Purpose of review: 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. Recent findings: Anti-nonGal xenoantibodies pre-exist at low levels in humans and nonhuman primates, and are notably absent in neonates. Exposure of nonhuman primates to α1,3-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. Summary: 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.
AB - Purpose of review: 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. Recent findings: Anti-nonGal xenoantibodies pre-exist at low levels in humans and nonhuman primates, and are notably absent in neonates. Exposure of nonhuman primates to α1,3-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. Summary: 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.
KW - 3-galactosyltransferase gene knockout
KW - 3gal carbohydrate
KW - Gala1
KW - Xenotransplantation
KW - α-1
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U2 - 10.1097/MOT.0b013e328336b854
DO - 10.1097/MOT.0b013e328336b854
M3 - Review article
C2 - 20075731
SN - 1087-2418
VL - 15
SP - 207
EP - 211
JO - Current Opinion in Organ Transplantation
JF - Current Opinion in Organ Transplantation
IS - 2
ER -