Abstract
Seventy to ninety percentage of preformed xenoreactive antibodies in human serum bind to the galactose-α(1,3)-galactose Gal epitope, and the creation of Gal knockout (KO) pigs has eliminated hyperacute rejection as a barrier to xenotransplantation. Now other glycan antigens are barriers to move ahead with xenotransplantation, and the N-glycolyl neuraminic acid, Neu5Gc (or Hanganutziu-Deicher antigen), is also a major pig xenoantigen. Humans have anti-Neu5Gc antibodies. Several data indicate a strong immunogenicity of Neu5Gc in humans that may contribute to an important part in antibody-dependent injury to pig xenografts. Pig islets express Neu5Gc, which reacted with diet-derived human antibodies and mice deleted for Neu5Gc reject pancreatic islets from wild-type counterpart. However, Neu5Gc positive heart were not rejected in Neu5Gc KO mice indicating that the role of Neu5Gc-specific antibodies has to be nuanced and depend of the graft situation parameters (organ/tissue, recipient, implication of other glycan antigens). Recently generated Gal/Neu5Gc KO pigs eliminate the expression of Gal and Neu5Gc, and improve the crossmatch of humans with the pig. This review summarizes the current and recent experimental and (pre)clinical data on the Neu5Gc immunogenicity and emphasize of the potential impact of anti-Neu5Gc antibodies in limiting xenotransplantation in humans.
Highlights
Organ transplantation is the treatment of choice for end-stage organ failure, but there are not enough human donors to transplant everyone who could benefit
Contrary to Gal KO graft that is assessable in Old World non-human primate (NHP) that do not express the GGTA1 [20, 25, 31,32,33], and as only the New World monkeys and humans exhibit a lack of cytidine monophosphate N-acetylneuraminic acid hydroxylase (CMAH) expression, the pig-to-NHP animal model is not conclusive to study the immunogenicity and the deleterious effects of antiNeu5Gc antibodies on vascularized or cellular xenografts and may not provide a direct translation to the clinic
Anti-N-glycolyl neuraminic acid (Neu5Gc) may participate, together with anti-Gal antibodies, to the humoral rejection of the WT pig xenotransplant
Summary
Organ transplantation is the treatment of choice for end-stage organ failure, but there are not enough human donors to transplant everyone who could benefit. Contrary to Gal KO graft that is assessable in Old World NHP that do not express the GGTA1 [20, 25, 31,32,33], and as only the New World monkeys and humans exhibit a lack of CMAH expression, the pig-to-NHP animal model is not conclusive to study the immunogenicity and the deleterious effects of antiNeu5Gc antibodies on vascularized or cellular xenografts and may not provide a direct translation to the clinic.
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