Are N-glycolylneuraminic acid (Hanganutziu-Deicher) antigens important in pig-to-human xenotransplantation?

:  Background:  N‐glycolylneuraminic acid (NeuGc) epitopes, so called Hanganutziu–Deicher (HD) antigens, which are widely expressed on endothelial cells of all mammals except humans, are considered to be potential targets for natural and elicited anti‐nonGalα1‐3 Gal (Gal) antibodies in humans. We pr...

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Published in:Xenotransplantation (Københaven) 2004-05, Vol.11 (3), p.247-253
Main Authors: Miwa, Yuko, Kobayashi, Takaaki, Nagasaka, Takaharu, Liu, DaGe, Yu, Ma, Yokoyama, Itsuo, Suzuki, Akemi, Nakao, Akimasa
Format: Article
Language:English
Subjects:
Animals
antibodies
antigens
Antigens, Heterophile - immunology
Cell Adhesion
Cells, Cultured
Endothelium, Vascular - cytology
Erythrocytes - cytology
Erythrocytes - immunology
glycolipid
glycoprotein
Hanganutziu-Deicher antigen
heterologous
heterophile
Humans
N-glycolylneuraminic acid
Neuraminic Acids - analysis
Neuraminidase - pharmacology
Papio
Primates
Swine
Transplantation
Transplantation, Heterologous - immunology
xenotransplantation
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Summary::  Background:  N‐glycolylneuraminic acid (NeuGc) epitopes, so called Hanganutziu–Deicher (HD) antigens, which are widely expressed on endothelial cells of all mammals except humans, are considered to be potential targets for natural and elicited anti‐nonGalα1‐3 Gal (Gal) antibodies in humans. We previously reported that anti‐NeuGc antibodies were not detected in healthy humans by enzyme‐linked immunosorbent assay (ELISA) using NeuGc‐GM3‐coated plates, and no antibody production was observed in patients with a history of exposure to pig cells. However, a recent paper has revealed that (i) anti‐NeuGc antibodies to porcine red blood cells (PRBC) are detectable in most healthy humans, and (ii) the majority of anti‐nonGal antibodies are specific for NeuGc epitopes. The purpose of this study was to reassess whether NeuGc is important as an immunogenic nonGal epitope. Methods: The binding of antibodies to PRBC and porcine aortic endothelial cells (PAEC) was compared. Cells were treated with (i) α‐galactosidase, and then (ii) neuraminidase, which digests sialic acids, including NeuGc epitopes. Cells were incubated with human pooled sera, and applied to flow cytometric analysis. After enzyme digestion, almost complete reduction of Gal and NeuGc expression was confirmed by GS‐IB4 and HU/Ch2‐7 (a chicken monoclonal antibody against HD antigens), respectively. Trypsin, which removes membrane glycoproteins, and endoglycoceramidase which cleaves glycolipids, were used for differentiating between NeuGc‐containing glycoproteins and glycolipids. Results:  Neuraminidase‐treatment reduced the binding of immunoglobulin G (IgG) antibodies to PRBC; about half of the anti‐nonGal IgG antibodies to PRBC were directed to NeuGc. In contrast, anti‐nonGal antibodies to PAEC were not directed to NeuGc. Trypsin‐treatment markedly reduced the expression of NeuGc only on PRBC. Endoglycoceramidase‐treatment was followed by a greater reduction in NeuGc epitopes on PAEC than on PRBC. Most NeuGc on PRBC appeared to be linked to proteins, but most NeuGc on PAEC was expressed on glycolipids. Conclusions:  Carbohydrate structures on PRBC are different from those on PAEC. Healthy human sera contain anti‐nonGal IgG antibodies to NeuGc expressed on PRBC, but not on PAEC. We speculate that anti‐nonGal IgG antibodies to PRBC can recognize both NeuGc and protein, and this may be the reason why such antibodies have not been detected by ELISA. A definite conclusion about the immunogenicity of NeuGc has
ISSN:0908-665X
1399-3089
DOI:10.1111/j.1399-3089.2004.00126.x