Immunological property of antibodies against N-glycolylneuraminic acid epitopes in cytidine monophospho-N-acetylneuraminic acid hydroxylase-deficient mice.
The generation of pigs devoid of Galalpha1,3Galbeta1,4GlcNAc (Gal) residues has stimulated interest in non-Gal Ags as potentially important targets for Ab binding leading to rejection of pig organ xenografts in humans. Although N-glycolylneuraminic acid (NeuGc) epitopes, which are widely expressed on the endothelial cells of all mammals except humans, are likely targets of anti-non-Gal Abs, this aspect has not been investigated intensively owing to the absence of an appropriate animal model. In this study, we used CMAH(-/-) mice, which are completely deficient in NeuGc and thus produce anti-NeuGc Abs. Sera obtained from CMAH(-/-) mice and healthy human volunteers having anti-NeuGc Abs initiated complement-mediated lysis against CMAH(+/+) cells in vitro. The cytotoxic activity of anti-NeuGc Abs was also determined in vivo (i.e., NeuGc-expressing CMAH(+/+) mouse splenocytes that had been i.v. injected were completely eliminated in syngeneic CMAH(-/-) mice). CMAH(-/-) mice rejected the islets transplanted from syngeneic CMAH(+/+) mice. Thus, the anti-NeuGc Ab-mediated response may be crucially involved in xenograft loss. This is the first direct demonstration of the immunogenic property of NeuGc determinants as targets of the corresponding Abs in CMAH(+/+)-to-CMAH(-/-) transplantation setting.
Tahara
Hiroyuki
H
Division of Frontier Medical Science, Department of Surgery, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan.
Ide
Kentaro
K
Basnet
Nabin Bahadur
NB
Tanaka
Yuka
Y
Matsuda
Haruo
H
Takematsu
Hiromu
H
Kozutsumi
Yasunori
Y
Ohdan
Hideki
H
D000818:Animals; D000906:Antibodies / Q000633:toxicity*; D001666:Binding Sites, Antibody; D003601:Cytotoxicity Tests, Immunologic; D003921:Diabetes Mellitus, Experimental / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism; D000939:Epitopes / Q000096:biosynthesis / Q000276:immunology*; D005260:Female; D005700:Galactosyltransferases / Q000172:deficiency / Q000235:genetics; D006084:Graft Rejection / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000633:toxicity; D007075:Immunoglobulin M / Q000633:toxicity; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000172:deficiency* / Q000235:genetics*; D009438:Neuraminic Acids / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013552:Swine; D014183:Transplantation, Heterologous
D000906:Antibodies; D000939:Epitopes; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D009438:Neuraminic Acids; C032592:N-glycolylneuraminic acid; D006899:Mixed Function Oxygenases; C074383:CMPacetylneuraminate monooxygenase; D005700:Galactosyltransferases