Remodeling of the major pig xenoantigen by N-acetylglucosaminyltransferase III in transgenic pig.
We have been successful in generating several lines of transgenic mice and pigs that contain the human beta-d-mannoside beta-1,4-N-acetylglucosaminyltransferase III (GnT-III) gene. The overexpression of the GnT-III gene in mice and pigs reduced their antigenicity to human natural antibodies, especially the Galalpha1-3Galbeta1-4GlcNAc-R, as evidenced by immunohistochemical analysis. Endothelial cell studies from the GnT-III transgenic pigs also revealed a significant down-regulation in antigenicity, including Hanganutziu-Deicher antigen, and dramatic reductions in both the complement- and natural killer cell-mediated pig cell lyses. Changes in the enzymatic activities of other glycosyltransferases, such as alpha1,3-galactosyltransferase, GnT-IV, and GnT-V, did not support cross-talk between GnT-III and these enzymes in the transgenic animals. In addition, we demonstrated the effect of GnT-III in down-regulating the xenoantigen of pig heart grafts, using a pig to cynomolgus monkey transplantation model, suggesting that this approach may be useful in clinical xenotransplantation in the future.
Miyagawa
S
S
Department of Regenerative Medicine, Osaka University Graduate School of Medicine, the Genome Information Research Center, Osaka University, Suita, Osaka 565-0871, Japan. miyagawa@orgtrp.med.osaka-u.ac.jp
Murakami
H
H
Takahagi
Y
Y
Nakai
R
R
Yamada
M
M
Murase
A
A
Koyota
S
S
Koma
M
M
Matsunami
K
K
Fukuta
D
D
Fujimura
T
T
Shigehisa
T
T
Okabe
M
M
Nagashima
H
H
Shirakura
R
R
Taniguchi
N
N
D000818:Animals; D030801:Animals, Genetically Modified; D015478:Antigens, Heterophile / Q000737:chemistry* / Q000235:genetics*; D002460:Cell Line; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D016695:Glycosyltransferases / Q000378:metabolism; D016027:Heart Transplantation; D006801:Humans; D007150:Immunohistochemistry; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D013552:Swine; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D015478:Antigens, Heterophile; D007770:L-Lactate Dehydrogenase; D016695:Glycosyltransferases; D017351:N-Acetylglucosaminyltransferases; C054599:beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase