Abstract
The α-Gal epitope (Gal α1-3Galβ1-4 GlcNAc-R), which is biosynthesized by the action of α1,3-galactosyltransferase (α1,3GT), is closely associated with hyperacute rejection (HAR) in pig to human xenotransplantation. On the other hand, the Hanganutziu-Deicher (H-D) epitope, which is produced by cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) and contains N-glycolylneuraminic acid (NeuGc), and other currently unknown non-Gal epitopes are also factors in the xenotransplantation field. At present, α1,3GT/CMAH knockout pigs have already been produced.
A variety of strategies have been pursued to reduce or eliminate the α-Gal epitope from pig tissues. In addition to knocking out α1,3GT/CMAH by nuclear transplantation techniques from the targeted somatic cells, other strategies, such as enzyme competition of α1,3GT with α1,2-fucosyltransferase (α1,2FT), control of sugar processing by β-d-mannoside β1,4-N-acetylglucosaminyltransferase III (GnT-III), and digesting α-Gal epitopes by cleaving the β-galactosidic linkage, have provided very interesting insights into the downregulation of the xenogeneic epitope. Some of the above strategies continue to be downregulating the non-α-Gal epitopes in transgenic animals after α1,3GT and CMAH are eliminated.
In addition, porcine endogenous retrovirus (PERV) contains a ligand with an N-linked sugar. Modification of the glycosylation pattern of the PERV ligand appears to be associated with regulating PERV infectivity.
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References
Blixt O, Kumagai-Braesch M, Tibell A, Groth CG, Holgersson J (2009) Anticarbohydrate antibody repertoires in patients transplanted with fetal pig islets revealed by glycan arrays. Am J Transplant 9:83–90
Chou HH, Takematsu H, Diaz S, Iber J, Nickerson E, Wright KL, Muchmore EA, Nelson DL, Warren ST, Varki A (1998) A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence. Proc Natl Acad Sci U S A 95:11751–11756
Costa C, Zhao L, Burton WV, Bondioli KR, Williams BL, Hoagland TA, Ditullio PA, Ebert KM, Fodor WL (1999) Expression of the human alpha1,2-fucosyltransferase in transgenic pigs modifies the cell surface carbohydrate phenotype and confers resistance to human serum-mediated cytolysis. FASEB J 13:1762–1773
Dai Y, Vaught TD, Boone J, Chen SH, Phelps CJ, Ball S, Monahan JA, Jobst PM, McCreath KJ, Lamborn AE, Cowell-Lucero JL, Wells KD, Colman A, Polejaeva IA, Ayares DL (2002) Targeted disruption of the alpha1,3-galactosyltransferase gene in cloned pigs. Nat Biotechnol 20:251–255
Galili U, Clark MR, Shohet SB, Buehler J, Macher BA (1987) Evolutionary relationship between the natural anti-Gal antibody and the Gal alpha 1–3Gal epitope in primates. Proc Natl Acad Sci U S A 84:1369–1373
Irie A, Koyama S, Kozutsumi Y, Kawasaki T, Suzuki A (1998) The molecular basis for the absence of N-glycolylneuraminic acid in humans. J Biol Chem 273:15866–15871
Joziasse DH, Shaper JH, Van den Eijnden DH, Van Tunen AJ, Shaper NL (1989) Bovine alpha 1–3-galactosyltransferase: isolation and characterization of a cDNA clone. Identification of homologous sequences in human genomic DNA. J Biol Chem 264:14290–14297
Koike C, Katayama A, Kadomatsu K, Hiraiwa N, Hayashi S, Kobayashi T, Hayash S, Yokoyama I, Takagi H (1997) Reduction of alpha-Gal epitopes in transgenic pig by introduction of human alpha 1–2 fucosyltransferase. Transplant Proc 29:894
Larsen RD, Rivera-Marrero CA, Ernst LK, Cummings RD, Lowe JB (1990) Frameshift and nonsense mutations in a human genomic sequence homologous to a murine UDP-Gal:beta-D-Gal(1,4)-D-GlcNAc alpha(1,3)-galactosyltransferase cDNA. J Biol Chem 265:7055–7061
Lutz AJ, Li P, Estrada JL, Sidner RA, Chihara RK, Downey SM, Burlak C, Wang ZY, Reyes LM, Ivary B, Yin F, Blankenship RL, Paris LL, Tector AJ (2013) Double knockout pigs deficient in N-glycolylneuraminic acid and galactose α-1,3-galactose reduce the humoral barrier to xenotransplantation. Xenotransplantation 20:27–35
Miyagawa S, Murakami H, Takahagi Y, Nakai R, Yamada M, Murase A, Koyota S, Koma M, Matsunami K, Fukuta D, Fujimura T, Shigehisa T, Okabe M, Nagashima H, Shirakura R, Taniguchi N (2001) Remodeling of the major pig xenoantigen by N-acetylglucosaminyltransferase III in transgenic pig. J Biol Chem 276:39310–39319
Sandrin MS, Fodor WL, Mouhtouris E, Osman N, Cohney S, Rollins SA, Guilmette ER, Setter E, Squinto SP, McKenzie IF (1995) Enzymatic remodelling of the carbohydrate surface of a xenogenic cell substantially reduces human antibody binding and complement-mediated cytolysis. Nat Med 1:1261–1267
Takahagi Y, Fujimura T, Miyagawa S, Nagashima H, Shigehisa T, Shirakura R, Murakami H (2005) Production of alpha 1,3-galactosyltransferase gene knockout pigs expressing both human decay-accelerating factor and N-acetylglucosaminyltransferase III. Mol Reprod Dev 71:331–338
Yazaki S, Iwamoto M, Onishi A, Miwa Y, Suzuki S, Fuchimoto D, Sembon S, Furusawa T, Hashimoto M, Oishi T, Liu D, Nagasaka T, Kuzuya T, Maruyama S, Ogawa H, Kadomatsu K, Uchida K, Nakao A, Kobayashi T (2009) Successful cross-breeding of cloned pigs expressing endo-beta-galactosidase C and human decay accelerating factor. Xenotransplantation 16:511–521
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Maeda, A., Eguchi, H., Kawamura, T., Okuyama, H., Miyagawa, S. (2014). Glycoantigen and Xenotransplantation. In: Endo, T., Seeberger, P., Hart, G., Wong, CH., Taniguchi, N. (eds) Glycoscience: Biology and Medicine. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54836-2_98-1
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DOI: https://doi.org/10.1007/978-4-431-54836-2_98-1
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