title: Delayed rejection of porcine cartilage is averted by transgenic expression of alpha1,2-fucosyltransferase.
abstract: The use of xenogeneic cells or tissues for tissue engineering applications may lead to advances in biomedical research. Hyperacute and delayed rejection are immunologic hurdles that must be addressed to achieve xenograft survival in the pig-to-primate setting. Expression of human alpha1,2-fucosyltransferase (HT) in the donor cell or tissue protects from hyperacute rejection (HAR) by reducing expression of Galalpha1,3-Gal epitope, the major xenoantigen recognized by human natural antibodies. We hypothesized that Galalpha1,3-Gal antigen contributes to delayed tissue rejection. To test this hypothesis, we transplanted control or HT-transgenic engineered porcine cartilage s.c. into alpha1,3-galactosyltransferase knockout (Gal KO) mice. Control porcine cartilage grafted in Gal KO mice was not susceptible to HAR but was rejected in several wk by a prominent cellular immune infiltrate and elevated antibody titers. In contrast, Gal KO mice receiving the HT engineered cartilage showed a markedly reduced anti-pig antibody response and no anti-Galalpha1,3-Gal-elicited antibody response. The HT implants had a mild cellular infiltrate that was confined to the graft periphery. Our study demonstrates that a marked reduction of Galalpha1,3-Gal antigen in HT-transgenic porcine cartilage confers resistance to a process of delayed rejection. Further development of tissue engineering applications that use genetically modified porcine tissues is encouraged.
authors.affiliation: Department of Molecular Sciences, Alexion Pharmaceuticals Inc., Cheshire, Connecticut 06410 , USA. costac@alxn.com
authors.forename: Cristina
authors.initials: C
authors.lastname: Costa
authors.forename: Jane L
authors.initials: JL
authors.lastname: Brokaw
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: William L
authors.initials: WL
authors.lastname: Fodor
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002356:Cartilage / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000276:immunology; D004187:Disaccharides / Q000032:analysis / Q000276:immunology; D005647:Fucosyltransferases / Q000235:genetics* / Q000378:metabolism; D005700:Galactosyltransferases / Q000235:genetics; D015870:Gene Expression; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D018448:Models, Immunological; D009000:Monocytes / Q000276:immunology; D030781:Organisms, Genetically Modified; D013552:Swine; D014183:Transplantation, Heterologous; D000097631:Galactoside 2-alpha-L-fucosyltransferase
chemical_list: D000906:Antibodies; D004187:Disaccharides; D005647:Fucosyltransferases; D005700:Galactosyltransferases; D000097631:Galactoside 2-alpha-L-fucosyltransferase; C055075:galactosyl-(1-3)galactose