title: Genetically-engineered pig-to-baboon liver xenotransplantation: histopathology of xenografts and native organs.
abstract: Orthotopic liver transplantation was carried out in baboons using wild-type (WT, n = 1) or genetically-engineered pigs (α1,3-galactosyltransferase gene-knockout, GTKO), n = 1; GTKO pigs transgenic for human CD46, n = 7) and a clinically-acceptable immunosuppressive regimen. Biopsies were obtained from the WT pig liver pre-Tx and at 30 min, 1, 2, 3, 4 and 5 h post-transplantation. Biopsies of genetically-engineered livers were obtained pre-Tx, 2 h after reperfusion and at necropsy (4-7 days after transplantation). Tissues were examined by light, confocal, and electron microscopy. All major native organs were also examined. The WT pig liver underwent hyperacute rejection. After genetically-engineered pig liver transplantation, hyperacute rejection did not occur. Survival was limited to 4-7 days due to repeated spontaneous bleeding in the liver and native organs (as a result of profound thrombocytopenia) which necessitated euthanasia. At 2 h, graft histology was largely normal. At necropsy, genetically-engineered pig livers showed hemorrhagic necrosis, platelet aggregation, platelet-fibrin thrombi, monocyte/macrophage margination mainly in liver sinusoids, and vascular endothelial cell hypertrophy, confirmed by confocal and electron microscopy. Immunohistochemistry showed minimal deposition of IgM, and almost absence of IgG, C3, C4d, C5b-9, and of a cellular infiltrate, suggesting that neither antibody- nor cell-mediated rejection played a major role.
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Burcin
authors.initials: B
authors.lastname: Ekser
authors.forename: Edwin
authors.initials: E
authors.lastname: Klein
authors.forename: Jing
authors.initials: J
authors.lastname: He
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Echeverri
authors.forename: Cassandra
authors.initials: C
authors.lastname: Long
authors.forename: Chih Che
authors.initials: CC
authors.lastname: Lin
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ezzelarab
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Hara
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Veroux
authors.forename: David
authors.initials: D
authors.lastname: Ayares
authors.forename: David K C
authors.initials: DK
authors.lastname: Cooper
authors.forename: Bruno
authors.initials: B
authors.lastname: Gridelli
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D005260:Female; D005700:Galactosyltransferases / Q000502:physiology; D005818:Genetic Engineering; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000276:immunology / Q000473:pathology*; D017093:Liver Failure / Q000276:immunology* / Q000628:therapy; D016031:Liver Transplantation / Q000276:immunology / Q000473:pathology*; D008297:Male; D010215:Papio; D034421:Sus scrofa; D014183:Transplantation, Heterologous / Q000276:immunology / Q000473:pathology*
chemical_list: D005700:Galactosyltransferases; C047006:N-acetyllactosaminide alpha-1,3-galactosyltransferase