Genetically-Engineered Pig-to-Baboon Liver Xenotransplantation: Histopathology of Xenografts and Native Organs

摘要

Orthotopic liver transplantation was carried out in baboons using wild-type (WT, n = 1) or genetically-engineered pigs (a1,3-galactosyltransferase gene-knockout, GTKO), n = 1; GTKO pigs transgenic for human CD46, n = 7) and a clinically-acceptableimmunosuppressive regimen. Biopsies were obtained from the WT pig liver pre-Tx and at 30 min, 1, 2, 3, 4 and 5 h posttransplantation.Biopsies of genetically-engineered livers were obtained pre-Tx, 2 h after reperfusion and at necropsy (4–7days after transplantation). Tissues were examined by light, confocal, and electron microscopy. All major native organs werealso 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 andnative organs (as a result of profound thrombocytopenia) which necessitated euthanasia. At 2 h, graft histology was largelynormal. At necropsy, genetically-engineered pig livers showed hemorrhagic necrosis, platelet aggregation, platelet-fibrinthrombi, monocyte/macrophage margination mainly in liver sinusoids, and vascular endothelial cell hypertrophy, confirmedby confocal and electron microscopy. Immunohistochemistry showed minimal deposition of IgM, and almost absence ofIgG, C3, C4d, C5b-9, and of a cellular infiltrate, suggesting that neither antibody- nor cell-mediated rejection played a majorrole.