Immunobiology of liver xenotransplantation

Abstract

Pigs are currently the preferred species for future organ xenotransplantation. With advances in the development of genetically modified pigs, clinical xenotransplantation is becoming closer to reality. In preclinical studies (pig-to-nonhuman primate), the xenotransplantation of livers from pigs transgenic for human CD55 or from α1,3-galactosyltransferase gene-knockout pigs+/− transgenic for human CD46, is associated with survival of approximately 7–9 days. Although hepatic function, including coagulation, has proved to be satisfactory, the immediate development of thrombocytopenia is very limiting for pig liver xenotransplantation even as a ‘bridge’ to allotransplantation. Current studies are directed to understand the immunobiology of platelet activation, aggregation and phagocytosis, in particular the interaction between platelets and liver sinusoidal endothelial cells, hepatocytes and Kupffer cells, toward identifying interventions that may enable clinical application.

Recent Progress in Xenotransplantation, with Emphasis on Virological Safety

“…More difficult is the situation with pig liver transplantation [55]. In pig to non-human primate studies, the transplantation of livers from pigs transgenic for hCD55 or from GTKO animals, which in addition expressed hCD46, was associated with a survival time of 7 to 9 days [55][56][57] including coagulation, have proved to be satisfactory, the immediate development of thrombocytopenia was extremely limiting.…”

“…In pig to non-human primate studies, the transplantation of livers from pigs transgenic for hCD55 or from GTKO animals, which in addition expressed hCD46, was associated with a survival time of 7 to 9 days [55][56][57] including coagulation, have proved to be satisfactory, the immediate development of thrombocytopenia was extremely limiting. The thrombocytopenia resulted in hemorrhages in various organs and tissues, as well as in the transplanted liver [56].…”

New Concepts of Immune Modulation in Xenotransplantation

“…However, for the purposes of this review, subsequent attention will be concentrated on the adaptive response and, particularly, on what biologic and pharmacologic agents are likely to play an important role in its control. Pig liver (81) and lung (82) transplantation into NHPs result in rapid graft loss through complex mechanisms that are unrelated to the adaptive response, and in pig islet transplantation the problem of the instant blood-mediated inflammatory reaction has to be overcome (3). These topics deserve in depth consideration in another context, but in this review attention will be directed to immunosuppressive regimens that have been utilized in pig heart and kidney xenotransplantation models.…”

Pig Liver Xenotransplantation

“…At necropsy some days later, some livers showed macroscopic changes consistent with cholestasis, except for some patchy dark areas which microscopically showed hemorrhagic necrosis, platelet-fibrin thrombi, monocyte/macrophage margination, and vascular endothelial cell hypertrophy (Figure 2C). 12,28,36–38 No cell infiltration was seen. Confocal microscopy has confirmed tissue factor expression on platelets, and platelet and platelet/leukocyte aggregates in liver sinusoids.…”