The investigation of the mechanism of xenogeneic immunoreaction and its control…Examination from the organ specificity of the liver in xenotrnaplantation…

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1. Role of hepatic nonparenchymal cells in the xenogeneic immunoreactionsWe evaluated the role of hepatic nonparenchymal cells in the xenogeneic immunoreactions, using rat livers perfused with fresh human blood. In xenoperfused rat livers, humoral mediators initially caused the disturbance of microcirculation, which would induce long ischemia in the pericentral areas, resulting in massive necrosis. Necrosis of hepatic nonparenchymal cells may be responsible for less production of cytokines and adhesion molecules in the xenoperfused livers. In the xenogeneic perfused rat livers treated with gadolinium chloride (GdCI3), in which Kupffer cells were inactivated, hepatic tissue injury increased. Isolated Kupffer cells treated with GdCI3 showed no uptake of human C3 in the cytoplasm. The ability of Kupffer cells to absorb xenogeneic complement may contribute to the liver's resistance to humoral injury.2. Suppressed complement activation in human Decay Accelerating Factor (hDAF) transgenic porcine liver cross-circulated with non human primatesWe evaluated the suppressive effects of hDAF transgenic porcine livers on xenogeneic immunoreactions. hDAF transgenic porcine livers cross-circulated with non human primate (healthy baboons) were compared with non-transgenic porcine livers. The baboon, cross-circulated with non-transgenic porcine liver for 10 hours, died of acute renal failure caused by macroscopic hemolysis 2_days later. The 5 baboons, cross-circulated with wild type porcine liver for maximally 6 hours (mean, 4.4±1.2 hours), survived over 1 year without organ dysfunction or immunological disturbance. Three cross-circulations with hDAF transgenic porcine livers performed for 24 hours (mean, 20.4±5.1 hours). No baboons showed any serious complications after the cross-circulation. The hDAF transgenic porcine, liver reduced complement activation in xenoperfusion with healthy non-human primate blood, and lead extended duration of cross-circulation.