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

异种免疫反应机制及其控制的研究…从异种移植中肝脏的器官特异性考察…

基本信息

批准号：
11470244
负责人：
IKAI Iwao
金额：
$ 9.09万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

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.

1.肝非实质细胞在异种免疫反应中的作用我们用新鲜人血灌流的大鼠肝脏研究了肝非实质细胞在异种免疫反应中的作用。在异种灌流的大鼠肝脏中，体液介质首先引起微循环障碍，引起中央周围区长时间缺血，导致大面积坏死。肝非实质细胞的坏死可能是异种灌流肝脏细胞因子和粘附分子产生减少的原因。在用氯化钆（GdCI 3）处理的异种灌注大鼠肝脏中，枯否细胞被灭活，肝组织损伤增加。用GdCl 3处理的分离的库普弗细胞显示在细胞质中没有摄取人C3。枯否细胞吸收异种补体的能力可能与肝脏抵抗体液损伤有关.人衰变加速因子（Decay Accelerating Factor，hTNF）转基因猪肝与非人灵长类动物交叉循环中补体激活的抑制作用将与非人灵长类动物（健康狒狒）交叉循环的受抑制的转基因猪肝与非转基因猪肝进行比较。狒狒与非转基因猪肝交叉循环10小时，2天后死于肉眼溶血引起的急性肾功能衰竭。5只狒狒与野生型猪肝交叉循环最长6小时（平均4.4±1.2小时），存活超过1年，无器官功能障碍或免疫功能紊乱。进行三次与转基因猪肝的交叉循环，持续24小时（平均，20.4±5.1小时）。交叉循环后，没有狒狒出现任何严重并发症。在异种灌流中，转基因猪肝降低了健康非人灵长类动物血液的补体激活，并延长了交叉循环的持续时间。