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Regulation of xenograft rejection for the clinical utilization of porcine livers - Inhibiton of complement cascade and Kupffer cell activation

猪肝临床应用中异种移植排斥的调节——补体级联和库普弗细胞激活的抑制

基本信息

批准号：
09470266
负责人：
IKAI Iwao
金额：
$ 2.24万
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：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

The use of xenogenic livers for artificial liver or xenotransplantation has been extensively studied. Xenoperfused or xenotransplanted organs are rapidly injured by hyperacute rejection, which is caused by humoral mediators such as xenoreactive natural antibody and complement. However, the mechanism of hepatic xenograft rejection is still unclear. Above all, it is not clear whether Kupffer cells are involved with hepatic xenograft rejection. To investigate the role of Kupffer cells in hepatic xenograft rejection, rat livers were perfused ex situ with fresh human blood after pretreatment either with normal saline or with gadolinium chloride (GdClィイD23ィエD2), a selective inhibitor of Kupffer cells. Tissue injury in the xenoperfused liver was more severe in GdClィイD23ィエD2-treated group than in control group, as evaluated by alanine aminotransferase (ALT) release in the perfusate and histological examination. To examin the relationship between the phagocytotic activity of Kupffer cells and human complement and antibodies, Kupffer cells were isolated from rats pretreated either with normal saline or with GdClィイD23ィエD2 and incubated with culture medium containing human serum. Localization of human C3 and IgM was examined by immunofluorescence. An uptake of human C3 was observed in the cytoplasm of saline-treated Kupffer cells, whereas no uptake was observed in GdClィイD23ィエD2-treated cells. The uptake of human IgM did not differ between the two groups. It was suggested that Kupffer cells have an ability to absorb xenogeneic complement and protect the liver from hyperacute rejection.

异种肝用于人工肝或异种移植已被广泛研究。异种灌流或异种移植的器官会迅速受到超急性排斥反应的损伤，而超急性排斥反应是由体液介质如异种反应性天然抗体和补体引起的。然而，异种肝移植排斥反应的机制仍不清楚。总之，库普弗细胞是否参与异种肝移植排斥反应尚不清楚。为了研究枯否细胞在肝脏异种移植排斥反应中的作用，在用生理盐水或氯化钆（GdClイD23 D2）（枯否细胞的选择性抑制剂）预处理后，用新鲜人血对大鼠肝脏进行离体灌注。GdCl-23-D23-D2处理组的肝脏组织损伤较对照组严重，通过灌流液中丙氨酸氨基转移酶（ALT）的释放和组织学检查进行评价。为研究枯否细胞吞噬活性与人补体和抗体的关系，从用生理盐水或GdCl γ-D23 γ-D2预处理的大鼠中分离枯否细胞，并与含人血清的培养基一起孵育。通过免疫荧光法检测人C3和IgM的定位。在盐水处理的库普弗细胞的细胞质中观察到人C3的摄取，而在GdCl γ D23 γ D2处理的细胞中没有观察到摄取。人IgM的摄取在两组之间没有差异。提示枯否细胞具有吸收异种补体的能力，对肝脏超急性排斥反应具有保护作用。