Analysis of the molecular mechanism of DXR and the therapeutic method

为了探讨迟发性异种移植排斥反应(DXR)的分子机制，寻找其治疗手段，我们以猪细胞系(PK15)为靶细胞，以人NK细胞为效应细胞，进行了分子生物学分析。(结果/结论)：在人血清存在的情况下，未激发的人PBL同时引起细胞膜和DNA的损伤，提示NK细胞依赖的ADCC机制在这种猪到人的DXR中起作用。人FasL或小鼠Bcl2分子在PK15上的表达可部分抑制DNA损伤。虽然我们试图通过载体技术将这些分子导入体内的豚鼠心脏，但这些分子在心脏中没有得到足够的表达，并且这些心脏移植到LEW大鼠身上并没有显示出与对照组相比移植物存活的显著延长。这些结果表明，FasL和/或Bcl2的表达可以抑制DXR的发生。然而，在临床试验之前，有必要建立更可靠、更安全的方法将这些分子引入体内器官。

In order to investigate the molecular mechanism of delayed xenograft rejection (DXR), and to look for its therapeutic means, we have used pig cell line (PK15) as target cells and human NK cells as effector cells, and performed the molecular analyses. (Results/Conclusion) ; In the presence of human serum, unprimed human PBL caused both the membrane and DNA-damages, implying that NK-cell dependent ADCC mechanism operates in this pig-to-human DXR. The expression of human FasL or mouse Bcl-2 molecules on the PK15 were able to partially inhibit the DNA damage. Although we have tried to introduce these molecules into in vivo ginea pig heart using vector techniques, sufficient expression of these molecules in hearts were not obtained, and the xenotransplantation of these hearts to LEW rats did not show the significant prolongation of the grafts survival as compared to controls. From these results, it is concluded that the DXR can be inhibited by the expression of FasL and/or Bcl-2. However, it is necessary to establish more reliable and safe methods to introduce these molecules into in vivo organs before clinical trials.