Diamond L E, McCurry K R, Martin M J, McClellan S B, Oldham E R, Platt J L, Logan J S
Nextran, Princeton, NJ 08540, USA.
Transplantation. 1996 Apr 27;61(8):1241-9. doi: 10.1097/00007890-199604270-00021.
The critical shortage of human donor organs has generated interest in the potential for porcine to human xenotransplantation. The initial immunological barrier to xenotransplantation is hyperacute rejection, which is mediated by xenoreactive antibodies and complement, and results in rapid and irreversible tissue destruction. While endogenous complement regulatory proteins (CRPs) protect cells from injury caused by autologous complement, they are relatively species specific and most likely ineffectual in this setting. This has led to the hypothesis that expression of human CRPs in transgenic pigs may affect susceptibility to complement-mediated tissue injury in a porcine-to-human xenograft. Using specific lines of transgenic pigs that express low levels of human CD59, a CRP that acts at the terminal stage of the complement cascade, we present evidence that shows that the human CD59 protein inhibits membrane attack complex assembly and reduces tissue damage when the heart is transplanted to a baboon. Examination by immunohistochemistry of transgenic porcine hearts after transplantation revealed markedly reduced deposition of C5b and MAC, but a similar level of C3 deposition as compared with transplanted control hearts. This finding supports the concept that the species specific function of CRPs contributes to the humoral barrier to xenotransplantation and, given the low level of human CD59 protein expression in the porcine heart, argues that the human protein contributes a unique rather than an additive function in regulation of complement in a xenogeneic setting.
人类供体器官的严重短缺引发了人们对猪到人的异种移植潜力的兴趣。异种移植最初的免疫屏障是超急性排斥反应，它由异种反应性抗体和补体介导，会导致迅速且不可逆的组织破坏。虽然内源性补体调节蛋白（CRP）可保护细胞免受自身补体造成的损伤，但它们具有相对的物种特异性，在这种情况下很可能无效。这就引出了一个假说，即在转基因猪中表达人类CRP可能会影响猪到人的异种移植中补体介导的组织损伤易感性。我们使用表达低水平人类CD59（一种在补体级联反应末期起作用的CRP）的特定转基因猪品系，提供了证据表明，当心脏移植到狒狒体内时，人类CD59蛋白可抑制膜攻击复合物的组装并减少组织损伤。移植后对转基因猪心脏进行免疫组织化学检查发现，C5b和MAC的沉积明显减少，但与移植的对照心脏相比，C3沉积水平相似。这一发现支持了CRP的物种特异性功能促成异种移植体液屏障的概念，并且鉴于猪心脏中人类CD59蛋白的低表达水平，表明人类蛋白在异种环境中对补体的调节发挥的是独特而非附加的功能。
