Characterization of transgenic pigs expressing functionally active human CD59 on cardiac endothelium
Characterization of transgenic pigs expressing functionally active human CD59 on cardiac endothelium
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DOI：
10.1097/00007890-199604270-00021
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发表时间：
1996-04-27
期刊：
影响因子：
6.2
通讯作者：
Logan, JS
中科院分区：
文献类型：
--
作者：
Diamond, LE;McCurry, KR;Logan, JS
人类供体器官的严重短缺引起了人们对猪到人异种移植潜力的兴趣。异种移植的最初免疫屏障是超急性排斥反应，其由异种反应性抗体和补体介导，并导致快速和不可逆的组织破坏。虽然内源性补体调节蛋白（CRP）保护细胞免受自体补体引起的损伤，但它们具有相对的种属特异性，并且在这种情况下很可能无效。这导致了一种假设，即转基因猪中人CRP的表达可能影响猪-人异种移植物对补体介导的组织损伤的易感性。使用表达低水平人CD 59（一种在补体级联反应终末阶段起作用的CRP）的转基因猪的特定品系，我们提供的证据表明，当心脏移植到狒狒身上时，人CD 59蛋白抑制膜攻击复合物组装并减少组织损伤，移植后转基因猪心的免疫组织化学检查显示C5 b和MAC的沉积显著减少，但与移植的对照心脏相比，C3沉积水平相似。这一发现支持CRP的物种特异性功能有助于异种移植的体液屏障的概念，并且，考虑到猪心脏中人CD 59蛋白表达水平低，认为人类蛋白质在异种环境中的补体调节中贡献了独特的而不是附加的功能。
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.