EXPRESSION OF A FUNCTIONAL HUMAN-COMPLEMENT INHIBITOR IN A TRANSGENIC PIG AS A MODEL FOR THE PREVENTION OF XENOGENEIC HYPERACUTE ORGAN REJECTION
EXPRESSION OF A FUNCTIONAL HUMAN-COMPLEMENT INHIBITOR IN A TRANSGENIC PIG AS A MODEL FOR THE PREVENTION OF XENOGENEIC HYPERACUTE ORGAN REJECTION
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DOI：
10.1073/pnas.91.23.11153
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发表时间：
1994-11-08
影响因子：
11.1
通讯作者：
SQUINTO, SP
中科院分区：
文献类型：
--
作者：
FODOR, WL;WILLIAMS, BL;SQUINTO, SP
可用于移植的人体器官的严重短缺引起了人们对使用动物器官(异种移植)进行移植的高度兴趣。然而，非协调性异种器官移植成功的主要障碍是超急性排斥现象。超急性排斥反应是由于高效价预形成抗体的沉积，这些抗体激活了血管内皮细胞管腔表面的血清补体，导致血管闭塞和移植失败，在几分钟到几个小时内。虽然内源性膜相关补体抑制剂通常保护内皮细胞免受自体补体的影响，但它们是物种受限的，因此对激活的异种补体具有有限的抵抗力。为了解决异种移植超急性排斥反应的发病机制，设计了表达人补体末端抑制因子hCD59的转基因小鼠和转基因猪。HCD59在多种类型的小鼠和猪细胞中都有高水平的细胞表面表达，尤其是在大血管和毛细血管内皮细胞上。表达hCD59的猪细胞对高效价抗猪抗体和人补体的攻击具有明显的抵抗力。这些实验展示了一种开发猪到灵长类异种移植模型的策略，以测试人类补体抑制物在转基因猪中的表达是否可以使异种器官对超急性排斥反应产生抵抗。
The serious shortage of human organs available for transplantation has engendered a heightened interest in the use of animal organs (xenografts) for transplantation. However, the major barrier to successful discordant xenogeneic organ transplantation is the phenomenon of hyperacute rejection. Hyperacute rejection results from the deposition of high-titer preformed antibodies that activate serum complement on the luminal surface of the vascular endothelium, leading to vessel occlusion and graft failure within minutes to hours. Although endogenous membrane-associated complement inhibitors normally protect endothelial cells from autologous complement, they are species restricted and thus confer limited resistance to activated xenogeneic complement. To address the pathogenesis of hyperacute rejection in xenotransplantation, transgenic mice and a transgenic pig were engineered to express the human terminal complement inhibitor hCD59. High-level cell surface expression of hCD59 was achieved in a variety of murine and porcine cell types, most importantly on both large vessel and capillary endothelium. hCD59-expressing porcine cells were significantly resistant to challenge with high-titer anti-porcine antibody and human complement. These experiments demonstrate a strategy for developing a pig-to-primate xenogeneic transplantation model to test whether the expression of a human complement inhibitor in transgenic pigs could render xenogeneic organs resistant to hyperacute rejection.