Transgenic porcine valves show no signs of delayed cardiac xenograft rejection
Transgenic porcine valves show no signs of delayed cardiac xenograft rejection
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DOI：
10.1016/s0003-4975(01)02505-x
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发表时间：
2001-05-01
影响因子：
4.6
通讯作者：
Adams, DH
中科院分区：
文献类型：
--
作者：
Chen, RH;Adams, DH
背景资料。戊二醛固定使猪瓣膜的结构完整性变得坚硬，尽管这种溶液也会破坏组织的活力并加速钙化。最近，我们证明了家猪新鲜心脏瓣膜不表达半乳糖α1，3半乳糖(cu-Gal)抗原，可能是免疫学上独一无二的。没有α-Gal解释了为什么猪心脏的瓣膜在60分钟内被灵长类免疫球蛋白M(IgM)和补体膜攻击复合体(MAC)破坏，而心脏的其余部分却保持着原始状态。我们试图阐明来自携带人类补体调节蛋白(CD59/DAF)的转基因猪的新鲜猪瓣是否可以在灵长类动物中存活更长时间，以及猪心脏瓣膜在长期暴露后是否保持免疫特权。采用苏木精-伊红染色和免疫组织化学方法，对6例未移植、3例野生型移植和3例表达人CD59/DAF蛋白的转基因猪移植到灵长类动物心脏的组织切片进行检测。Alpha-Gal抗原在转基因猪的血管内皮细胞上高表达，但在瓣膜内皮细胞上不表达。CD59/DAF转基因猪心脏存活5、7和11天，但IgM和MAC沉积增加，直至衰竭。瓣膜在外植体上保持形态完整，而GalNAc染色显示内皮细胞表面完整。然而，瓣膜没有显示出由IgM或MAC介导的损伤迹象。尽管表达人类补体调节蛋白的转基因猪的心脏可以在灵长类受体体内存活数天，但由于灵长类IgM和MAC不断升级的攻击，异种移植最终失败。缺乏α-半乳糖抗原可保护未固定的猪瓣膜免受排斥反应。(C)2001年，由胸外科医生学会提供。
Background. Glutaraldehyde fixation stiffens the structural integrity of porcine valves, although the solution also destroys tissue viability and accelerates calcification. Recently, we demonstrated that fresh cardiac valves from domestic pigs do not express the galactose alpha1, 3 galactose (cu-Gal) antigen and may be immunologically unique. The absence of alpha -Gal explained why the valves remained pristine while the rest of the porcine heart was destroyed by primate immunoglobulin M (IgM) and complement membrane attack complex (MAC) within 60 minutes. We sought to clarify whether fresh porcine valves from transgenic pigs bearing human complement regulatory proteins (CD59/DAF) can survive longer in primates and whether porcine cardiac valves remained immunologically privileged after prolonged exposure.Methods. Tissue sections from wild-type untransplanted (n = 6), wild-type transplanted (n = 3), and transgenic pigs expressing human CD59/DAF proteins transplanted (n = 3) porcine-to-primate cardiac grafts were examined by hematoxylin and eosin, and by immunohistochemistry for the porcine endothelial marker (GalNac), alpha -Gal, primate IgM and MAC.Results. alpha -Gal antigens were highly expressed on the vascular, but not valvular, endothelium of transgenic pigs. Hearts from CD59/DAF transgenic pigs survived 5, 7, and 11 days, but showed increasing IgM and MAC deposition until failure. Valves remained morphologically intact at explant, and strong GalNac staining suggested an intact endothelial surface. However, the valves showed no signs of IgM- or MAC-mediated damage.Conclusions. Although hearts from transgenic pigs expressing human complement regulatory proteins can survive for days in the primate recipient, the xenografts eventually fail because of escalating attacks of primate IgM and MAC. The absence of the alpha -Gal antigens protects unfixed porcine valves from rejection. (C) 2001 by The Society of Thoracic Surgeons.