Mechanism of delayed rejection in transgenic pig-to-primate cardiac xenotransplantation
Mechanism of delayed rejection in transgenic pig-to-primate cardiac xenotransplantation
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DOI：
10.1006/jsre.2000.5864
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发表时间：
2000-05-15
影响因子：
2.2
通讯作者：
Adams, DH
中科院分区：
文献类型：
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作者：
Chen, RH;Kadner, A;Adams, DH
背景猪-灵长类动物心脏异种移植物发生超急性排斥反应（HAR），其中灵长类动物IgM与猪内皮α-Gal分子结合并激活膜攻击复合物（MAC）沉积。通过使用转基因猪供体可以延长移植物的存活时间，所述转基因猪供体表达人补体调节蛋白（hCRP）以抑制MAC，然而，这些异种移植物总是由于延迟性异种移植物排斥（DXR）而失败。材料和方法：将野生型（n = 3）和转基因（n = 3）猪心异位移植到狒狒体内。通过组织学和免疫组织化学分析活检组织中的猪内皮标志物（VWF、α-Gal和β-Gal）和灵长类动物IgM和MAC沉积。野生型异种移植物存活60 - 80分钟，但死于快速IgM/MAC沉积和微血管血栓形成。转基因异种移植物避免了HAR，但在第5、7和11天的排斥反应前显示出IgM/MAC沉积增加。转基因异种移植物排斥反应后狒狒的血清显示出对猪内皮细胞的活性增加，未移植的猪心脏切片与致敏狒狒血清的体外孵育显示出微血管IgM结合增加。IgM沉积增加似乎特异于α-Gal，由于它与α-Gal特异性GS-4凝集素特异性竞争，而不与β-Gal特异性RCA-1凝集素竞争，因此如果使用幼稚狒狒血清，则没有观察到与GS-4的竞争。DXR可能通过增加狒狒IgM与猪微血管内皮细胞α-Gal分子的结合来介导。(C)北京大学出版社.
Background. Pig-to-primate cardiac xenografts undergo hyperacute rejection (HAR), in which primate IgM bind to porcine endothelial alpha-Gal molecules and activate membrane attack complex (MAC) deposition. Prolonged graft survival can be achieved by using transgenic pig donors, which express human complement regulatory proteins (hCRP) to inhibit MAC, However, these xenografts invariably fail from delayed xenograft rejection (DXR). We sought to investigate the poorly understood DXR process.Materials and methods, Wild-type (n = 3) and transgenic (n = 3) porcine hearts were heterotopically transplanted into baboons. Biopsies were analyzed by histology and by immunohistochemistry for porcine endothelial markers (VWF, alpha-Gal, and beta-Gal) and primate IgM and MAC deposition.Results. Wild-type xenografts survived 60-80 min but succumbed to rapid IgM/MAC deposition and microvascular thrombosis. Transgenic xenografts avoided HAR but showed increasing IgM/MAC deposition before rejection on days 5, 7, and 11, Serum from baboons after transgenic xenograft rejection showed increased activity against porcine endothelial cells, and in vitro incubation of untransplanted porcine cardiac sections with sensitized baboon serum showed elevated microvascular IgM binding, Increased IgM deposition appeared specific to alpha-Gal, since it competes specifically with alpha-Gal-specific GS-4 lectin, but not with beta-Gal-specific RCA-1 lectin, Competition with GS-4 was not seen if naive baboon serum was used.Conclusion. DXR may be mediated by increasing baboon IgM binding on porcine microvascular endothelial alpha-Gal molecules. (C) 2000 Academic Press.