Thrombotic microangiopathic glomerulopathy in human decay accelerating factor-transgenic swine-to-baboon kidney xenografts
Thrombotic microangiopathic glomerulopathy in human decay accelerating factor-transgenic swine-to-baboon kidney xenografts
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DOI：
10.1681/asn.2004121148
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发表时间：
2005-09-01
影响因子：
13.6
通讯作者：
Colvin, RB
中科院分区：
文献类型：
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作者：
Shimizu, A;Yamada, K;Colvin, RB
采用猪-狒狒异种移植模型，研究急性体液性异种移植排斥反应(AHXR)的发生机制和病理特点。将人衰变加速因子转基因猪的胸腺和肾脏(复合胸腺肾)移植到16只狒狒体内，进行免疫抑制治疗，包括体外免疫吸附抗α-Gal抗体和抑制补体激活。对常规活检和嫁接标本进行了形态和免疫组织化学研究。所有移植肾均避免了超急性排斥反应。然而，移植排斥反应与受体循环中抗agal抗体的增加是一致的。根据免疫吸附后抗AgA抗体的快速回升(组1)和逐渐回升(组2)将16例移植瘤分为两组。在I组(n=6)，移植肾排斥至第27天，出现典型的AHXR，其特征是肾间质明显出血和肾血管血栓性微血管病变。在第2组(n=10)，移植肾在30天前也出现血栓性微血管病变，主要累及肾小球，但间质损伤和出血的证据也很少。在受损的肾小球中，IgM和C4D沉积，随着von Willebrand因子和组织因子的上调，血管内皮细胞的死亡和激活，CD39的表达减少，形成纤维蛋白-血小板多发性微血栓。在这个模型中，来自人类衰变加速因子转基因猪的异种肾在狒狒身上进行了AHXR。在进展缓慢的AHXR中，移植物丢失与血栓性微血管病理性肾小球病变的发展有关。此外，抗AGAL IgM沉积和随后的补体激活在肾小球内皮细胞损伤和激活以及多发性微血栓形成的机制中也起着重要作用。
Models of pig-to-baboon xenografting were examined to identify the mechanisms and pathologic characteristics of acute humoral xenograft rejection (AHXR). Thymus and kidney (composite thymokidney) from human decay accelerating factor-transgenic swine were transplanted into baboons (n = 16) that were treated with an immunosuppressive regimen that included extracorporeal immunoadsorption of anti-alpha Gal antibody and inhibition of complement activation. Morphologic and immunohistochemical studies were performed on protocol biopsies and graftectomy samples. All renal xenografts avoided hyperacute rejection. However, graft rejection coincided with the increase of anti-aGal antibody in the recipient's circulation. The 16 xenografts studied were divided into two groups dependent on the rapid return (group 1) or gradual return (group 2) of anti-aGal antibody after immunoadsorption. In group I (n = 6), grafts were rejected to day 27 with development of typical AHXR, characterized by marked interstitial hemorrhage and thrombotic microangiopathy in the renal vasculature. In group 2 (n = 10), grafts also developed thrombotic microangiopathy affecting mainly the glomeruli by day 30 but also showed minimal evidence of interstitial injury and hemorrhage. In the injured glomeruli, IgM and C4d deposition, subsequent endothelial cell death and activation with upregulation of von Willebrand factor and tissue factor, and a decrease of CD39 expression developed with the formation of fibrin-platelet multiple microthrombi. In this model, the kidney xenografts, from human decay accelerating factor-transgenic swine, in baboons undergo AHXR. In slowly evolving AHXR, graft loss is associated with the development of thrombotic microangiopathic glomerulopathy. Also, anti-aGal IgM deposition and subsequent complement activation play an important role in the mechanism of glomerular endothelial injury and activation and the formation of multiple microthrombi.