Thrombotic Microangiopathic Glomerulopathy in Human Decay Accelerating Factor–Transgenic Swine-to-Baboon Kidney Xenografts

作者：Akira Shimizu, Kazuhiko Yamada, Shin Yamamoto, John M. Lavelle, Rolf N. Barth, Simon C. Robson, David H. Sachs, Robert B. Colvin · 发表于：Journal of the American Society of Nephrology · 年份：2005 · DOI：10.1681/asn.2004121148 · 被引用次数：87 · 研究领域：Xenotransplantation and immune response、Animal Genetics and Reproduction、Pluripotent Stem Cells Research

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-alphaGal 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-alphaGal 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-alphaGal antibody after immunoadsorption. In group 1 (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 fibri...