Platt J L, Holzknecht Z E
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710.
Transplantation. 1994 Feb;57(3):327-35. doi: 10.1097/00007890-199402150-00003.
Hyperacute xenograft rejection of porcine organs by primates is initiated by the binding of recipient natural antibodies to endothelium in the donor organ. We showed previously that human natural antibodies recognize 3 porcine endothelial cell glycoproteins with molecular masses of 115 kDa, 125 kDa, and 135 kDa; we called the glycoproteins gp115/135. We also showed that porcine platelets contain glycoprotein antigens that are the same or very similar to gp115/135 from endothelial cells. The studies reported here were aimed at identifying these porcine platelet antigens and evaluating their potential relevance for the pathogenesis of xenograft injury. The importance of gp115/135 as targets of human natural antibodies was supported by the demonstration that (a) antibodies against porcine platelet gp115/135 are absorbed from the blood of nonhuman primates during the perfusion of a porcine kidney; (b) purified gp115/135 glycoproteins at concentrations < 500 pM, block the binding of human natural antibodies to cultured porcine endothelial cells; (c) the binding of human antibodies to porcine platelet extracts is significantly decreased by removal of gp115 or gp135 from the extracts; (d) antibody binding to gp115/135 initiates the activation of complement. Amino-terminal sequencing of gp115/135 revealed that gp115 has significant homology to human integrin beta 3 chains, gp125 to human alpha IIb chains, and gp135 to human alpha 2 chains. Ligand binding properties of the porcine glycoproteins were consistent with the identity of the antigens revealed by amino acid sequencing and molecular weight. Human natural antibodies also recognized a 250 kDa porcine platelet glycoprotein which was found to be homologous to human von Willebrand factor (vWF). Antibodies against vWF in the blood of nonhuman primates are absorbed during ex vivo perfusion of a porcine organ. The identification of gp115/135 as integrins, the functions of which in endothelium might include cell signaling and maintenance of barrier function, provides potential insight into the pathogenesis of the rejection reaction in which these processes are manifestly aberrant. The identification of vWF as a potential target antigen raises several questions, including whether vWF provides one basis for antibody binding to xenogeneic endothelium or whether upon secretion from an endothelial cell vWF might actually block antibody binding.
灵长类动物对猪器官的超急性异种移植排斥反应是由受体天然抗体与供体器官中的内皮细胞结合引发的。我们之前表明，人类天然抗体可识别分子量分别为115 kDa、125 kDa和135 kDa的3种猪内皮细胞糖蛋白；我们将这些糖蛋白称为gp115/135。我们还表明，猪血小板含有与内皮细胞的gp115/135相同或非常相似的糖蛋白抗原。本文报道的研究旨在鉴定这些猪血小板抗原，并评估它们在异种移植损伤发病机制中的潜在相关性。gp115/135作为人类天然抗体靶点的重要性得到了以下证据的支持：(a) 在猪肾灌注过程中，针对猪血小板gp115/135的抗体从非人类灵长类动物的血液中被吸收；(b) 浓度<500 pM的纯化gp115/135糖蛋白可阻断人类天然抗体与培养的猪内皮细胞的结合；(c) 从提取物中去除gp115或gp135后，人类抗体与猪血小板提取物的结合显著减少；(d) 抗体与gp115/135的结合引发补体激活。gp115/135的氨基末端测序显示，gp115与人整合素β3链具有显著同源性，gp125与人αIIb链具有显著同源性，gp135与人α2链具有显著同源性。猪糖蛋白的配体结合特性与氨基酸测序和分子量所揭示的抗原特性一致。人类天然抗体还识别一种250 kDa的猪血小板糖蛋白，该糖蛋白与人血管性血友病因子（vWF）同源。在猪器官的体外灌注过程中，非人类灵长类动物血液中针对vWF的抗体被吸收。将gp115/135鉴定为整合素，其在内皮细胞中的功能可能包括细胞信号传导和维持屏障功能，这为这些过程明显异常的排斥反应发病机制提供了潜在的见解。将vWF鉴定为潜在的靶抗原引发了几个问题，包括vWF是否为抗体与异种内皮细胞结合提供了一个基础，或者内皮细胞分泌vWF后是否实际上可能阻断抗体结合。
