Maruyama S, Cantu E, Galili U, D'Agati V, Godman G, Stern D M, Andres G
Departments of Physiology, Surgery, and Pathology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Kidney Int. 2000 Feb;57(2):655-63. doi: 10.1046/j.1523-1755.2000.00887.x.
The pig is the donor animal of choice for human xenotransplantation. In the most relevant pig-to-baboon model, pig organs transplanted into baboons are hyperacutely rejected by natural xenoantibodies, which mainly bind to alpha-galactosyl (alphaGal) epitopes expressed at the surface of endothelial cells. Recent advances in controlling hyperacute rejection have led to improved survival of these xenografts, and it is now important to identify alphaGal binding sites in other cells and tissues that may be subject to immunologic attack. To this end, we have studied whether alphaGal antibodies bind to glycated proteins of the extracellular matrix in the kidney and other organs most likely to be used for human xenotransplantation.
High-titer anti-alphaGal antibodies, similar to human natural xenoantibodies, were prepared in baboons, and their reactivity with components of pig extracellular matrix was tested by serology and immunohistology.
The antibodies recognized epitopes of immobilized murine, bovine or porcine thyroglobulin, laminin, heparan sulfate proteoglycans, and fibronectin. In sections of pig tissue, the antibodies bound to endothelial and certain epithelial cells, as shown in previous studies, and also to mesenchymal cells, basement membranes, and extracellular matrices, in which they colocalized with matrix glycoproteins, especially laminin and heparan sulfate proteoglycans.
These results suggest that when pig xenografts can be made to survive for prolonged periods, the reactivity of alphaGal antibody with matrix molecules can induce basement membrane and matrix lesions similar to those induced in laboratory animals by antilaminin and antiheparan sulfate proteoglycans antibodies.
猪是人类异种移植首选的供体动物。在最相关的猪 - 狒狒模型中，移植到狒狒体内的猪器官会被天然异种抗体超急性排斥，这些抗体主要与内皮细胞表面表达的α - 半乳糖基（αGal）表位结合。控制超急性排斥的最新进展已提高了这些异种移植物的存活率，现在识别其他可能受到免疫攻击的细胞和组织中的αGal结合位点很重要。为此，我们研究了αGal抗体是否与肾脏及其他最有可能用于人类异种移植的器官中的细胞外基质糖化蛋白结合。
在狒狒体内制备了与人类天然异种抗体相似的高滴度抗αGal抗体，并通过血清学和免疫组织学检测其与猪细胞外基质成分的反应性。
这些抗体识别固定化的鼠、牛或猪甲状腺球蛋白、层粘连蛋白、硫酸乙酰肝素蛋白聚糖和纤连蛋白的表位。在猪组织切片中，这些抗体如先前研究所示，与内皮细胞和某些上皮细胞结合，也与间充质细胞、基底膜和细胞外基质结合，它们在其中与基质糖蛋白，特别是层粘连蛋白和硫酸乙酰肝素蛋白聚糖共定位。
这些结果表明，当猪异种移植物能够长期存活时，αGal抗体与基质分子的反应性可诱导基底膜和基质损伤，类似于抗层粘连蛋白和抗硫酸乙酰肝素蛋白聚糖抗体在实验动物中诱导的损伤。
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