Xenotransplantation:: in vitro analysis of synthetic α-galactosyl inhibitors of human anti-Galα1→3Gal IgM and IgG antibodies
Xenotransplantation:: in vitro analysis of synthetic α-galactosyl inhibitors of human anti-Galα1→3Gal IgM and IgG antibodies
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DOI：
10.1093/glycob/10.2.141
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发表时间：
2000-02-01
期刊：
影响因子：
4.3
通讯作者：
Joziasse, DH
中科院分区：
文献类型：
--
作者：
Rieben, R;Bovin, NV;Joziasse, DH
猪到人的异种移植可能是解决人类供体器官日益短缺的一种选择。然而，人类血液中天然存在的针对猪内皮细胞上的 Gal α 1-->3Gal 抗原的抗体会导致猪移植物的超急性或如果预防的话，会导致急性或迟发性血管排斥。因此，本研究的目的是评估具有末端 Gal α 1-->3Gal 的合成寡糖，以抑制抗 α Gal 抗体针对猪细胞的抗原结合和细胞毒性。不同的寡糖是通过化学和酶法相结合的方法合成的。这些包括单体二糖、三糖和五糖、聚丙烯酰胺缀合物 (PAA-Bdi) 以及 Gal α 1→3Gal 的二聚体、四聚体和八聚体。所有这些都通过抗-α Gal ELISA 和补体依赖性细胞毒性测试测试了抑制活性。 PAA-Bdi 是抗 α Gal 抗体结合和细胞毒性的最佳抑制剂。单体寡糖可有效阻止抗 α Gal IgG 的结合，但阻止抗 α Gal IgM 的结合效果较差，三糖和五糖比二糖显示出更好的功效。两种三糖Gal α 1-->3Gal β 1-->4GlcNAc和Gal α 1-->3Gal β 1-->3GlcNAc同样有效。 Gal α 1-->3Gal 的寡聚体在阻断抗-α Gal IgG 的结合方面比单体更有效，但是，它们不能阻断 IgM 结合，也无法与 PAA-Bdi 的功效相媲美。我们得出结论，末端 Gal α 1-->3Gal 的寡糖，最有效的是作为 PAA 缀合物，可以在体外阻止人抗-α Gal 的结合和细胞毒性。 PAA-Bdi 缀合物可能最适合用作琼脂糖结合的免疫吸收材料。
Pig-to-human xenotransplantation might be an option to overcome the increasing shortage of human donor organs. However, naturally occurring antibodies in human blood against the Gal alpha 1-->3Gal antigen on pig endothelial cells lead to hyperacute or, if prevented, acute or delayed vascular rejection of the pig graft. The purpose of this study was therefore to evaluate synthetic oligosaccharides with terminal Gal alpha 1-->3Gal to inhibit antigen-binding and cytotoxicity of anti-alpha Gal antibodies against pig cells. Different oligosaccharides were synthesized chemically and by a combined chemico-enzymatic approach. These included monomeric di-, tri, and pentasaccharides, a polyacrylamide-conjugate (PAA-Bdi), as well as di-, tetra-, and octamers of Gal alpha 1-->3Gal. All were tested for inhibitory activity by anti-alpha Gal ELISA and complement-dependent cytotoxicity tests. PAA-Bdi was the best inhibitor of binding as well as cytotoxicity of anti-alpha Gal antibodies. Monomeric oligosaccharides efficiently prevented binding of anti-alpha Gal IgG, but less well that of anti-alpha Gal IgM, with tri- and pentasaccharides showing a better efficacy than the disaccharide. The two trisaccharides Gal alpha 1-->3Gal beta 1-->4GlcNAc and Gal alpha 1-->3Gal beta 1-->3GlcNAc were equally effective. Oligomers of Gal alpha 1-->3Gal were more effective than monomers in blocking the binding of anti-alpha Gal IgG, However, they could not block IgM binding, nor could they match the efficacy of PAA-Bdi, We conclude that oligosaccharides with terminal Gal alpha 1-->3Gal, most effectively as PAA-conjugates, can prevent binding and cytotoxicity of human anti-alpha Gal in vitro. The PAA-Bdi conjugate might be most suited for use as a Sepharose-bound immunoabsorption material.