Genetic engineering for xenotransplantation
Genetic engineering for xenotransplantation
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DOI：
10.1111/j.1540-8191.2001.tb00549.x
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发表时间：
2001-11-01
影响因子：
1.6
通讯作者：
McKenzie, IFC
中科院分区：
文献类型：
--
作者：
Sandrin, MS;Loveland, BE;McKenzie, IFC
异种器官移植正在被大力推行，以解决同种异体供体器官短缺的问题。主要异种抗原（Gal）和补体调节的实验研究使模型异种移植物能够在超急性排斥反应中存活。当Gal抗原被去除或减少并且补体激活被控制时，异种移植物存活的主要障碍包括移植物内的不受调节的凝血和涉及巨噬细胞、中性粒细胞、自然杀伤（NK）细胞和T淋巴细胞的细胞反应。与同种异体移植物不同，其中特异性免疫应答是移植物存活的唯一障碍，异种移植物和受体之间影响正常受体-配体相互作用的分子差异（在细胞表面很大程度上是活性的，并且可能不是免疫原性的）也参与异种移植物失败。转基因策略提供了控制抗原表达、补体激活和凝血的最佳选择。虽然Gal抗原可以通过基因敲除在小鼠中消除，但由于最近在核移植后克隆猪，该结果仅在猪中成为可能。相反，使用转基因糖基转移酶和糖苷酶，其在糖脂和糖蛋白上产生替代的末端碳水化合物，在实验模型中减少了抗原。因此，正在测试新的战略，以寻求最有效的解决方案。转基因猪表达人类补体调节蛋白（CD 45/CD 55，MCP/CD 46或CD 59）已经揭示了凝血系统的失调调节需要关注。毫无疑问，还有其他分子上的不相容性需要解决。异种移植，然而，提供了希望，作为一种治疗方案，并提供了许多信息的自我平衡机制。
Xenotransplantation is being pursued vigorously to solve the shortage of allogeneic donor organs. Experimental studies of the major xenoantigen (Gal) and of complement regulation enable model xenografts to survive hyperacute rejection. When the Gal antigen is removed or reduced and complement activation is controlled, the major barriers to xenograft survival include unregulated coagulation within the graft and cellular reactions involving macrophages, neutrophils, natural killer (NK) cells, and T lymphocytes. Unlike allografts, where specific immune responses are the sole barrier to graft survival, molecular differences between xenograft and recipient that affect normal receptor-ligand interactions (largely active at the cell surface and which may not be immunogenic), are also involved in xenograft failure. Transgenic strategies provide the best options to control antigen expression, complement activation, and coagulation. Although the Gal antigen can be eliminated by gene knockout in mice, that outcome has only become a possibility in pigs due to the recent cloning of pigs after nuclear transfer. Instead, the use of transgenic glycosyl transferase enzymes and glycosidases, which generate alternative terminal carbohydrates on glycolipids and glycoproteins, has reduced antigen in experimental models. As a result, novel strategies are being tested to seek the most effective solution. Transgenic pigs expressing human complement-regulating proteins (DAF/CD55, MCP/CD46, or CD59) have revealed that disordered regulation of the coagulation system requires attention. There will undoubtedly be other molecular incompatibilities that need addressing. Xenotransplantation, however, offers hope as a therapeutic solution and provides much information about homeostatic mechanisms.