Lack of iGb3 and Isoglobo-Series Glycosphingolipids in Pig Organs Used for Xenotransplantation: Implications for Natural Killer T-Cell Biology.
Lack of iGb3 and Isoglobo-Series Glycosphingolipids in Pig Organs Used for Xenotransplantation: Implications for Natural Killer T-Cell Biology.
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用于异种移植的猪器官中缺乏 iGb3 和 Isoglobo 系列糖鞘脂：对自然杀伤 T 细胞生物学的影响。
DOI：
10.1080/07328303.2012.741637
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发表时间：
2013
影响因子：
1
通讯作者：
Zhou,Dapeng
中科院分区：
文献类型：
--
作者：
Tahiri,Fatima;Li,Yunsen;Hawke,David;Ganiko,Luciane;Almeida,Igor;Levery,Steven;Zhou,Dapeng
糖蛋白和鞘糖脂上的α-1，3-末端半乳糖残基被人血清中的天然抗α-1，3-半乳糖抗体识别，并在猪-人异种移植中引起超急性排斥反应。猪α-1，3-半乳糖基转移酶-1基因缺失可消除超急性排斥反应然而，猪中的异三葡萄糖基神经酰胺（iGb 3）合酶可能在鞘糖脂上产生额外的α-1，3-末端半乳糖残基。在α-1，3-半乳糖基转移酶-1敲除小鼠和猪中，均可诱导细胞毒性抗α-1，3-半乳糖抗体;因此，存在一个悖论，即抗α-1，3-半乳糖抗体存在于具有功能性iGb 3转移酶的动物中。此外，已经发现iGb 3是自然杀伤T（NKT）细胞的内源性抗原，所述自然杀伤T（NKT）细胞是可以启动适应性免疫应答的先天类型的淋巴细胞。据推测，iGb 3可能通过NKT细胞对适应性免疫细胞的强效刺激作用，触发NKT细胞的活化并引起α-1，3-半乳糖基转移酶-1缺陷器官的排斥反应（参见参考文献103）。[20]）。在这项研究中，我们通过离子阱质谱法检测了猪器官（包括心脏、肝脏、胰腺和肾脏）中iGb 3和异糖系列鞘糖脂的表达，当存在5 μg/mL的总iGb 3/Gb 3混合物时，离子阱质谱法具有测量1% iGb 3异构体的灵敏度（参见参考文献10）。[35]）。我们没有检测到iGb 3或其他isoglobo系列鞘糖脂在任何这些器官，虽然他们很容易检测到小鼠和人类胸腺和树突状细胞。猪器官中iGb 3和异糖系列鞘糖脂的缺乏表明iGb 3不太可能是异种移植中的相关免疫表位。
α-1,3-Terminated galactose residues on glycoproteins and glycosphingolipids are recognized by natural anti-α-1,3-galactose antibodies in human serum and cause hyperacute rejection in pig-to-human xenotransplantation. Genetic depletion of α-1,3-galactosyl- transferase-1 in pigs abolishes the hyperacute rejection reaction. However, the isoglo- botriosylceramide (iGb3) synthase in pigs may produce additional α-1,3-terminated galactose residues on glycosphingolipids. In both α-1,3-galactosyltranserase-1 knockout mice and pigs, cytotoxic anti-α-1,3-galactose antibodies could be induced; thus, a paradox exists that anti-α-1,3-galactose antibodies are present in animals with functional iGb3 synthases. Furthermore, iGb3 has been found to be an endogenous antigen for natural killer T (NKT) cells, an innate type of lymphocyte that may initiate the adaptive immune responses. It has been reasoned that iGb3 may trigger the activation of NKT cells and cause the rejection of α-1,3-galactosyltransferase-1-deficient organs through the potent stimulatory effects of NKT cells on adaptive immune cells (see ref.[20]). In this study, we examined the expression of iGb3 and the isoglobo-series glycosphingolipids in pig organs, including the heart, liver, pancreas, and kidney, by ion-trap mass spectrometry, which has a sensitivity of measuring 1% iGb3 among Gb3 isomers, when 5 μg/mL of the total iGb3/Gb3 mixture is present (see ref.[35]). We did not detect iGb3 or other isoglobo-series glycosphingolipids in any of these organs, although they were readily detected in mouse and human thymus and dendritic cells. The lack of iGb3 and isoglobo-series glycosphingolipids in pig organs indicates that iGb3 is unlikely to be a relevant immune epitope in xenotransplantation.