Synthesis and evaluation of an α-C-Galactosylceramide analogue that induces Th1-biased responses in human natural killer T cells
Synthesis and evaluation of an α-C-Galactosylceramide analogue that induces Th1-biased responses in human natural killer T cells
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DOI：
10.1002/cbic.200600197
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发表时间：
2006-11-01
期刊：
影响因子：
3.2
通讯作者：
Bittman, Robert
中科院分区：
文献类型：
--
作者：
Lu, Xuequan;Song, Liping;Bittman, Robert
α -半乳糖神经酰胺（α GalCer, 1）及其等构c -糖苷类似物(2)被发现具有很好的免疫刺激活性，因为它们能够激活自然杀伤T （NKT）细胞。我们报道了化合物3的合成，这是一个截断的非等构c - α GalCer类似物，像2一样，在糖苷键上不具有酶活性，但有一个端粒碳直接连接到植物神经酰胺主链的C1上。我们用人树突状细胞作为抗原提呈细胞，人NKT细胞作为应答细胞，在体外系统中比较了这三种配体的生物活性。虽然3对NKT细胞的激动剂作用不如1和2，但它诱导细胞因子的产生具有最高的ifn - γ:IL-4和ifn - γ:IL-13比率。因此，我们的数据表明，新的α GalCer模拟物可能优先促进th1免疫反应，并在癌症和传染病的免疫治疗中作为一种有效的辅助剂。
An alpha-galactosylceramide (alpha GalCer, 1) and its isosteric C-glycoside analogue (2) were found to possess promising immunostimulatory activity because of their ability to activate natural killer T (NKT) cells. We report the synthesis of compound 3, a truncated nonisosteric C-alpha GalCer analogue, that like 2 is not enzymatically labile at the glycosidic linkage, but has the anomeric carbon directly bonded to the C1 of the phytoceramide backbone. We compared the biological activity of the three ligands using an in vitro system with human dendritic cells as the antigen-presenting cells and human NKT cells as the responding cells. Although 3 was a less potent agonist for NKT cells than 1 and 2, it induced cytokine production with the highest IFN-gamma:IL-4 and IFN-gamma:IL-13 ratios. Therefore, our data suggest that the new mimetic of alpha GalCer might preferentially promote Th1-immune responses and serve as a potent adjuvant in the immunotherapy of cancer and infectious diseases.