1. Induction of Th1-biased cytokine production by alpha-carba-GalCer, a neoglycolipid ligand for NKT cells.
- Author
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Tashiro T, Sekine-Kondo E, Shigeura T, Nakagawa R, Inoue S, Omori-Miyake M, Chiba T, Hongo N, Fujii S, Shimizu K, Yoshiga Y, Sumida T, Mori K, Watarai H, and Taniguchi M
- Subjects
- Adjuvants, Immunologic chemical synthesis, Adjuvants, Immunologic chemistry, Animals, Cell Line, Cyclohexanols chemical synthesis, Cyclohexanols chemistry, Cytokines analysis, Galactosylceramides chemical synthesis, Galactosylceramides chemistry, Glycolipids metabolism, Humans, Injections, Intravenous, Ligands, Mice, Natural Killer T-Cells immunology, Adjuvants, Immunologic pharmacology, Cyclohexanols pharmacology, Cytokines biosynthesis, Galactosylceramides pharmacology, Natural Killer T-Cells drug effects, Th1 Cells immunology
- Abstract
NKT cells are characterized by their production of both T(h)1 and T(h)2 cytokines immediately after stimulation with alpha-galactosylceramide (alpha-GalCer), which is composed of alpha-galactopyranose linked to ceramide (itself composed of sphingosine and fatty-acyl chains); the chain length of the ceramide varies and this affects the ability of alpha-GalCer to stimulate cytokine production. However, the contribution of its galactopyranose sugar moiety remains unclear. We synthesized alpha-carba-GalCer, which has an alpha-linked carba-galactosyl moiety; here, the 5a'-oxygen atom of the D-galactopyranose ring of alpha-GalCer is replaced by a methylene group. The alpha-carba-GalCer was more stable and showed higher affinity to the NKT receptor. It thus enhanced and prolonged production of IL-12 and IFN-gamma compared with alpha-GalCer, resulting in augmented NKT cell-mediated adjuvant effects in vivo. The alpha-carba-GalCer, which has an ether linkage, was more resistant to degradation by liver microsomes than was alpha-GalCer, which has an acetal bond. Modulation of the sugar moiety in glycolipids might therefore provide optimal therapeutic reagents for protective immune responses against tumor or pathogens.
- Published
- 2010
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