The Journal of Experimental Medicine
StemCell Technologies
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Published 1 December 2003. doi:10.1084/jem.20031192
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© Rockefeller University Press, 0022-1007/2003/12/1631 $5.00
The Journal of Experimental Medicine, Volume 198, Number 11, 1631-1641

Superior Protection against Malaria and Melanoma Metastases by a C-glycoside Analogue of the Natural Killer T Cell Ligand {alpha}-Galactosylceramide

John Schmieg1, Guangli Yang2, Richard W. Franck2 and Moriya Tsuji1,3

1 Department of Medical and Molecular Parasitology, New York University School of Medicine, New York, NY 10010
2 Department of Chemistry, Hunter College, New York, NY 10021
3 Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY 10016

Address correspondence to Moriya Tsuji, Dept. of Medical and Molecular Parasitology, New York University School of Medicine, 341 E. 25th St., New York, NY 10010. Phone: (212) 448-5021; Fax: (212) 263-8116; email: moriya.tsuji{at}med.nyu.edu

{alpha}-Galactosylceramide ({alpha}-GalCer) is a glycolipid that stimulates natural killer T cells to produce both T helper (Th) 1 and Th2 cytokines. This property enables {alpha}-GalCer to ameliorate a wide variety of infectious, neoplastic, and autoimmune diseases; however, its effectiveness against any one disease is limited by the opposing activities of the induced Th1 and Th2 cytokines. Here, we report that a synthetic C-glycoside analogue of {alpha}-GalCer, {alpha}-C-galactosylceramide ({alpha}-C-GalCer), acts as natural killer T cell ligand in vivo, and stimulates an enhanced Th1-type response in mice. In two disease models requiring Th1-type responses for control, namely malaria and melanoma metastases, {alpha}-C-GalCer exhibited a 1,000-fold more potent antimalaria activity and a 100-fold more potent antimetastatic activity than {alpha}-GalCer. Moreover, {alpha}-C-GalCer consistently stimulated prolonged production of the Th1 cytokines interferon-{gamma} and interleukin (IL)-12, and decreased production of the Th2 cytokine IL-4 compared with {alpha}-GalCer. Finally, {alpha}-C-GalCer's enhanced therapeutic activity required the presence of IL-12, which was needed to stimulate natural killer cells for optimal interferon-{gamma} production, but did not affect IL-4. Overall, our results suggest that {alpha}-C-GalCer may one day be an excellent therapeutic option for diseases resolved by Th1-type responses.

Key Words: NKT cell • NK cell • {alpha}-C-galactosylceramide • IFN-{gamma} • IL-12

Abbreviations used in this paper: {alpha}-C-GalCer, {alpha}-C-galactosylceramide; {alpha}-GalCer, {alpha}-galactosylceramide; ICCS, intracellular cytokine staining; NKT cell, natural killer T cell.


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