Superior protection against malaria and melanoma metastases by a C-glycoside analogue of the natural killer T cell ligand alpha-Galactosylceramide.
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.
Schmieg
John
J
Dept. of Medical and Molecular Parasitology, New York University School of Medicine, 341 E. 25th St., New York, NY 10010. email: moriya.tsuji@med.nyu.edu
Yang
Guangli
G
Franck
Richard W
RW
Tsuji
Moriya
M
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D005699:Galactosylceramides / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008288:Malaria / Q000276:immunology*; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000276:immunology*
D017931:DNA Primers; D005699:Galactosylceramides; D008024:Ligands; D007371:Interferon-gamma