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Superior protection against malaria and melanoma metastases by a C-glycoside analogue of the natural killer T cell ligand alpha-Galactosylceramide.

Schmieg J, Yang G, Franck RW, Tsuji M - J. Exp. Med. (2003)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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

ABSTRACT
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.

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α-C-GalCer protects mice from malaria liver stages in a manner dependent on CD1d, Vα14 NKT cells, and IFN-γ. (a) WT BALB/c mice were treated intraperitoneally with 2 μg of either α-C-GalCer or α-GalCer or with nothing 2 d before challenge with live P. yoelii sporozoites, and checked for malaria liver stage development. (b) CD1d- or Jα18-deficient mice were treated intraperitoneally with 2 μg of either α-C-GalCer or α-GalCer or with nothing 2 d before challenge with sporozoites, and checked for malaria liver stage development. (c) IFN-γ– or IFN-γ receptor–deficient mice were treated intraperitoneally with 2 μg of either α-C-GalCer or α-GalCer or with nothing 2 d before challenge with sporozoites, and checked for malaria liver stage development. (a–c) The results are expressed as the mean ± SD of five mice. In all figures, the data represent one of two or more experiments with similar results.
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fig2: α-C-GalCer protects mice from malaria liver stages in a manner dependent on CD1d, Vα14 NKT cells, and IFN-γ. (a) WT BALB/c mice were treated intraperitoneally with 2 μg of either α-C-GalCer or α-GalCer or with nothing 2 d before challenge with live P. yoelii sporozoites, and checked for malaria liver stage development. (b) CD1d- or Jα18-deficient mice were treated intraperitoneally with 2 μg of either α-C-GalCer or α-GalCer or with nothing 2 d before challenge with sporozoites, and checked for malaria liver stage development. (c) IFN-γ– or IFN-γ receptor–deficient mice were treated intraperitoneally with 2 μg of either α-C-GalCer or α-GalCer or with nothing 2 d before challenge with sporozoites, and checked for malaria liver stage development. (a–c) The results are expressed as the mean ± SD of five mice. In all figures, the data represent one of two or more experiments with similar results.

Mentions: We showed previously that α-GalCer, when administered to mice 2 d before challenge with plasmodial sporozoites, suppressed development of malaria liver stages in a manner dependent on both CD1d-restricted, Vα14+ NKT cells and IFN-γ–IFN-γ receptor signaling (23). To see if α-C-GalCer exhibited a similar behavior, we injected WT mice with either α-GalCer or α-C-GalCer 2 d before challenge with live P. yoelii sporozoites, and measured the degree of liver stage development using a quantitative real-time RT-PCR assay (16). Mice treated with either α-GalCer or α-C-GalCer showed virtually no liver stage development as compared with untreated control mice, showing that α-C-GalCer has in vivo antimalaria activity similar to that of α-GalCer (Fig. 2 a).


Superior protection against malaria and melanoma metastases by a C-glycoside analogue of the natural killer T cell ligand alpha-Galactosylceramide.

Schmieg J, Yang G, Franck RW, Tsuji M - J. Exp. Med. (2003)

α-C-GalCer protects mice from malaria liver stages in a manner dependent on CD1d, Vα14 NKT cells, and IFN-γ. (a) WT BALB/c mice were treated intraperitoneally with 2 μg of either α-C-GalCer or α-GalCer or with nothing 2 d before challenge with live P. yoelii sporozoites, and checked for malaria liver stage development. (b) CD1d- or Jα18-deficient mice were treated intraperitoneally with 2 μg of either α-C-GalCer or α-GalCer or with nothing 2 d before challenge with sporozoites, and checked for malaria liver stage development. (c) IFN-γ– or IFN-γ receptor–deficient mice were treated intraperitoneally with 2 μg of either α-C-GalCer or α-GalCer or with nothing 2 d before challenge with sporozoites, and checked for malaria liver stage development. (a–c) The results are expressed as the mean ± SD of five mice. In all figures, the data represent one of two or more experiments with similar results.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2194137&req=5

fig2: α-C-GalCer protects mice from malaria liver stages in a manner dependent on CD1d, Vα14 NKT cells, and IFN-γ. (a) WT BALB/c mice were treated intraperitoneally with 2 μg of either α-C-GalCer or α-GalCer or with nothing 2 d before challenge with live P. yoelii sporozoites, and checked for malaria liver stage development. (b) CD1d- or Jα18-deficient mice were treated intraperitoneally with 2 μg of either α-C-GalCer or α-GalCer or with nothing 2 d before challenge with sporozoites, and checked for malaria liver stage development. (c) IFN-γ– or IFN-γ receptor–deficient mice were treated intraperitoneally with 2 μg of either α-C-GalCer or α-GalCer or with nothing 2 d before challenge with sporozoites, and checked for malaria liver stage development. (a–c) The results are expressed as the mean ± SD of five mice. In all figures, the data represent one of two or more experiments with similar results.
Mentions: We showed previously that α-GalCer, when administered to mice 2 d before challenge with plasmodial sporozoites, suppressed development of malaria liver stages in a manner dependent on both CD1d-restricted, Vα14+ NKT cells and IFN-γ–IFN-γ receptor signaling (23). To see if α-C-GalCer exhibited a similar behavior, we injected WT mice with either α-GalCer or α-C-GalCer 2 d before challenge with live P. yoelii sporozoites, and measured the degree of liver stage development using a quantitative real-time RT-PCR assay (16). Mice treated with either α-GalCer or α-C-GalCer showed virtually no liver stage development as compared with untreated control mice, showing that α-C-GalCer has in vivo antimalaria activity similar to that of α-GalCer (Fig. 2 a).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus