Failure of alpha-galactosylceramide to prevent diabetes in virus-inducible models of type 1 diabetes in the rat.

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CD4-Positive-T-Lymphocytes, CD8-Positive-T-Lymphocytes, Diabetes-Mellitus-Type-1, Disease-Models-Animal, Galactosylceramides, Interferon-gamma, Interleukin-12, Interleukin-4, Mice-Inbred-C57BL, Mice-Inbred-NOD, Rats, Sex-Factors, Spleen

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see Reprint Collection (a pdf is available)

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In Vivo 2009 Mar-Apr; 23(2):195-201.


BACKGROUND: Alpha-galactosylceramide (alpha-GalCer) is an invariant natural killer T (iNKT) cell ligand that prevents type 1 diabetes in NOD mice. However, alpha-GalCer can activate or suppress immune responses, raising concern about its potential use in human diabetes. MATERIALS AND METHODS: To evaluate this therapeutic issue further, BBDR and LEW.1WR1 rats were treated with Kilham rat virus (KRV) plus polyinosinic-polycytidylic acid, with or without alpha-GalCer, and followed for onset of diabetes. RESULTS: alpha-GalCer did not prevent diabetes in inducible rat models. To investigate this discrepancy, we analyzed iNKT cell function. Splenocytes stimulated with alpha-GalCer produced similar levels of IFNgamma in all rat strains, but less than mouse splenocytes. Rat splenocytes stimulated with alpha-GalCer preferentially produced IL-12, whereas mouse splenocytes preferentially produced IL-4. CONCLUSION: alpha-GalCer elicits species-specific cytokine responses in iNKT cells. In humans with type 1 diabetes, differences in iNKT cell responses to stimulation with alpha-GalCer due to age, genetic variability and other factors may influence its therapeutic potential.

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