Failure of alpha-galactosylceramide to prevent diabetes in virus-inducible models of type 1 diabetes in the rat
Department of Medicine, Division of Diabetes; Department of Medicine, Division of Endocrinology and Metabolism
Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Diabetes Mellitus, Type 1; Disease Models, Animal; Female; Galactosylceramides; Interferon-gamma; Interleukin-12; Interleukin-4; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Rats; Sex Factors; Spleen
Life Sciences | Medicine and Health Sciences
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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Citation: In Vivo. 2009 Mar-Apr;23(2):195-201.