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


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.


CONCLUSIONS
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.
Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Prerna
P
Chopra
Philip
P
Diiorio
Steven C
SC
Pino
S Brian
SB
Wilson
Nancy E
NE
Phillips
John P
JP
Mordes
Aldo A
AA
Rossini
Dale L
DL
Greiner
Leonard D
LD
Shultz
Rita
R
Bortell
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control* / Q000821:virology; D004195:Disease Models, Animal; D005260:Female; D005699:Galactosylceramides / Q000378:metabolism* / Q000502:physiology; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D051381:Rats; D012737:Sex Factors; D013154:Spleen / Q000166:cytology / Q000378:metabolism
D005699:Galactosylceramides; C493154:alpha-galactosylceramide; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma