Activation of natural killer T cells by alpha-galactosylceramide treatmentprevents the onset and recurrence of autoimmune Type 1 diabetes

Type 1 diabetes (T1D) in non-obese diabetic (NOD) mice may be favored by im mune dysregulation leading to the hyporesponsiveness of regulatory T cells and activation of effector T-helper type 1 (Th1) cells'. The immunoregulato ry activity of natural killer T (NKT) cells is well documented(2,3) and bot h interleukin (IL)-4 and IL-10 secreted by NKT cells have important roles i n mediating this activity(4,5). NKT cells are less frequent and display def icient IL-4 responses in both NOD mice(6,7) and individuals at risk for T1D (ref. 8), and this deficiency may lead to T1D (refs. 1,6-9). Thus, given t hat NKT cells respond to the alpha -galactosylceramide (alpha -GalCer) glyc olipid in a CD1d-restricted manner by secretion of Th2 cytokines(10-12), we reasoned that activation of NKT cells by alpha -GalCer might prevent the o nset and/or recurrence of T1D. Here we show that alpha -GalCer treatment, e ven when initiated after the onset of insulitis, protects female NOD mice f rom T1D and prolongs the survival of pancreatic islets transplanted into ne wly diabetic NOD mice. In addition, when administered after the onset of in sulitis, alpha -GalCer and IL-7 displayed synergistic effects, possibly via the ability of IL-7 to render NKT cells fully responsive to alpha -GalCer. Protection from T1D by alpha -GalCer was associated with the suppression o f both T- and B-cell autoimmunity to islet beta cells and with a polarized Th2-like response in spleen and pancreas of these mice. These findings rais e the possibility that alpha -GalCer treatment might be used therapeuticall y to prevent the onset and recurrence of human T1D.