Nature Medicine
7, 1057 - 1062 (2001)
doi:10.1038/nm0901-1057
Activation of natural killer T cells by  -galactosylceramide treatment prevents the onset and recurrence of autoimmune Type 1 diabetesShayan Sharif1, 9, Guillermo A. Arreaza1, 9, Peter Zucker1, 9, Qing-Sheng Mi1, 9, Jitin Sondhi1, 9, Olga V. Naidenko2, 9, Mitchell Kronenberg2, 9, Yasuhiko Koezuka3, 9, Terry L. Delovitch1, 4, 9, Jean-Marc Gombert5, 6, 9, Maria Leite-de-Moraes7, 9, Christine Gouarin5, 9, Ren Zhu5, 9, Agathe Hameg5, 9, Toshinori Nakayama8, 9, Masaru Taniguchi8, 9, Françoise Lepault7, 9, Agnès Lehuen5, 9, Jean-François Bach5, 9
& André Herbelin5, 91
Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada
2
La Jolla Institute for Allergy and Immunology, San Diego, California, USA
3
Pharmaceutical Research Laboratory, Kirin Brewery Co, Ltd., Gunma, Japan
4
Departments of Microbiology and Immunology, and Medicine, University of Western Ontario, London, Ontario, Canada
5
Institut National de la Santé et de la Recherche Médicale (INSERM), U 25 et Centre de l'Association Claude Bernard, Hôpital Necker, Paris, France
6
Present adress: Laboratoire d'Immunologie, Centre Hospitalier Universitaire de Poitiers-FRE, Poitiers 86000, France
7
Centre National de la Recherche Scientifique (CNRS) UMR 8603, Hôpital Necker, Paris, France
8
Core Research for Evolutional Science and Technology, Chiba University, Chiba, Japan
9
These two groups contributed equally to this study.
Correspondence should be addressed to Terry L. Delovitch del@rri.on.ca or Jean-François Bach bach@necker.frType 1 diabetes (T1D) in non-obese diabetic (NOD) mice may be favored by immune dysregulation leading to the hyporesponsiveness of regulatory T cells and activation of effector T-helper type 1 (Th1) cells1. The immunoregulatory activity of natural killer T (NKT) cells is well documented2,
3, and both interleukin (IL)-4 and IL-10 secreted by NKT cells have important roles in mediating this activity4,
5. NKT cells are less frequent and display deficient IL-4 responses in both NOD mice6,
7 and individuals at risk for T1D (ref. 8), and this deficiency may lead to T1D (refs. 1,6−9). Thus, given that NKT cells respond to the  -galactosylceramide (-GalCer) glycolipid in a CD1d-restricted manner by secretion of Th2 cytokines10,
11,
12, we reasoned that activation of NKT cells by -GalCer might prevent the onset and/or recurrence of T1D. Here we show that -GalCer treatment, even when initiated after the onset of insulitis, protects female NOD mice from T1D and prolongs the survival of pancreatic islets transplanted into newly diabetic NOD mice. In addition, when administered after the onset of insulitis, -GalCer and IL-7 displayed synergistic effects, possibly via the ability of IL-7 to render NKT cells fully responsive to -GalCer. Protection from T1D by -GalCer was associated with the suppression of both T- and B-cell autoimmunity to islet  cells and with a polarized Th2-like response in spleen and pancreas of these mice. These findings raise the possibility that-GalCer treatment might be used therapeutically to prevent the onset and recurrence of human T1D.
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-galactosylceramide prevents autoimmune diabetes in non-obese diabetic mice
