Sharif S, Arreaza G A, Zucker P, Mi Q S, Sondhi J, Naidenko O V, Kronenberg M, Koezuka Y, Delovitch T L, Gombert J M, Leite-De-Moraes M, Gouarin C, Zhu R, Hameg A, Nakayama T, Taniguchi M, Lepault F, Lehuen A, Bach J F, Herbelin A
Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario, Canada.
Nat Med. 2001 Sep;7(9):1057-62. doi: 10.1038/nm0901-1057.
Type 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) cells. The immunoregulatory activity of natural killer T (NKT) cells is well documented, and both interleukin (IL)-4 and IL-10 secreted by NKT cells have important roles in mediating this activity. NKT cells are less frequent and display deficient IL-4 responses in both NOD mice 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 alpha-galactosylceramide (alpha-GalCer) glycolipid in a CD1d-restricted manner by secretion of Th2 cytokines, we reasoned that activation of NKT cells by alpha-GalCer might prevent the onset and/or recurrence of T1D. Here we show that alpha-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, 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 of 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 raise the possibility that alpha-GalCer treatment might be used therapeutically to prevent the onset and recurrence of human T1D.
非肥胖糖尿病（NOD）小鼠中的1型糖尿病（T1D）可能因免疫失调而加剧，这种失调会导致调节性T细胞反应低下以及1型效应辅助性T细胞（Th1）激活。自然杀伤T（NKT）细胞的免疫调节活性已有充分记载，NKT细胞分泌的白细胞介素（IL）-4和IL-10在介导这种活性中发挥重要作用。在NOD小鼠和有患T1D风险的个体中，NKT细胞数量较少且IL-4反应不足（参考文献8），这种不足可能导致T1D（参考文献1、6 - 9）。因此，鉴于NKT细胞通过分泌Th2细胞因子以CD1d限制性方式对α-半乳糖神经酰胺（α-GalCer）糖脂作出反应，我们推测α-GalCer激活NKT细胞可能预防T1D的发生和/或复发。在此我们表明，即使在胰岛炎发作后开始进行α-GalCer治疗，也能保护雌性NOD小鼠不患T1D，并延长移植到新患糖尿病的NOD小鼠体内的胰岛的存活时间。此外，在胰岛炎发作后给予α-GalCer和IL-7，二者显示出协同效应，这可能是通过IL-7使NKT细胞对α-GalCer完全反应的能力实现的。α-GalCer对T1D的保护作用与对胰岛β细胞的T细胞和B细胞自身免疫的抑制以及这些小鼠脾脏和胰腺中类似Th2的极化反应有关。这些发现增加了α-GalCer治疗可能用于预防人类T1D发生和复发的可能性。
