A study on the mechanism for the acceleration of atherosclerotic development by NKT cells

1.以CD 1d ^<-/->、β_2m^<-/->、Jα18^<-/->或WT小鼠作为供体，Ldlr^<-/->小鼠作为宿主，建立辐射嵌合体，并在骨髓重建后，在高脂肪西方饮食（WD）喂养5周后定量动脉粥样硬化病变面积。各供体嵌合体的病变面积均大于β_2m^<-/->> WT = Jα18^<-/->> CD 1d ^<-/->，而血清脂质谱无差异.脂多糖（LPS）治疗可加重动脉粥样硬化。为了检测NKT细胞是否参与了这一过程，apoE^<-/->和apoE^<-/-> CD 1d ^<-/->小鼠用LPS 0.5μg/g/wk处理5 wk。在apoE^<-/->小鼠中观察到疾病发展的加速，表明NKT细胞对于该过程是必需的。用去唾液酸GM_1抗体去除NK细胞后，病变面积减小，提示NK细胞在其中起着重要作用.用β-半乳糖神经酰胺（13-GalCer）治疗WT小鼠并没有减少动脉粥样硬化病变的面积。然而，它增加高密度脂蛋白胆固醇水平和体重时，小鼠喂养WD。在CD ld 7-小鼠中未观察到这些现象。13-GalCer可能具有PPARγ样作用.用WD喂养WT和CD 1d ^<-/->小鼠，检查NKT细胞动力学和功能调节。在WT中，脾脏中NK 1.1 ^+TCRβ^+或α-GC负载的CD 1d二聚体^+ TCRβ^+细胞以及IFN-γ的产生均减少。对卵清蛋白（OVA）的免疫应答和上清液中IFN-γ的产生减少。对OVA的迟发型超敏反应（DTH）也受到抑制。在CD 1d ^<-/->小鼠中未观察到这些增殖反应和DTH的增加。

1. Irradiation chimeras were established with CD1d^<-/->, β_2m^<-/->, Jα18^<-/->, or WT mice as donors and Ldlr^<-/-> mice as host and atherosclerotic lesion areas were quantified following 5-wk feeding of high-fat, western diet (WD) after reconstitution of bone marrow. The lesion areas were greater in chimeras of each donor as β_2m^<-/->> WT = Jα18^<-/->> CD1d^<-/->, whereas there was no difference in lipid profile in sera.2. Lipopolysaccharide (LPS) treatment aggravates atherosclerosis. To examine whether NKT cells are involved in this process, apoE^<-/-> and apoE^<-/-> CD1d^<-/-> mice were treated for 5 wk with LPS 0.5μg/g/wk. The acceleration of disease development was observed in apoE^<-/-> mice suggesting that NKT cells are necessary for the process. Moreover, the removal of NK cells with asialo-GM_1 Ab reduced the lesion areas, suggesting that NK cells play a critical role.3. Treatment of WT mice with P-galactosylceramide (13-GalCer) did not reduce the areas of atherosclerotic lesions. However, it increased HDL cholesterol level and body weight when mice were fed with WD. These phenomena were not observed in CD ld7-mice. 13-GalCer may possess PPARγ-like action.4. NKT-cell dynamics and functional modulation were examined with WD-feeding on WT and CD1d^<-/-> mice. In WT, the reductions of NK1.1^+TCRβ^+ or α-GC-loaded CD1d dimer^+ TCRβ^+ cells in spleen and of IFN-γ production were demonstrated. Proliferative responses against ovalbumin (OVA) and IFN-γ production in the supernatant were reduced. Delayed type hypersensitivity (DTH) response against OVA was also suppressed. These suppressions in proliferative responses and in DTH were not observed in CD1d^<-/-> mice.