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

NKT细胞加速动脉粥样硬化发展的机制研究

基本信息

批准号：
17590331
负责人：
IWABUCHI Kazuya
金额：
$ 2.24万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590331/
关键词：
atherosclerosis mouse model cardiovascular medicine NKT cells lipopolysaccharide apolipoprotein E CD1d PPARy リポ多糖 CDld 高脂肪食 CD1

项目摘要

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.

1. 以CD1d^<-/->、β_2m^<-/->、Jα18^<-/->或WT小鼠为供体，Ldlr^<-/->小鼠为宿主，建立辐照嵌合体，重建骨髓后给予高脂西餐（WD） 5周，定量动脉粥样硬化病变面积。各供体嵌合体病变面积均较大，β_2m^<-/->> WT = Jα18^<-/->> CD1d^<-/->，血清脂质谱无差异。脂多糖（LPS）治疗加重动脉粥样硬化。为了研究NKT细胞是否参与了这一过程，我们将apoE^<-/->和apoE^<-/-> CD1d^<-/->小鼠用0.5μg/g/周的LPS处理5周。在apoE^<-/->小鼠中观察到疾病发展的加速，这表明NKT细胞是这一过程所必需的。此外，用asialo-GM_1 Ab去除NK细胞后，病变面积减少，表明NK细胞在其中起关键作用。用p -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，当小鼠被喂食WD时，它增加了高密度脂蛋白胆固醇水平和体重。这些现象在cdld7小鼠中未观察到。galcer可能具有ppar - γ样作用。以WT和CD1d^<-/->小鼠为实验对象，用wd喂养观察nkt细胞动力学和功能调节。在WT中，脾脏中NK1.1^+TCRβ^+或α- gc负载的CD1d二聚体^+TCRβ^+细胞减少，IFN-γ产生减少。上清液中卵白蛋白（OVA）和IFN-γ产生的增殖反应降低。延迟型超敏反应（DTH）对OVA的反应也被抑制。在CD1d^<-/->小鼠中未观察到这些对增殖反应和DTH的抑制。