2006 Fiscal Year Final Research Report Summary
A study on the mechanism for the acceleration of atherosclerotic development by NKT cells
| Project/Area Number |
17590331
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
IWABUCHI Kazuya Hokkaido Univ., Inst.Genetic Medicine, Associate professor, 遺伝子病制御研究所, 助教授 (20184898)
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| Project Period (FY) |
2005 – 2006
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| Keywords | atherosclerosis / mouse model / cardiovascular medicine / NKT cells / lipopolysaccharide / apolipoprotein E / CD1d / PPARy |
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| Research Abstract |
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.
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