DEVELOPMENT OF NEW THERAPY FOR ATHEROSCLEROSIS TARGETING NATURAL KILLER T (NKT) CELLS

研究了cd1限制性自然杀伤T细胞（NKT）在动脉粥样硬化发展中的潜在作用。当喂食致动脉粥样硬化饮食（AD）时，NKT细胞缺陷CD1d^<-/->小鼠的动脉粥样硬化病变明显小于喂食AD的C57BL/6 （WT）小鼠。与正常喂养的WT小鼠相比，ad喂养的WT小鼠给予NKT细胞配体α-半乳糖神经酰胺（α-GalCer）可导致T辅助1 （Th1）移位的细胞因子反应。此外，在动脉粥样硬化早期，反复注射α-GalCer或相关糖脂OCH给载脂蛋白E敲除（apoE^<-7->）的小鼠，与注射对照小鼠相比，损伤区域明显扩大。然而，在疾病晚期（已经形成动脉粥样硬化病变）给apoE^<-/->小鼠α-GalCer对病变面积没有显著影响，但胶原含量显著降低。在ad喂养的WT或apoE^<-/->小鼠中，动脉粥样硬化的发展与动脉粥样硬化壁中Vα14Jα18转录物的存在有关，这表明NKT细胞被招募到这些病变中。巯基乙酸诱导的巨噬细胞与氧化的低密度脂蛋白一起表达增强的CD1d水平，并诱导NKT细胞产生干扰素-γ，一种潜在的促动脉粥样硬化的Th1细胞因子。总的来说，我们得出结论，NKT细胞在小鼠中是促动脉粥样硬化的。

The potential role of CD1d-restricted natural killer T (NKT) cells in the development of atherosclerosis was investigated. When fed an atherogenic diet (AD), NKT cell-deficient CD1d^<-/-> mice had significantly smaller atherosclerotic lesions than AD-fed C57BL/6 (WT) mice. As compared with chow-fed WT mice, administration of the NKT cell ligand α-galactosylceramide (α-GalCer) to AD-fed WT mice resulted in a T helper 1 (Th1)-shifted cytokine response. In addition, repeated injection of α-GalCer or the related glycolipid OCH to apolipoprotein E knockout (apoE^<-7->) mice during the early phase of atherosclerosis significantly enlarged the lesion areas compared to mice injected with vehicle control. However, administration of α-GalCer to apoE^<-/-> mice at the late phase of the disease process (with already established atherosclerotic lesions) exerted no significant influence on the lesion area, but considerably decreased the collagen content. Development of atherosclerosis in either AD-fed WT or apoE^<-/-> mice was associated with the presence of Vα14Jα18 transcripts in the atherosclerotic arterial walls, indicating that NKT cells were recruited to these lesions. Thioglycolate-elicited macrophages pursed with oxidized low-density lipoproteins expressed enhanced CD1d levels and induced NKT cells to produce interferon-γ, a potentially pro-atherogenic Th1 cytokine. Collectively, we conclude that NKT cells are pro-atherogenic in mice.