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Studies on Immunobiological Mechanisms in Atherogenesis

动脉粥样硬化形成的免疫生物学机制研究

基本信息

批准号：
07457047
负责人：
WATANABE Teruo
金额：
$ 4.67万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

项目摘要

(1) To elucidate the role of T cell-macrophage interactions in atherogeness we studied the distribution pattern of T cells and macrophages in T cell-depleted athymic homozygous (rnu/rnu) rats fed a cholesterol-enriched diet. In comparison with run/・・・rats, the lesion development was limited in size. whereas foam cell transformation of intimal macrophages was more prominent in rnu/rnu rats. (2) We found that cells from the family of antigen presenting dendritic cells reside in the intima of large arteries. These vascular dendritic cells (VDC) are common in atherosclerotic lesions, and express CDla and S-100. Present ultrastructural examination disclosed in the cytoplasm of VDC Birbeck granule-like structures that are uniquely present in Langerhans cells. Further studies using Lag antibody. which specifically stains Bioreck granules and Biobeck granule-associated structures in Langerhans cells demonstrated that Lag-positive cells were found in the aortic wall. The findings obtained mayimply that mechanisms of antigen presentaion migh be similar to those involved in atherosclerosis. (3) We demonstrated that ICAM-1 expression is up-regulated in the lesionprone areas of aorta in diet-induced hypercholesterolemic rats. Increased expression of [CAM-1 was associated with enhanced macrophage intimal recruitment. Injection of anti-ICAM-1/LFA-1 mab reduced macrophage adherence and their migration into the intima. These results suggest that the ICAM-1/LFA-1 pathway is involved in macrophage-endothelial cell interactions during the early stage of cholesterol-induced atherogenesis. (4) Using a three dimensional culture model simulating in vivo arterial intima. we provided evidence that nLDLs and oxidized LDLs may act as a potential mediator for the increased release of ET-1 in hyperlipidemia and atherosclerosis.

(1)为了阐明T细胞-巨噬细胞相互作用在动脉粥样硬化形成中的作用，我们研究了T细胞耗竭无胸腺纯合子（rnu/rnu）大鼠中T细胞和巨噬细胞的分布模式，这些大鼠喂食富含胆固醇的饮食。与run/··大鼠相比，病变发展的大小有限。而rnu/rnu大鼠内膜巨噬细胞的泡沫细胞转化更为显著。(2)我们发现，来自抗原呈递树突状细胞家族的细胞存在于大动脉的内膜中。这些血管树突状细胞（VDC）在动脉粥样硬化病变中是常见的，并且表达CDla和S-100。目前的超微结构检查在VDC Birbeck颗粒样结构的细胞质中揭示了这种结构，这种结构独特地存在于朗格汉斯细胞中。使用Lag抗体的进一步研究。其特异性染色朗格汉斯细胞中的Bioreck颗粒和Biobeck颗粒相关结构，证明在主动脉壁中发现了Lag阳性细胞。这些发现可能暗示抗原呈递的机制可能与动脉粥样硬化的机制相似。(3)我们证明，ICAM-1的表达上调，在病变的主动脉在饮食诱导的高胆固醇血症大鼠的地区。CAM-1表达的增加与巨噬细胞内膜募集的增强有关。注射抗ICAM-1/LFA-1单抗可减少巨噬细胞粘附及其向内膜的迁移。这些结果表明，ICAM-1/LFA-1途径参与巨噬细胞-内皮细胞相互作用的早期阶段，胆固醇诱导的动脉粥样硬化。(4)采用模拟在体动脉内膜的三维培养模型。我们提供的证据表明，nLDL和氧化LDL可能作为一个潜在的介质，增加释放的ET-1在高脂血症和动脉粥样硬化。