Studies on Immunobiological Mechanisms in Atherogenesis

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(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.