LOCALIZATION OF T-LYMPHOCYTES AND MACROPHAGES EXPRESSING IL-1, IL-2 RECEPTOR, IL-6 AND TNF IN HUMAN AORTIC INTIMA - ROLE OF CELL-MEDIATED-IMMUNITY IN HUMAN ATHEROGENESIS

Recent observations have demonstrated the presence of activated T lymp hocytes and macrophages in human atherosclerotic lesions. Cells found within these lesions produce cytokines that alter vascular homeostasis in a manner that promotes atherogenesis. To elucidate the role of the se immunocompetent cells in human atherosclerosis, the localization of various cytokines with an analysis of immunophenotypic features of th e cellular infiltrates was studied in normal aortas from children; and in later phases of the disease (including fatty streaks and fibrous o r atheromatous plaques). Semi-quantitative analysis of cytokine-expres sing cells was also investigated with serial sectioning. In 4 of 9 you ng subjects, the grossly normal aorta contained relatively cell-rich a reas which were located preferentially around the ostia of intercostal arteries and were composed of isolated or layered T lymphocytes and m acrophages. In these prelesional areas, interleukin-1 (IL-1), IL-2 rec eptor (IL-2R) and tumour necrosis factor (TNF) were detected in the cy toplasm of the infiltrating cells, whereas no detectable reactivity wa s noted for IL-2, IL-6, interferon-gamma (IFN-gamma) or lymphotoxin (L T). In fatty streaks and full-grown atheromas including ''cap'' and '' shoulder'' regions, various numbers of T lymphocytes, macrophages and macrophage foam cells were present. In these lesion areas, especially where the cellular infiltrates were numerous, macrophage foam cells a nd smooth muscle cells expressed not only IL-1 and TNF but also IL-6. The ratio of IL-2R positive cells showed a tendency to decrease with a dvance of the disease process. Electron-microscopic examination of les ion areas demonstrated ultrastructural aspects of the cognate cell-to- cell interaction, as shown by the direct apposition of lymphocytes to macrophages or macrophage foam cells. These results suggest that a spe cific in situ, cell mediated hypersensitivity plays a pivotal role in the nascent as well as the progression stages of human atherosclerosis .