The evolution of atherosclerotic lesions involves an interaction between four major cell types, endothelial cells (Ecs), smooth muscle cells (SMCs), macrophages (Mphis) and lymphocytes. The contribution of ECs, Mphis and SMCs to lesion development has been characterized extensively, but the role of T-cells is poorly understood. Although these T-cells secrete Interferon (IFN)-gamma, the effect of this potent immunostimulatory cytokine remains controversial. Studies from our laboratory, using a murine model of diet induced atherosclerosis and IFN-gamma receptor (IFNgammaR) defectiv mice, have determined that IFN-gamma is a potent proatherogenic cytokine. These observations also implicate lesional T-cells, a source of this cytokine, in atherogenesis and suggest that a cell mediated immune response may contribute to the pathogeneis of atheroscleotic lesions. In this proposal we plan to examine the potential role of a cell mediated immune response in atherogenesis byh manipulating both the source and targets of IFN-gamma. Specifically, we plan to define the role of IFN-gamma in atherogenesis by examining atherosclerosis prone mice with defective IFN-gamma receptors in greater detail. This will entail establishing mice which are tissue specifically defective in IFN-gamma receptor function in each of the potential target tissues of IFN-gamma during atherogenesis (e.g., macrophages, T-cells, endothelial cells, smooth muscle cells, and hepatocytes). In a complementary set of experiments, to define the role of lymphocytes in atherogenesis, we plan to establish atherosclerosis prone mice which are defective in defined lymphocyte populations (e.g. B-cells, T-cells, CD4 plus and CD8 plus cells). Then we propose to correlate our studies on the role of the immune system in murine atherosclerosis to human disease by examining human lesions iwht a new set of diagnostic T-cell lymphocyte markers we have developed. The proposed aims are closely tied to the major focus of this SCOR, the employment of murine models to study important pathophysiological events in atherogenesis. Moreover, our studies will involve collaborations with each of the other projects and make extensive use of the Molecular Biology and Pathology Cores. For example, we will examine the role of IFN-gamma and lymphocytes in diabetic atherosclerosis (Project 4), and in HDL metabolism (Projects 2 and 3), and LPL action (Projects 2 and 3). These studies are likely to provide novel insight into the role of IFN-gamma and the immune system in human and murine atherosclerosis.
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