Experimental evidence from animal and human studies indicate that activated T lymphocytes and the cytokines they produce are present within atherosclerotic lesions. However there is little information on how atheroma-based T cell mediated responses may be initiated or how they may influence atherogenesis. In this project, we will study the relationship between T cell mediated immune responses and atherogenesis. We will utilize LDL-receptor deficient (LDLR- l-) mice in which atherosclerotic lesions containing T lymphocytes can be induced by high-lipid diet. This model will permit us to apply several sophisticated and well established methods for studying T cell activation and function to the problem of atherosclerosis. Such methods are only feasible with inbred strains of mice. We will focus on three specific issues. First, we will examine how helper T lymphocyte activation and differentiation may be influenced by components of the atheroma environment. Studies will include the analysis of antigen presenting capabilities of foam cells, the influence of products of LDL oxidation on T cell activation, and the effects of foam cells and their products on helper T cell subset differentiation. Second, we will examine if helper T cells, including Th1 and Th2 cells specific for atheroma-associated antigens, can initiate or modify the development of atherosclerosis. We will generate T cell lines specific for form cell antigens and examine their effects upon adoptive transfer into LDLR-l-mice. The cytokine-secretory phenotype of T cells from atherosclerotic lesions will be determined. Cross-breeding of LDLR-l- mice with mice deficient in class II MHC, interferon-gamma, and IL-4 will be performed in order to address the in vivo role of CD4 T cell activation, and Th1 versus Th2 cells on atherosclerotic disease progression. Third, we will address the question of how T lymphocytes get into atherosclerotic lesions. We will focus on the role of adventitial microvascular endothelium on recruitment of T cells to lesions and we will examine if form cell products alter lymphocyte adhesion to endothelium under flow conditions. We will also examine trafficking of helper T cells to atherosclerotic lesions in vivo by adoptively transferring labeled T cell populations which vary in antigen specificity, subset phenotype, and adhesion molecule expression. The results of these studies will determine if T cell responses can influence atherosclerotic disease, and if different helper T cell subsets have qualitatively divergent effects. The information obtained will determine the potential for, and permit the rationale design of, immunomodulatory interventions into atherosclerotic disease.
Showing the most recent 10 out of 139 publications
