verbatim): Coronary atherosclerosis can be a slowly progressive rather benign disease, or it can cause acute coronary syndromes such as unstable angina, myocardial infarction, and sudden cardiac death. The major cause of acute coronary ischemia is disruption of atherosclerotic plaque with superimposed thrombosis. Several factors contribute to plaque erosion, but a critical role has been attributed to plaque inflammation mediated by tissue-infiltrating macrophages and T lymphocytes. In preliminary studies, we have found that patients with unstable angina can be distinguished from patients with stable disease by the expression of an unusual subset of T lymphocytes, CD4+CD28null T cells. CD4+CD28null T cells circulate in the blood, release large amounts of IFN-gamma, and can activate macrophages to produce acute phase proteins and procoagulant substances. Most importantly, they expand to form large clonal populations, likely reflecting stimulation by persistent antigen, such as in chronic infection. CD4+CD28null clonotypes infiltrate into """"""""culprit"""""""" but not """"""""non-culprit"""""""" lesions in patients with fatal myocardial infarction. This application proposes to examine the hypothesis that abnormal T-cell responses, possibly driven by microbial antigens, are critically involved in plaque instability. Experiments have been designed to search for the antigens recognized in the atheroma and to investigate the costimulatory pathways used by CD4+CD28null T cells in the plaque. Specifically, the contribution of CD47, thrombospondin, and CD36 and of CD4O-ligand interaction in facilitating the cross talk of CD4+CD28null T cells with atheroma-associated cells will be evaluated, and the possible role of cytolytic CD4+CD28null T cells in smooth muscle cell apoptosis and cap destruction will be examined. Because CD4+CD28null T cells are explicitly infrequent in normal donors, we will also explore whether these T cells can be used to identify asymptomatic individuals at risk to develop acute coronary syndromes and to risk-stratify patients presenting in the emergency room with acute onset chest pain. The clinical significance of these two specific aims stems from the potential to identify a novel prognostic marker for acute coronary syndromes and to characterize molecules and pathways with relevance in plaque instability, providing a host of new targets for drug and gene therapy.
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