IMMUNOPATHWAYS IN ACUTE CORONARY SYNDROMES

描述(申请人逐字描述)：冠状动脉粥样硬化 可以是一种缓慢进展的良性疾病，也可以引起急性 冠脉综合征，如不稳定心绞痛、心肌梗死和突发 心源性死亡。急性冠脉缺血的主要原因是 动脉粥样硬化斑块合并血栓形成。以下几个因素起了作用 导致斑块侵蚀，但斑块被认为是一个关键因素 组织浸润性巨噬细胞和T淋巴细胞介导的炎症。在……里面 初步研究发现，不稳定型心绞痛患者可 通过一种不寻常的表达来区别于稳定期疾病患者 T淋巴细胞亚群，即CD_4~+CD28~+零T细胞。CD_4~+CD_(28)零T细胞循环 在血液中，释放大量的干扰素-γ，并能激活巨噬细胞 生产急性期蛋白质和促凝血物质。最重要的是， 它们扩张形成大量的克隆种群，可能反映了 持久性抗原，如在慢性感染中。CD4+CD28无效克隆型 致死性皮损渗入“罪魁祸首”而非“非罪魁祸首”病变 心肌梗死。此应用程序建议检查以下假设： 异常的T细胞反应，可能是由微生物抗原驱动的 严重参与斑块不稳定。实验的目的是为了 寻找在动脉粥样硬化中识别的抗原，并研究 斑块中CD4+CD28零T细胞使用的共刺激通路。 具体地说，CD47、血栓反应蛋白和CD36的贡献以及 CD4O-配体相互作用促进CD_4~+CD_(28)零T细胞的相互作用 与动脉粥样硬化相关的细胞将被评估，并可能发挥作用 细胞溶解的CD4+CD28ullT细胞在平滑肌细胞凋亡和CAP中的作用 我们将检查破坏情况。因为CD4+CD28零T细胞是明确的 在正常捐赠者中很少见，我们还将探索这些T细胞是否可以 用于识别有患急性冠状动脉病变风险的无症状个体 对出现在急诊室的患者进行症状和风险分层 急性发作的胸痛。这两项指标的临床意义 源于发现一种新的急性白血病预后标记物的可能性 冠脉综合征和表征分子和途径的相关性 斑块不稳定，为药物和基因治疗提供了许多新的靶点。

DESCRIPTION (the applicant's description 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.