IMMUNOPATHWAYS IN ACUTE CORONARY SYNDROMES

急性冠状动脉综合征的免疫途径

• 批准号: 6741847
• 负责人: Cornelia M. Weyand
• 金额: $ 37.32万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-05 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6741847
• 关键词: CD40 molecule; CD47 molecule; T lymphocyte; angina pectoris; apoptosis; atherosclerotic plaque; biomarker; clinical research; coronary disorder; disease /disorder etiology; human subject; human tissue; inflammation; leukocyte activation /transformation; macrophage; microorganism antigen; patient oriented research; prognosis; thrombosis; thrombospondins

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.

描述（申请人的逐字描述）：冠状动脉粥样硬化 可能是一种缓慢进展的良性疾病，也可能导致急性 冠状动脉综合征，如不稳定型心绞痛、心肌梗塞和突发心脏病 心源性死亡。急性冠状动脉缺血的主要原因是 动脉粥样硬化斑块叠加血栓形成。有几个因素促成 菌斑侵蚀，但其中一个关键作用归因于菌斑 由组织浸润巨噬细胞和T淋巴细胞介导的炎症。在 初步研究，我们发现不稳定型心绞痛患者可以 与疾病稳定的患者的区别在于异常的表达 T 淋巴细胞亚群，CD4+CD28null T 细胞。 CD4+CD28null T细胞循环 在血液中释放大量IFN-γ，并能激活巨噬细胞 产生急性期蛋白和促凝血物质。最重要的是， 它们扩展形成大量克隆种群，可能反映了 持久性抗原，例如慢性感染。 CD4+CD28无效克隆型 渗透到致命患者的“罪魁祸首”病灶，但不渗透到“非罪魁祸首”病灶 心肌梗塞。本申请旨在检验以下假设： 可能由微生物抗原驱动的异常 T 细胞反应 严重参与斑块不稳定。实验的目的是 寻找在粥样斑块中识别的抗原并研究 斑块中 CD4+CD28null T 细胞使用的共刺激途径。 具体而言，CD47、血小板反应蛋白和 CD36 的贡献 CD4O-配体相互作用促进 CD4+CD28null T 细胞的串扰 将评估与动脉粥样硬化相关的细胞，以及其可能的作用 溶细胞性 CD4+CD28null T 细胞在平滑肌细胞凋亡和帽中的作用 将检查破坏情况。因为 CD4+CD28null T 细胞明确 在正常捐献者中很少见，我们还将探讨这些 T 细胞是否可以 用于识别有患急性冠状动脉风险的无症状个体 综合征并对急诊室就诊的患者进行风险分层 急性发作的胸痛。这两个具体目标的临床意义 源于识别急性急性发作的新预后标记物的潜力 冠状动脉综合征并表征与相关的分子和途径 斑块不稳定性，为药物和基因治疗提供了许多新靶标。