IMMUNOPATHWAYS IN ACUTE CORONARY SYNDROMES

急性冠状动脉综合征的免疫途径

• 批准号: 6756728
• 负责人: Cornelia M. Weyand
• 金额: $ 3.59万
• 依托单位: MAYO CLINIC ROCHESTER
• 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 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6756728
• 关键词: CD antigens; CD40 molecule; T lymphocyte; angina pectoris; apoptosis; atherosclerotic plaque; biomarker; 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、心肌梗死和突发性 心源性死亡急性冠状动脉缺血的主要原因是 动脉粥样硬化斑块伴血栓形成。几个因素促成了 牙菌斑侵蚀，但一个关键的作用已被归因于牙菌斑 炎症由组织浸润巨噬细胞和T淋巴细胞介导。在 初步研究，我们发现不稳定型心绞痛患者可以 通过表达一种不寻常的 T淋巴细胞亚群，CD 4 + CD 28 null T细胞。CD 4 + CD 28 null T细胞循环 在血液中，释放大量的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， 它们扩展形成大的克隆种群，可能反映了 持久性抗原，如慢性感染。CD 4 + CD 28空克隆型 浸润到“罪犯”而不是“非罪犯”病变患者的致命 心肌梗死本申请提出检验以下假设： 异常的T细胞反应，可能是由微生物抗原驱动的， 与斑块不稳定性密切相关。实验的目的是 寻找动脉粥样硬化中识别的抗原，并研究动脉粥样硬化的发生机制。 斑块中CD 4 + CD 28 null T细胞使用的共刺激途径。 特别是，CD 47、血小板反应蛋白和CD 36以及 CD 4 O-配体相互作用促进CD 4 + CD 28 null T细胞的相互作用 与动脉粥样硬化相关的细胞将被评估，和可能的作用， CD 4 + CD 28 null T细胞在平滑肌细胞凋亡和帽中的作用 销毁将被审查。因为CD 4 + CD 28 null T细胞是明确的， 在正常供体中不常见，我们还将探索这些T细胞是否可以被移植到正常供体中。 用于识别有发生急性冠状动脉疾病风险的无症状个体 综合征，并对急诊室出现的患者进行风险分层， 急性发作性胸痛。这两个具体目标的临床意义 源于有可能确定一种新的急性胰腺炎的预后标志物， 冠状动脉综合征和表征分子和途径与相关的， 斑块不稳定性，为药物和基因治疗提供了许多新的靶点。