T-cell subsets as CVD risk factors in CHS and MESA

T 细胞亚群作为 CHS 和 MESA 的 CVD 危险因素

• 批准号: 8890872
• 负责人: Bruce M Psaty
• 金额: $ 70.8万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8890872
• 关键词: Adoption; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Atherosclerosis; Biological Assay; Biological Markers; Biological Products; Biology; Blood Vessels; CD14 gene; CD28 gene; CD3 Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cardiovascular system; Cell Density; Cell Proliferation; Cells; Chronic; Clinical Trials; Cohort Studies; Coronary; Coronary heart disease; Cryopreserved Cell; Data; Data Analyses; Development; Disease; Evaluation; Event; FCGR3B gene; Flow Cytometry; Funding; Future; Goals; Health; IL2RA gene; Immune; Immune Targeting; Immune response; Immune system; Incidence; Individual; Inflammatory; Inflammatory Response; Interferons; Interleukin-17; Interleukin-4; Kidney Diseases; LDL Cholesterol Lipoproteins; Lipids; Low-Density Lipoproteins; Lymphocyte; Lymphocyte Subset; Malignant Neoplasms; Medicine; Memory; Modeling; Molecular; Morbidity - disease rate; Myocardial Infarction; NCAM1 gene; National Heart, Lung, and Blood Institute; Natural Immunity; Natural Killer Cells; Outcome; Participant; Patients; Pharmaceutical Preparations; Physicians; Pilot Projects; Play; Population; Primary Prevention; Process; Regulatory T-Lymphocyte; Research; Rheumatoid Arthritis; Risk; Risk Factors; Role; Sampling; Smooth Muscle Myocytes; Specific qualifier value; Stroke; Study Subject; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Th1 Cells; Th2 Cells; Therapeutic; Time; Variant; adaptive immunity; atherogenesis; cardiovascular disorder risk; cardiovascular health; case finding; cohort; density; design; disorder prevention; drug development; follow-up; immune activation; improved; monocyte; mortality; novel; novel therapeutic intervention; population based; primary outcome; prospective; response to injury; senescence; theories

DESCRIPTION (provided by applicant): The dramatic decline in the morbidity and mortality associated with atherosclerotic cardiovascular disease (CVD) in the last 50 years is attributable in part to the identification of risk factors, the development of relevant therapies, their evaluaton in clinical trials, and the widespread adoption of those treatments by patients and physicians. Prospective cohort studies have provided some of the most reliable evidence about whether risk factors are likely to be a cause or a consequence of disease. Among individuals with the same levels of traditional risk factors, the risk of CVD varies widely, and part of this variation in evnt rates is likely to be the result of inter-individual variation in the type and intensity of the innte and adaptive- immune inflammatory responses that influence the development and progression of atherosclerosis. Advances in vascular biology have identified the specific roles that various lymphocyte subsets have in the chronic inflammatory disease called atherosclerosis. The goal of this research is to evaluate prospectively whether the densities of specific lymphocyte subsets are novel independent risk factors for the incidence of myocardial infarction (MI) and the composite of MI and new-onset angina (ANG). The proposed case- cohort study is nested within the Cardiovascular Health Study (CHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Several pilot studies have demonstrated that the cryopreserved samples from CHS and MESA are well suited to the study aims. Using flow cytometry to characterize the innate and adaptive-immune lymphocytes from cryopreserved cells (1998-99 in CHS and 2000-02 in MESA), we will assay 16 different lymphocyte subsets in 1200 MESA and 1200 CHS participants. With adjustment for multiple testing, the primary aim is to evaluate the association of each of the 16 lymphocyte subsets with the two primary outcomes, MI and the composite of first MI and new-onset ANG. The 16 lymphocyte subsets cluster into three groups: 1) high levels of pro-inflammatory cells with direct roles in atherosclerosis will increase the risk of CVD events 2) high levels of chronic adaptive-immune activation will increase the risk of CVD events; and 3) high levels of anti-inflammatory cells with antiatherogenic activity will decrease the risk of CVD events. All the T-cell subsets in Group 1, for instance, have a direct role in atherogenesis, plaque progression or plaque instability: indeed, in the vessel wall, they are not biomarkers, but the active agents of atherosclerosis. The proposed case-cohort study in a primary-prevention population will enable us to evaluate the associations of 16 lymphocyte subsets not only with incident coronary events but also with other outcomes. The study has excellent power. Although treatments targeting the immune system have improved the therapeutic options for serious conditions such as rheumatoid arthritis and cancer, the development and use of immune-related therapies in cardiovascular medicine awaits further discovery. Findings from this case-cohort study may yield novel immune targets and new therapeutic approaches.

描述（由申请人提供）：过去 50 年来，与动脉粥样硬化性心血管疾病 (CVD) 相关的发病率和死亡率急剧下降，部分原因在于危险因素的识别、相关疗法的开发、临床试验中的评估以及患者和医生广泛采用这些疗法。前瞻性队列研究提供了一些关于危险因素是否可能是疾病的原因或后果的最可靠的证据。在传统危险因素水平相同的个体中，心血管疾病的风险差异很大，这种事件发生率的差异可能是个体间影响动脉粥样硬化发生和进展的内在和适应性免疫炎症反应的类型和强度差异的结果。血管生物学的进展已经确定了各种淋巴细胞亚群在称为动脉粥样硬化的慢性炎症性疾病中的特定作用。本研究的目的是前瞻性评估特定淋巴细胞亚群的密度是否是心肌梗死（MI）以及MI和新发心绞痛（ANG）复合发病的新的独立危险因素。拟议的病例队列研究属于心血管健康研究（CHS）和动脉粥样硬化多种族研究（MESA）。多项试点研究表明，CHS 和 MESA 的冷冻保存样本非常适合研究目标。使用流式细胞术来表征冷冻细胞（CHS 中的 1998-99 年和 MESA 中的 2000-02）的先天性和适应性免疫淋巴细胞的特征，我们将检测 1200 名 MESA 和 1200 名 CHS 参与者中的 16 种不同的淋巴细胞亚群。通过对多项测试进行调整，主要目的是评估 16 个淋巴细胞亚群中的每一个与两个主要结果（MI 以及首次 MI 和新发 ANG 的复合结果）之间的关联。这 16 种淋巴细胞亚群分为三组：1）在动脉粥样硬化中具有直接作用的高水平促炎细胞会增加 CVD 事件的风险；2）高水平的慢性适应性免疫激活会增加 CVD 事件的风险； 3）高水平的具有抗动脉粥样硬化活性的抗炎细胞将降低CVD事件的风险。例如，第 1 组中的所有 T 细胞亚群在动脉粥样硬化形成、斑块进展或斑块不稳定中具有直接作用：事实上，在血管壁中，它们不是生物标志物，而是动脉粥样硬化的活性剂。拟议的初级预防人群病例队列研究将使我们能够评估 16 种淋巴细胞亚群不仅与冠状动脉事件的关联，而且还与其他结果的关联。研究具有极好的威力。尽管针对免疫系统的治疗已经改善了类风湿性关节炎和癌症等严重疾病的治疗选择，但心血管医学中免疫相关疗法的开发和使用还有待进一步发现。该病例队列研究的结果可能会产生新的免疫靶点和新的治疗方法。