Interleukin-21 and endothelial dysfunction in hypertension

白细胞介素 21 与高血压内皮功能障碍

基本信息

批准号：
9908443
负责人：
Charles Duncan Smart
金额：
$ 3.02万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9908443
关键词：
Adaptive Immune System Adult Affinity Angiotensin II Autoimmune Diseases Autoimmune Process Automobile Driving B-Lymphocytes BLR1 gene Biological Availability Biological Products CD4 Positive T Lymphocytes Cardiovascular Diseases Cardiovascular system Cells Clinical Diagnosis Disease Endothelium Event Functional disorder Future Goals Heart Helper-Inducer T-Lymphocyte Home environment Human Hypertension Immune system Immunoglobulin Class Switching Incidence Individual Infiltration Inflammatory Infusion procedures Interleukin-17 Kidney Knowledge Location Malignant Neoplasms Mediating Mediator of activation protein Mus Nitric Oxide Organ Outcome Patients Peripheral Play Population Process Production Psoriasis Reactive Oxygen Species Resistant Hypertension Retrospective Studies Risk Factors Role Secondary to Source Stimulus Superoxides Surface T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Tissues United States Vascular Diseases Work base blood pressure reduction blood pressure regulation cardiovascular risk factor cellular targeting chemokine receptor cytokine endothelial dysfunction immune activation improved in vivo insight interleukin-21 mortality novel novel therapeutics programmed cell death protein 1 response secondary lymphoid organ targeted agent targeted treatment therapeutic development

项目摘要

PROJECT SUMMARY Hypertension is the most common primary diagnosis in the United States, and even treated individuals remain at elevated cardiovascular risk, suggesting that current therapeutic options are suboptimal. Emerging evidence implicates activation of the immune system as a central feature of hypertension, particularly CD4+ T helper lymphocytes and T cell-derived cytokines. Hypertension is characterized by infiltration of T lymphocytes into end-organs such as the vasculature, kidney, and heart. Interleukin-21 (IL-21) is a pro-inflammatory cytokine produced by multiple T helper subsets that potentiates IL-17A production by T helper cells. A recently described CD4+ subset of T peripheral helper cells (TPH) cells were shown to produce IL-21 in the context of autoimmune disease. IL-17A is a cytokine known to contribute to immune activation in hypertension and act directly on the endothelium. Preliminary studies have shown that IL-21 deficient mice have a blunted hypertensive response, and neutralization of IL-21 both reverses endothelial dysfunction and lowers blood pressure in mice. This compelling evidence suggest that IL-21 is a key cytokine driving activation of the adaptive immune system and end-organ damage in hypertension; however, which T cell subsets produce IL-21 in hypertension and whether IL-21 acts directly on the endothelium is unknown. This project will (a) test the hypothesis that TPH cells are the primary source of IL-21 in hypertension and that IL-21 producing T cells are sufficient to promote hypertension in vivo, (b) mechanistically determine the role of IL-21 in endothelial dysfunction and (c) evaluate the long-term impact of cytokine-neutralizing therapy on clinical cardiovascular outcomes. The completion of these studies will yield critical insights into the mechanism underlying immune activation in hypertension and identify potential novel cellular targets.

项目摘要高血压是美国最常见的主要诊断，甚至接受治疗的个体仍然存在处于升高的心血管风险，这表明当前的治疗选择是次优的。新兴证据暗示将免疫系统激活作为高血压的主要特征，尤其是CD4+ T助手淋巴细胞和T细胞衍生的细胞因子。高血压的特征是将T淋巴细胞浸润脉管系统，肾脏和心脏等末端。白介素21（IL-21）是促炎性细胞因子由多个T辅助子集生产，可增强T辅助细胞产生IL-17A的生产。最近描述的C的CD4+ TPHERAL辅助细胞（TPH）细胞的CD4+子集显示在自身免疫性疾病。 IL-17a是一种已知的细胞因子，可导致高血压和作用中的免疫激活直接在内皮上。初步研究表明，IL-21缺乏小鼠有钝的小鼠 IL-21的高血压反应和中和逆转均可逆转内皮功能障碍并降低血液小鼠的压力。这种令人信服的证据表明，IL-21是关键的细胞因子驱动激活高血压中的自适应免疫系统和末期损伤；但是，T细胞子集产生IL-21 在高血压以及IL-21是否直接在内皮上起作用是未知的。该项目将（a）测试假设TPH细胞是高血压中IL-21的主要来源，而IL-21产生T细胞是足以促进体内高血压，（b）机械地确定IL-21在内皮中的作用功能障碍和（c）评估细胞因子中和疗法对临床心血管的长期影响结果。这些研究的完成将产生对免疫潜在机制的关键见解高血压激活并鉴定潜在的新细胞靶标。