Mechanisms of Immune Activation in Hypertension

高血压的免疫激活机制

• 批准号: 10543181
• 负责人: David G Harrison
• 金额: $ 75.15万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543181
• 关键词: Adult; Affect; Antigen-Presenting Cells; Biological Markers; CD8-Positive T-Lymphocytes; Cells; Collaborations; Data; Dendritic Cells; Disease; Experimental Models; Healthcare; Histocompatibility Antigens Class I; Human; Hypertension; IL17 gene; Immunization; Individual; Inflammation; Interferon Type II; Kidney Diseases; Lipids; Major Histocompatibility Complex; Mass Spectrum Analysis; Mitochondria; Mus; Myocardial Infarction; NADPH Oxidase; Natural Immunity; Pathogenicity; Peptides; Process; Proliferating; Proteins; Public Health; Reactive Oxygen Species; Research; Severity of illness; Source; Stroke; T memory cell; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; United States; adaptive immunity; adduct; care burden; hypertensive; immune activation; immunogenic; monocyte; neoantigens; novel; oxidation; prevent; programs; single cell sequencing; translational immunology

PROJECT SUMMARY In recent years, it has become apparent that both innate and adaptive immunity contribute to the genesis of hypertension. We have discovered a novel mechanism that underlies activation of adaptive immunity in hypertension, involving the formation of isolevuglandins (isoLGs) in dendritic cells (DCs) and other antigen presenting cells. These lipid oxidation products adduct to proteins, resulting in formation of neoantigens that are processed and presented by major histocompatibility complexes (MHCs). IsoLG-modified proteins are increased in DCs of both mice and humans with hypertension and drive proliferation of subsets of T cells, particularly CD8+ T cells. In this research program, we are examining mechanisms responsible for formation of isoLGs in DCs. We have evidence that isoLGs are formed as a result of both NADPH oxidase activation and by reactive oxygen species generated by the mitochondria in DCs. Using unique mice we have made we are defining potential immunogenic peptides presented in MHC class 1 and determining if there are different peptides derived from mitochondria versus non-mitochondrial sources. Mass spectroscopy will also be employed to determine if similar isoLG modified peptides are presented by monocytes of humans with hypertension. In parallel studies performed in collaboration with Dr. Simon Mallal, the director of the Translational Immunology Core at Vanderbilt, we are characterizing the alpha and beta chain sequences of T cell receptors (TCRα and TCRβ) in activated T cells of both mice and humans using single cell sequencing. This will allow us to produce surrogate T cells (transfectomas) that can be used to determine their responsiveness to isoLG-modified proteins and peptides presented in MHC class 1 of hypertensive mice. We have recently shown that hypertensive humans have a striking increase in circulating memory T cells that produce IL-17A and IFN-γ compared to matched controls. Data from single cell sequencing will identify the TCRα and TCRβ of these cells and to produce transfectomas expressing these sequences and to determine if they are also responsive to isoLG modified proteins presented in the context of APCs from the same individual. Identifying specific neoantigens in hypertension will provide an enormous advance in understanding this disease. These could serve as biomarkers of disease severity and be used to detect pathogenic T cells in hypertension. Ultimately immunization approaches could be employed to treat or prevent hypertension. Specific therapies to reduce isoLG formation have proven effective in experimental models and have substantial promise for treatment of human hypertension.

项目摘要 近年来，先天免疫和适应性免疫都有助于免疫缺陷的发生， 高血压我们已经发现了一种新的机制，它是适应性免疫激活的基础， 高血压，涉及树突状细胞（DC）和其他抗原中异evuglandins（isoLGs）的形成 递呈细胞。这些脂质氧化产物加合到蛋白质上，导致形成新抗原， 由主要组织相容性复合体（MHC）处理和呈递。IsoLG修饰的蛋白质是 在患有高血压的小鼠和人类的DC中增加，并驱动T细胞亚群的增殖， 特别是CD 8 + T细胞。在这项研究计划中，我们正在研究负责形成的机制， DC中的isoLG。我们有证据表明，isoLG的形成是NADPH氧化酶激活和 由树突状细胞中线粒体产生的活性氧簇。使用我们制造的独特的老鼠， 确定在MHC 1类中呈递的潜在免疫原性肽，并确定是否存在不同的 来源于线粒体的肽与非线粒体来源的肽。质谱也将是 用于确定类似的isoLG修饰的肽是否由具有以下特征的人的单核细胞呈递： 高血压在与Simon Mallal博士合作进行的平行研究中， 在范德比尔特的翻译免疫学核心，我们正在表征T细胞的α和β链序列， 细胞受体（TCRα和TCRβ）在小鼠和人类的活化T细胞中使用单细胞测序。 这将使我们能够产生替代T细胞（转染瘤），可以用来确定它们的功能。 对高血压小鼠MHC 1类中存在的isoLG修饰的蛋白质和肽的反应性。我们 最近表明，高血压患者的循环记忆T细胞显著增加， 产生IL-17 A和IFN-γ。来自单细胞测序的数据将鉴定 本发明的目的在于检测这些细胞的TCRα和TCRβ的表达，并产生表达这些序列的转染瘤，以及确定 它们还对来自同一个体的APC中存在的isoLG修饰的蛋白质有反应。 鉴定高血压中的特异性新抗原将为理解这一点提供巨大的进步 疾病这些可以作为疾病严重程度的生物标志物，并用于检测疾病中的致病性T细胞。 高血压最终，免疫方法可以用于治疗或预防高血压。 减少异LG形成的特定疗法已在实验模型中证明有效， 对治疗人类高血压有很大希望。