Activation, Phenotype and Function of CD4 T Cells in Schistosoma-Pulmonary Hypertension

血吸虫肺动脉高压中 CD4 T 细胞的激活、表型和功能

基本信息

批准号：
10685442
负责人：
Brian Barkley Graham
金额：
$ 57.46万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-15 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685442
关键词：
Address Affect Amplifiers Animal Model Antigen Presentation Antigens Area Autoimmune Diseases Automobile Driving Blood Blood Vessels Blood specimen Brazil CCL2 gene CCL7 gene CD4 Positive T Lymphocytes Cardiac Catheterization Procedures Cells Circulation Clinical Communicable Diseases Country Dendritic Cells Development Diagnosis Diagnostic tests Disease Echocardiography Equilibrium Event Exposure to Foundations Fractalkine Future Helminths Human Hypoxia ITGAM gene Immune Immune Tolerance Immune system Individual Inflammation Inflammatory Interleukin-1 Ligands Lung Macrophage Modeling Mus Natural Immunity Parasites Parasitic infection Pathogenesis Pathology Patients Phenotype Plasma Plasma Proteins Population Populations at Risk Predisposition Proteins Public Health Pulmonary Hypertension Resource-limited setting Risk Role SU 5416 Schistosoma Schistosomiasis Series Source Specimen Sterility T-Cell Activation Testing Thrombospondin 1 Transforming Growth Factor beta Vaccines Vascular Diseases Vascular remodeling Work adaptive immunity cell type clinical center cohort cross immunity cytokine diagnostic biomarker disease diagnosis experimental study interstitial monocyte mouse model novel diagnostics novel strategies prevent pulmonary arterial hypertension pulmonary vascular disorder recruit screening vascular inflammation

项目摘要

Summary/Abstract Inflammation has important roles in the pathogenesis of pulmonary arterial hypertension (PAH), but whether inflammation is causal, an amplifier of alternative triggering mechanisms, or an epiphenomenon remains unclear. Prior studies in this area have largely focused on innate immunity, sterile models, and single cytokines or cells in the absence of a well-defined pathobiological context—approaches that cannot address aspects of adaptive immunity or innate-adaptive immunity crosstalk which contribute to vascular disease. To address these limitations, our group studies the parasite Schistosoma, the cause of schistosomiasis which may be the most prevalent form of PAH worldwide. Using a Schistosoma-pulmonary hypertension (PH) murine model, studies in the prior period identified a series of mechanistic events which are critical for PH development: Th2-activation of CD4 T cells in the lungs; which recruit of CCR2+ Ly6c+ monocytes to the adventitial space that express thrombospondin-1 (TSP-1); and the TSP-1 functionally activates latent TGF-β, causing vascular remodeling. This proposal builds on this foundation by now interrogating adaptive and innate immune interfaces that we believe to be necessary to Schistosoma-PH pathogenesis. We extend our studies to translational analysis of human biospecimens, seeking proteins that correlate with PAH presence in an at-risk group with severe schistosomiasis. This proposal will test the hypothesis that intrapulmonary dendritic cells (DCs) present Schistosoma antigen to CD4 T cells which support Th2 polarization, causing activation of interstitial macrophages (IMs), who release the CCR2 ligands CCLs 2, 7 and 12, driving TSP-1+ monocyte recruitment, TGF-β activation, and PH. We also hypothesize that key proteins that increase risk of PAH—including CCL2, CCL7, CCL12, and TSP-1—can be detected in human plasma. We propose 4 Aims. Aim 1 will determine that antigen presentation by a specific DC subset, cDC2s, is required for T cell activation in Schistosoma-PH. Aim 2 will determine if the balance of Th1 to Th2 inflammation drives monocyte/macrophage and PH phenotypes in Schistosoma-PH. Aim 3 will determine that CCL2/7/12 release by IMs is required for TSP1+ monocyte recruitment in Schistosoma-PH. Aim 4 will identify plasma proteins associated with PAH development in subjects with schistosomiasis. This translational Aim will be achieved by developing and characterizing two cohorts of subjects recruited from 4 clinical centers in Brazil: subjects with the precursor condition schistosomiasis hepatosplenic disease (SchHSD) who are unlikely to have PAH on the basis of echocardiography screening, and subjects with SchHSD who have right heart catheterization-confirmed PAH. Completion of these studies will lead to understanding the role of innate and adaptive immunity in the development of Schistosoma-PAH, and create opportunities for entirely novel approaches to diagnosing and potentially treating this disease. We propose to identify mechanistic proteins which correlate with disease presence in blood, facilitating screening of at-risk subjects in low-resource areas.

摘要/摘要炎症在肺动脉高压（PAH）的发病机制中具有重要作用，但是否炎症是因果关系、替代触发机制的放大器，还是尚不清楚的附带现象。该领域的先前研究主要集中在先天免疫、无菌模型和单一细胞因子或细胞在缺乏明确的病理生物学背景的情况下，无法解决适应性问题的方法免疫或先天适应性免疫串扰会导致血管疾病。由于局限性，我们小组研究寄生虫血吸虫，血吸虫病的病因可能是最常见的使用血吸虫肺动脉高压 (PH) 小鼠模型进行的全球多环芳烃 (PAH) 的流行形式。前期确定了一系列对 PH 发展至关重要的机制事件：Th2 激活肺部 CD4 T 细胞将 CCR2+ Ly6c+ 单核细胞募集至表达的外膜腔血小板反应蛋白-1 (TSP-1)；并且 TSP-1 功能性地激活潜在的 TGF-β，引起血管重塑。该提案建立在这个基础上，现在询问适应性和先天免疫界面，我们我们相信这对于血吸虫-PH 发病机制是必要的，我们将我们的研究扩展到了转化分析。人类生物样本，寻找与重度高危人群中 PAH 存在相关的蛋白质该提案将检验肺内树突状细胞（DC）存在的假设。 CD4 T 细胞的血吸虫抗原支持 Th2 极化，导致间质激活巨噬细胞 (IM)，释放 CCR2 配体 CCL 2、7 和 12，驱动 TSP-1+ 单核细胞募集， TGF-β 激活和 PH 我们还采用了增加 PAH 风险的关键蛋白质，包括 CCL2、 CCL7、CCL12 和 TSP-1 可在人血浆中检测到，我们提出 4 个目标 1 将确定这一点。 Schistosoma-PH 中的 T 细胞激活需要特定 DC 亚群 cDC2 的抗原呈递。将确定 Th1 与 Th2 炎症的平衡是否驱动单核细胞/巨噬细胞和 PH 表型 Schistosoma-PH 目标 3 将确定 TSP1+ 单核细胞需要 IM 释放 CCL2/7/12。 Schistosoma-PH 中的招募将鉴定与受试者 PAH 发展相关的血浆蛋白。这一转化目标将通过开发和表征两个群体来实现。从巴西 4 个临床中心招募的受试者：患有血吸虫病前兆的受试者根据超声心动图筛查不太可能患有 PAH 的肝脾疾病 (SchHSD)，患有右心导管检查证实 PAH 的 SchHSD 受试者将完成这些研究。导致了解先天性和适应性免疫在血吸虫-PAH 发展中的作用，以及我们建议为诊断和治疗这种疾病的全新方法创造机会。识别与血液中疾病存在相关的机械蛋白，促进高危人群的筛查资源匮乏地区的科目。