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

• 批准号: 10897448
• 负责人: Brian Barkley Graham
• 金额: $ 8.25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/10897448
• 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

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）的发病机理中具有重要作用，但是是否是否 炎症是因果关系，是替代触发机制的放大器，或者epiphenomenon尚不清楚。 该领域的先前研究主要集中于先天免疫，无菌模型和单细胞因子或细胞 在没有明确定义的病理学环境的情况下 - 无法解决适应性方面 免疫或先天自适应免疫串扰，导致血管疾病。解决这些 局限性，我们的小组研究了寄生虫血吸虫，这是血吸虫病的原因，这可能是最多的 全球PAH的普遍形式。使用肺肺血吸虫高血压（pH）鼠模型，研究 前期确定了一系列对于pH发展至关重要的机械事件：Th2激活 肺中的CD4 T细胞； CCR2+ LY6C+单核细胞的招募到表达的冒险空间 血小板传播1（TSP-1）; TSP-1在功能上激活潜在的TGF-β，导致血管重塑。 这项建议基于这个基础，现在询问我们的适应性和先天免疫接口 认为是血吸虫 - ph发病机理所必需的。我们将研究扩展到翻译分析 人类生物测量，寻求与PAH存在相关的蛋白质 血吸虫病。该提案将检验以下假设：肺内树突状细胞（DC） 对支持Th2极化的CD4 T细胞的抗原，导致间质激活 释放CCR2配体CCLS 2、7和12的巨噬细胞（IMS），驱动TSP-1+单核细胞募集， TGF-β激活和pH。我们还假设关键蛋白质会增加PAH风险 - 包括CCL2， CCL7，CCL12和TSP-1-可以在人血浆中检测到。我们提出了4个目标。 AIM 1将确定 特异性DC子集Cdc2s的抗原表现是Scistosoma-PH中T细胞激活所必需的。目标2 将确定TH1至TH2注射的平衡是否驱动单核细胞/巨噬细胞和pH表型 血吸虫-ph。 AIM 3将确定tsp1+单核细胞需要IMS释放CCL2/7/12 Scistosoma-ph招募。 AIM 4将识别与受试者PAH开发相关的血浆蛋白 与血吸虫病。通过开发和表征两个人群，将实现这种翻译目标 从巴西的4个临床中心招募的受试者：具有前体状态血吸虫病的受试者 肝病（SCHHSD），他们不太可能在超声心动图筛查的基础上进行PAH， 以及具有正确心脏导管插入式PAH的Schhsd的受试者。这些研究的完成将 导致了解先天和适应性免疫在Scistosoma-Pah的发展中的作用，以及 为完全新颖的方法创造机会诊断和潜在治疗这种疾病。我们建议 鉴定机械蛋白与血液中存在相关的机械蛋白，以支持高危的筛查 低资源地区的受试者。

项目成果

TGF-β activation by bone marrow-derived thrombospondin-1 causes Schistosoma- and hypoxia-induced pulmonary hypertension.

• DOI: 10.1038/ncomms15494
• 发表时间: 2017-05-30
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Kumar R;Mickael C;Kassa B;Gebreab L;Robinson JC;Koyanagi DE;Sanders L;Barthel L;Meadows C;Fox D;Irwin D;Li M;McKeon BA;Riddle S;Dale Brown R;Morgan LE;Evans CM;Hernandez-Saavedra D;Bandeira A;Maloney JP;Bull TM;Janssen WJ;Stenmark KR;Tuder RM;Graham BB
• 通讯作者: Graham BB

A retrospective study of schistosomiasis-associated pulmonary hypertension from an endemic area in Brazil.

巴西血吸虫病流行区与血吸虫病相关的肺动脉高压的回顾性研究。

• DOI: 10.1016/j.ijcha.2019.100387
• 发表时间: 2019
• 期刊: International journal of cardiology. Heart & vasculature
• 作者: Botoni,FernandoAntônio;Marinho,CarolinaCoimbra;Carvalho,ViniciusTostes;Mickael,ClaudiaS;Graham,BrianB
• 通讯作者: Graham,BrianB

Sexual Dimorphism of Dexamethasone as a Prophylactic Treatment in Pathologies Associated With Acute Hypobaric Hypoxia Exposure.

• DOI: 10.3389/fphar.2022.873867
• 发表时间: 2022
• 期刊: FRONTIERS IN PHARMACOLOGY
• 影响因子: 5.6
• 作者: Chanana, Neha;Palmo, Tsering;Sharma, Kavita;Kumar, Rahul;Shah, Bhushan;Mahajan, Sudhanshu;Palleda, Girish M.;Gupta, Mohit D.;Kukreti, Ritushree;Faruq, Mohammad;Thinlas, Tashi;Graham, Brian B.;Pasha, Qadar
• 通讯作者: Pasha, Qadar

Paclitaxel blocks Th2-mediated TGF-β activation in Schistosoma mansoni-induced pulmonary hypertension.

紫杉醇阻断 Th2 介导的 TGF-β 激活曼氏血吸虫诱导的肺动脉高压。

• DOI: 10.1177/2045894018820813
• 发表时间: 2019
• 期刊: Pulmonary circulation
• 影响因子: 2.6
• 作者: Kassa,Biruk;Mickael,Claudia;Kumar,Rahul;Sanders,Linda;Koyanagi,Dan;Hernandez-Saavedra,Daniel;Tuder,RubinM;Graham,BrianB
• 通讯作者: Graham,BrianB

Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension.

• DOI: 10.1172/jci161077
• 发表时间: 2022-05-16
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Bertero, Thomas;Lu, Yu;Annis, Sofia;Hale, Andrew;Bhat, Balkrishen;Saggar, Rajan;Saggar, Rajeev;Wallace, W. Dean;Ross, David J.;Vargas, Sara O.;Graham, Brian B.;Kumar, Rahul;Black, Stephen M.;Fratz, Sohrab;Fineman, Jeffrey R.;West, James D.;Haley, Kathleen J.;Waxman, Aaron B.;Chau, B. Nelson;Cottrill, Katherine A.;Chan, Stephen Y.
• 通讯作者: Chan, Stephen Y.