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: 9217202
• 负责人: Brian Barkley Graham
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 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 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9217202
• 关键词: Accounting; Amplifiers; Animal Model; Antigen-Presenting Cells; Antigens; Aspergillus; Autoimmune Diseases; Biological Models; Blood Vessels; CD4 Positive T Lymphocytes; Cell Proliferation; Cells; Chronic; Clinical; Communicable Diseases; Data; Developed Countries; Developing Countries; Development; Disease; Etiology; Exposure to; Fractalkine; Goals; Human Pathology; Hypertension; Hypoxia; Immune; Immune Tolerance; Immune system; Immunity; Immunotherapy; Inflammation; Inflammatory; Interleukin-1; Interleukin-13; Interleukin-4; Link; Lung; Mediating; Modeling; Molecular; Monocrotaline; Mus; Natural Immunity; Parasites; Parasitic Diseases; Parasitic infection; Pathogenesis; Pathogenicity; Patients; Phenotype; Physiologic intraventricular pressure; Population; Predisposition; Process; Production; Publications; Pulmonary Hypertension; Pulmonary Pathology; Pulmonary artery structure; Rattus; Receptor Cell; Recruitment Activity; Regulatory T-Lymphocyte; Role; SU 5416; Schistosoma; Schistosoma mansoni; Schistosomiasis; Scleroderma; Series; Signal Transduction; Source; Stimulus; T-Lymphocyte; Transforming Growth Factor beta; Uncertainty; Vaccination; Vascular Diseases; Vascular remodeling; adaptive immunity; cytokine; egg; experimental study; human disease; macrophage; monocyte; mouse model; new therapeutic target; novel strategies; prevent; pulmonary arterial hypertension; reconstitution; research study; response; uptake

PROJECT SUMMARY / ABSTRACT The recognition that inflammation has important roles in the pathogenesis of pulmonary arterial hypertension (PAH) arises from evidence that autoimmune and infectious diseases are associated with the development of PAH; inflammation can generate experimental pulmonary hypertension (PH); and perivascular inflammation is present in the pathology of human PAH and animal models of PH. However, whether inflammation is causal, an amplifier of alternative triggering mechanisms, or an epiphenomenon remains unclear. Prior studies on the role of T cells in disease pathogenesis have generated data of unclear relevance to PAH: Th2 and Th17 cells are detrimental in Aspergillus-exposed and chronically hypoxic mice, respectively, while regulatory T cells (Tregs) are protective in rats treated with SU5416 or monocrotaline. The translational application of these data is hampered by limited inflammation in the chronic hypoxia model and unclear mechanisms linking inflammation to vascular remodeling. We propose to interrogate a model system with a relevant antigen that activates specific Type 2 immunity; a perivascular compartment in which there is antigen uptake and presentation, cell proliferation and recruitment; and molecular mechanisms involving TGF-β1 resulting in pulmonary artery remodeling. We employ a mouse model triggered by the parasite Schistosoma mansoni, which reproduces key phenotypes of likely the most common cause of PAH worldwide. Our proposal seeks to identify the precise role of antigen- specific CD4 T cells as the source of IL-4 and IL-13; how this population arises, expands, and is activated; and its impact on monocyte recruitment and TGF-β activation. We hypothesize that exposure to Schistosoma egg antigens results in clonogenic Th2 CD4 T cell activation and proliferation, leading to production of IL-4 and IL-13; this prototypic Th2 response recruits Ly6C+ monocytes causing TGF-β-driven PH. Our overall goals are to determine the molecular mechanisms underlying the pathogenesis of Schistosoma-PH; identify approaches to develop immunotherapies, such as vaccination, against this parasitic disease; and to more broadly identify novel therapeutic targets in the inflammatory cascade, which may also be applicable to other inflammation-driven PAH etiologies. Specific Aim 1 is to determine that T cell IL-4 and IL-13-driven inflammation caused by Schistosoma leads to TGF-β activation and PH. In this Aim we will investigate the necessity and sufficiency of Th2-activated CD4 T cells in Schistosoma-PH using a systematic series of experiments with deficient mice and immune reconstitution, to precisely determine whether CD4-derived IL-4/IL- 13 is critical for Ly6C+ monocyte recruitment and the overproduction of active TGF-β1 which results in PH. Specific Aim 2 is to determine the Schistosoma antigen(s) taken up by antigen presenting cells that activate pathogenic, clonogenic IL-4/IL-13 producing CD4 T cells in Schistosoma-PH. In this Aim we will identify specific pathogenic Schistosoma antigens; the cells taking up, processing and presenting Schistosoma antigens to activate CD4 T cells; and the CD4 T cell receptor (TCR) repertoire indicative of clonal selection.

项目总结/摘要 炎症在肺动脉高压发病机制中的重要作用 (PAH)有证据表明，自身免疫性疾病和传染病与以下疾病的发展有关： PAH;炎症可产生实验性肺动脉高压（PH）;血管周围炎症是 在人类PAH和PH动物模型的病理学中存在。然而，炎症是否是因果关系， 替代触发机制的放大器，或附带现象仍不清楚。先前关于作用的研究 T细胞在疾病发病机制中的作用产生了与PAH相关性尚不清楚的数据：Th 2和Th 17细胞 分别在暴露于铜绿假单胞菌和慢性缺氧的小鼠中有害，而调节性T细胞（TCFs） 在用SU 5416或野百合碱处理的大鼠中具有保护作用。这些数据的翻译应用是 慢性缺氧模型中有限的炎症和炎症与 血管重塑我们建议询问一个模型系统与相关抗原，激活特定的 2型免疫;血管周围区室，其中有抗原摄取和呈递，细胞增殖 和募集;以及涉及TGF-β1导致肺动脉重构的分子机制。我们 采用由寄生虫曼氏血吸虫（Schistosoma mansoni）触发的小鼠模型，该模型复制了 可能是全球PAH的最常见原因。我们的建议旨在确定抗原的确切作用- 特异性CD 4 T细胞作为IL-4和IL-13的来源;该群体如何产生，扩增和活化;以及 其对单核细胞募集和TGF-β活化的影响。我们假设接触血吸虫 卵抗原导致克隆性Th 2 CD 4 T细胞活化和增殖，导致产生 IL-4和IL-13;这种原型Th 2应答募集Ly 6C+单核细胞，引起TGF-β驱动的PH。 总体目标是确定血吸虫PH发病机制的分子机制; 确定开发免疫疗法的方法，如疫苗接种，以对抗这种寄生虫病;以及 更广泛地确定炎症级联反应中的新治疗靶点，这也可能适用于 其他炎症驱动的PAH病因。具体目的1是确定T细胞IL-4和IL-13驱动的 血吸虫引起的炎症导致TGF-β活化和PH。 使用一系列系统性研究方法，探讨血吸虫PH患者Th 2活化CD 4 T细胞的必要性和充分性。 用缺陷小鼠和免疫重建进行实验，以精确确定CD 4衍生的IL-4/IL-10是否 13对于Ly 6C+单核细胞募集和导致PH的活性TGF-β1的过度产生至关重要。 具体目的2是确定由抗原呈递细胞摄取的血吸虫抗原， 激活血吸虫PH中产生致病性克隆源性IL-4/IL-13的CD 4 T细胞。为此，我们将 识别特异性致病性血吸虫抗原;细胞摄取、加工和呈递血吸虫 抗原以激活CD 4 T细胞;和指示克隆选择的CD 4 T细胞受体（TCR）库。