Investigating paclitaxel treatment in a pre-clinical model of Schistosoma-pulmonary hypertension

研究血吸虫肺动脉高压临床前模型中的紫杉醇治疗

• 批准号: 9751561
• 负责人: Brian Barkley Graham
• 金额: $ 3.37万
• 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 2019-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751561
• 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; 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; Paclitaxel; Parasites; Parasitic Diseases; Parasitic infection; Pathogenesis; Pathogenicity; Patients; Phenotype; Physiologic intraventricular pressure; Population; Pre-Clinical Model; Predisposition; Process; Production; Publications; Pulmonary Hypertension; Pulmonary artery structure; Rattus; Regulatory T-Lymphocyte; Role; SU 5416; Schistosoma; Schistosoma mansoni; Schistosomiasis; Scleroderma; Series; Signal Transduction; Source; Stimulus; Structure; T-Cell Activation; T-Lymphocyte; T-cell receptor repertoire; Transforming Growth Factor beta; Uncertainty; Vaccination; Vascular Diseases; Vascular remodeling; adaptive immunity; cytokine; egg; experimental study; human disease; immune reconstitution; macrophage; monocyte; mouse model; new therapeutic target; novel strategies; prevent; pulmonary arterial hypertension; recruit; 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.

项目概要/摘要 认识到炎症在肺动脉高压的发病机制中具有重要作用 （PAH）源于自身免疫性疾病和传染病与以下疾病的发展相关的证据： 多环芳烃；炎症可产生实验性肺动脉高压（PH）；血管周围炎症是 存在于人类 PAH 和 PH 动物模型的病理学中。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。之前对角色的研究 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：Th2 和 Th17 细胞 分别对暴露于曲霉菌和长期缺氧的小鼠有害，而调节性 T 细胞 (Treg) 对使用 SU5416 或野百合碱治疗的大鼠具有保护作用。这些数据的翻译应用是 慢性缺氧模型中有限的炎症以及炎症与炎症相关的机制尚不明确，阻碍了这一研究 血管重塑。我们建议用激活特定抗原的相关抗原来询问模型系统 2型免疫；血管周围的隔室，其中有抗原的摄取和呈递、细胞增殖 和招聘；以及涉及 TGF-β1 导致肺动脉重塑的分子机制。我们 采用由寄生虫曼氏血吸虫触发的小鼠模型，该模型再现了以下关键表型 可能是全世界 PAH 最常见的原因。我们的建议旨在确定抗原的确切作用 特异性 CD4 T 细胞作为 IL-4 和 IL-13 的来源；这个群体是如何产生、扩张和激活的；和 它对单核细胞募集和 TGF-β 激活的影响。我们假设接触血吸虫 卵抗原导致克隆性 Th2 CD4 T 细胞活化和增殖，从而产生 IL-4和IL-13；这种原型 Th2 反应会招募 Ly6C+ 单核细胞，导致 TGF-β 驱动的 PH。我们的 总体目标是确定血吸虫PH发病机制的分子机制； 确定针对这种寄生虫病开发免疫疗法的方法，例如疫苗接种；并到 更广泛地确定炎症级联中的新治疗靶点，这也可能适用于 其他炎症驱动的 PAH 病因。具体目标 1 是确定 T 细胞 IL-4 和 IL-13 驱动 血吸虫引起的炎症导致 TGF-β 激活和 PH。为了这个目标，我们将调查 使用一系列系统性方法研究血吸虫PH中Th2激活的CD4 T细胞的必要性和充分性 使用缺陷小鼠和免疫重建进行实验，以精确确定 CD4 衍生的 IL-4/IL- 13 对于 Ly6C+ 单核细胞募集和活性 TGF-β1 过量产生（导致 PH）至关重要。 具体目标 2 是确定抗原呈递细胞摄取的血吸虫抗原， 激活 Schistosoma-PH 中产生致病性、克隆性 IL-4/IL-13 的 CD4 T 细胞。为了这个目标，我们将 识别特定的致病性血吸虫抗原；细胞吸收、处理和呈现血吸虫 激活 CD4 T 细胞的抗原；以及指示克隆选择的 CD4 T 细胞受体 (TCR) 库。