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: 9419493
• 负责人: Brian Barkley Graham
• 金额: $ 2.61万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-22 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9419493
• 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; Paclitaxel; Parasites; Parasitic Diseases; Parasitic infection; Pathogenesis; Pathogenicity; Patients; Phenotype; Physiologic intraventricular pressure; Population; Pre-Clinical Model; 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.

项目摘要 /摘要 认识到炎症在肺动脉高压的发病机理中具有重要作用 （PAH）源于证据，表明自身免疫性和感染性疾病与 pah;炎症会产生实验性肺动脉高压（pH）；血管周围注射是 存在于人类PAH的病理学和pH的动物模型中。但是，炎症是否是因果关系 替代触发机制或epiphenomenon的放大器尚不清楚。先前研究该角色 疾病发病机理中T细胞的数据与PAH的数据不清楚：Th2和Th17细胞是 在曲霉暴露和慢性低氧小鼠中有害，而调节性T细胞（Tregs） 在用SU5416或单蛋白治疗的大鼠中保护。这些数据的翻译应用是 在慢性缺氧模型中受到有限炎症的阻碍，将炎症与 血管重塑。我们建议用相关抗原询问模型系统，以激活特定 2型免疫力；血管周室，其中有抗原摄取和表现，细胞增殖 和招募；以及涉及TGF-β1的分子机制，导致肺动脉重塑。我们 员工Mansoni触发的小鼠模型，该模型重现了关键表型 Posal试图确定抗原的精确作用 特定的CD4 T细胞作为IL-4和IL-13的来源；该人群如何产生，扩展和激活；和 它对单核细胞募集和TGF-β激活的影响。我们假设暴露于血吸虫 卵抗原导致克隆性TH2 CD4 T细胞激活和增殖，导致产生 IL-4和IL-13;该原型TH2响应募集LY6C+单核细胞引起TGF-β驱动的pH。我们的 总体目标是确定血吸虫-PH发病机理的基本机制； 确定针对这种寄生疾病的开发免疫疗法（例如疫苗接种）的方法；然后 更广泛地识别炎症级联中的新型热目标，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。在此目标中，我们将调查 使用系统系列的SCISTOSOMA-PH中Th2激活CD4 T细胞的必要性和充分性 缺乏小鼠和免疫宪法的实验，以精确确定CD4衍生的IL-4/IL-是否 13对于LY6C+单核细胞募集和活性TGF-β1的过量生产至关重要，从而导致pH。 具体目的2是确定抗原呈现细胞所吸收的抗原血吸虫抗原 激活致病性克隆性IL-4/IL-13在血吸虫-PH中产生CD4 T细胞。在这个目标中，我们将 鉴定特定的致病血吸虫抗原；细胞占用，加工和呈现血吸虫 抗原激活CD4 T细胞；以及CD4 T细胞受体（TCR）曲目指示克隆选择。