Myeloid-Derived Regulatory Cells in "Atopic March"

“特应性行军”中的骨髓源性调节细胞

• 批准号: 8538754
• 负责人: Jessy Satyadas Deshane
• 金额: $ 3.88万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538754
• 关键词: Allergens; Allergic; Allergic rhinitis; Antibodies; Asthma; Atopic Dermatitis; Biological Markers; Bronchoalveolar Lavage; Cells; Defect; Early treatment; Equilibrium; Extrinsic asthma; Free Radicals; Functional disorder; Genetic; Goals; Inflammation; Instruction; Knock-out; Link; Lung; Lymphoid; Measures; Mediating; Mus; Myelogenous; Organ; Ovalbumin; Pathogenesis; Pathway interactions; Patients; Population; Recording of previous events; Regulation; Research; Research Design; Role; Route; Skin; Structure of parenchyma of lung; T cell response; Testing; Time; Transgenic Mice; airway hyperresponsiveness; allergic airway inflammation; antigen challenge; cytokine; inhibitor/antagonist; intraperitoneal; mouse model; novel; skin disorder

PROJECT SUMMARY (See instructions): Objective: The overall goal of this proposal is to test the hypothesis that during allergic airway inflammation, epicutaneous sensitization induces Thymic Stromal Lymphopoeitin (TSLP), a cytokine biomarker for skin barrier defects, which then regulates the recruitment and function of free radical producing-airway myeloid - derived regulatory cells (MDRC), that are critical modulators of airway hyper-responsiveness (AHR). The proposed studies may uncover mechanisms linking MDRC and progression of atopic dermatitis to allergic rhinitis to asthma, the concept called "atopic march". Specific Aims: (1) To test the hypothesis that route of allergen sensitization modulates the recruitment of airway MDRC during allergic airway inflammation via free radical dependent mechanisms (2)To determine whether increase in skin-derived or systemic TSLP levels regulates the activation and/or recruitment of 0 2 . - producing MDRC into allergic airway s and promotes AHR Research Design: Epicutaneous or intraperitoneal sensitization followed by intranasal challenge with ovalbumin induces allergic airway inflammation in the mouse model proposed in this study. MDRC will be analyzed and purified from bronchoalveolar lavage, lung tissue and secondary lymphoid organs at different time points following intranasal antigen challenge to determine their recruitment and function. Genetic knockouts and pharmacologic inhibitors of free radical pathways will be utiized to assess the free-radical mediated regulation of recruitment of MDRC and their potential to control T cell responses and AHR (measured by flexivent). The role of TSLP in modulating recruitment and function of MDRC will be delineated using anti-TSLP antibodies in conjunction with transgenic mice constitutively expressing TSLP. Rationale: Sub populations of NO- and 02.-producing mouse lung MDRC are master regulators of allergic airway inflammation. NO-producing MDRC suppress while 02.-producing MDRC enhances T cell responses and airway hyper-responsiveness. A balance in the ratio of immunosupressive and proinflammatory MDRC is critical for the control of inflammation. Recent studies indicate that high systemic levels of skin-derived TSLP is sufficient to render airway s hypersensitive to allergens. Studies to date have not investigated the potential role of TSLP in regulating the activation and/or recruitment of MDRC into allergic airway s. This study proposes a novel role for MDRC in understanding the relationship between skin barrier dysfunction and the pathogenesis of allergic asthma.

项目摘要（见说明）：目的：本提案的总体目标是检验以下假设：在过敏性气道炎症期间，表皮致敏诱导胸腺基质细胞生成素（TSLP），一种皮肤屏障缺陷的细胞因子生物标志物，其然后调节产生自由基的气道髓源性调节细胞（MDRC）的募集和功能，是气道高反应性（AHR）的关键调节剂。这项研究可能揭示MDRC与特应性皮炎、过敏性鼻炎和哮喘进展之间的联系机制，即所谓的“特应性进展”。具体目标：（1）验证过敏原致敏途径通过自由基依赖性机制调节过敏性气道炎症过程中气道MDRC的募集。（2）确定皮肤来源或全身TSLP水平的增加是否调节0 2的激活和/或募集。- 在过敏性气道中产生MDRC并促进AHR研究设计：在本研究中提出的小鼠模型中，表皮或腹膜内致敏后用卵清蛋白鼻内激发诱导过敏性气道炎症。将在鼻内抗原激发后的不同时间点从支气管肺泡灌洗液、肺组织和次级淋巴器官中分析和纯化MDRC，以确定其募集和功能。自由基途径的基因敲除和药理学抑制剂将用于评估自由基介导的MDRC募集调节及其控制T细胞应答和AHR（通过flexivent测量）的潜力。TSLP在调节MDRC的募集和功能中的作用将使用抗TSLP抗体结合组成型表达TSLP的转基因小鼠来描述。依据：NO-和02.-的亚群产生小鼠肺MDRC是过敏性气道炎症的主要调节剂。NO生成MDRC抑制，而02.-产生MDRC增强T细胞应答和气道高应答性。免疫抑制和促炎MDRC的比例平衡对于控制炎症至关重要。最近的研究表明，高全身水平的皮肤来源的TSLP足以使气道对过敏原过敏。迄今为止的研究尚未调查TSLP在调节MDRC活化和/或募集到过敏性气道中的潜在作用。这项研究提出了一个新的作用MDRC在了解皮肤屏障功能障碍和过敏性哮喘的发病机制之间的关系。