Myeloid-Derived Regulatory Cells in "Atopic March"

项目概述（见说明书）：目的：本研究的总体目标是验证过敏性气道炎症过程中，表皮致敏诱导胸腺基质淋巴生成素（TSLP）的假设，TSLP是皮肤屏障缺陷的细胞因子生物标志物，随后调节自由基产生的气道髓源性调节细胞（MDRC）的募集和功能，MDRC是气道高反应性（AHR）的关键调节剂。拟议的研究可能揭示MDRC与特应性皮炎、过敏性鼻炎和哮喘进展之间的机制，这一概念被称为“特应性进行曲”。具体目的：(1)验证过敏原致敏途径通过自由基依赖机制调节变应性气道炎症期间气道MDRC募集的假设(2)确定皮肤源性或全身TSLP水平的增加是否调节0 2的激活和/或募集。研究设计：在本研究提出的小鼠模型中，表皮或腹腔致敏后鼻内卵清蛋白激发可诱导过敏性气道炎症。MDRC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进行分析和纯化，以确定其募集和功能。基因敲除和自由基途径的药物抑制剂将用于评估自由基介导的MDRC募集调节及其控制T细胞反应和AHR的潜力（由flexivent测量）。TSLP在调节MDRC募集和功能中的作用将通过抗TSLP抗体和组成性表达TSLP的转基因小鼠来描述。理由：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因子。产生no的MDRC抑制02。-产生MDRC增强T细胞反应和气道超反应。免疫抑制和促炎MDRC比例的平衡对炎症的控制至关重要。最近的研究表明，高水平的全身皮肤源性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进入过敏性气道的激活和/或募集中的潜在作用。本研究提出了MDRC在理解皮肤屏障功能障碍与过敏性哮喘发病机制之间关系中的新作用。

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.