Myeloid-Derived Regulatory Cells in "Atopic March"

项目摘要(参见说明书)：目的：这项建议的总体目标是验证这样一种假设，即在过敏性呼吸道炎症过程中，皮肤表面致敏诱导胸腺基质淋巴生成素(TSLP)，这是皮肤屏障缺陷的细胞因子生物标志物，然后调节产生自由基的呼吸道髓系来源的调节细胞(MDRC)的招募和功能，而MDRC是呼吸道高反应性(AHR)的关键调节因子。这项拟议的研究可能会揭示MDRC与特应性皮炎、过敏性鼻炎和哮喘的进展之间的联系，这一概念被称为特应性进行曲。具体目的：(1)验证变应原致敏途径通过自由基依赖机制调节过敏性气道炎症过程中MDRC的募集的假说(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。-将MDRC产生到过敏性呼吸道S并促进AHR研究设计：在本研究提出的小鼠模型中，经皮或腹膜内致敏，然后用卵清蛋白鼻腔激发诱导过敏性呼吸道炎症。在鼻腔抗原攻击后的不同时间点，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。自由基通路的基因敲除和药物抑制将被用来评估自由基介导的MDRC招募的调节，以及它们控制T细胞反应和AHR(由FLEVIVENT测量)的潜力。TSLP在调节MDRC的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。原理：产生NO和02的小鼠肺MDRC亚群是过敏性呼吸道炎症的主要调节因子。产生NO的MDRC抑制，而产生02的MDRC增强T细胞反应和呼吸道高反应性。免疫抑制和促炎MDRC的比例平衡对于控制炎症是至关重要的。最近的研究表明，全身高水平的皮源性TSLP足以使S呼吸道对变应原过敏。到目前为止，还没有研究TSLP在调节MDRC的激活和/或募集到过敏性呼吸道S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的关系的新角色。

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.