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.
70% of patients with history of severe AD develop allergic asthma, a phenomenon referred to as atopic march. Understanding the underlying mechanisms could help develop strategies for early treatment of skin barrier defects and block the progression of atopic march in these patients. We propose a novel role for MDRC in the relationship between skin barrier dysfunction and the pathogenesis of allergic asthma.
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