Exploring TSLP as a Key Initiator and Novel Therapeutic Target for Asthma

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DESCRIPTION (provided by applicant): Asthma is an increasingly common disease that remains poorly understood and difficult to manage. Currently available treatments are palliative and require daily administration for life by some patients. Our goal is to elucidate the roles of thymic stromal lymphopoietin (TSLP) in the pathogenesis of asthma and explore TSLP as a novel therapeutic target to prevent and/or control the disease. Base upon the following facts, we hypothesize that TSLP is the key factor in the pathogenesis of allergic diseases and thus serves as candidate therapeutic target for allergy and asthma. (1) TSLP activates CD11c+ dendritic cells (DCs) which in turn prime na¿ve CD4+ T cells to differentiate into Th2 cells. (2) TSLP is up-regulated in epithelial cells of the lesional skins of atopic dermatitis patients as well as airway epithelial cells of asthma patients. (3) Lung-specific TSLP expression leads to an asthma-like disease while skin-specific expression leads to atopic dermatitis. (4) TSLP receptor deficient (Tslpr-/-) mice failed to develop an asthma-like disease in a mouse asthma model. Based on these data, the experiments designed in this proposal is to: 1. Define the regulation of pulmonary TSLP expression in acute mouse asthma model. We will determine whether presence of Th2 polarized OVA-specific CD4+ T cells and/or OVA-loaded DCs could upregulate TSLP expression in airway epithelial cells upon OVA challenge. 2. Define the functional impairment of Tslpr-/- DCs in OVA-induced asthma model through bone marrow chimera technique. We will also determine the relative contributions of DCs and CD4+ T cells in the pathogenesis of TSLP-induced airway inflammation. 3. Explore TSLP as a novel therapeutic target for asthma. Our recent data showed that administration of an anti-TSLP neutralization antibody at both sensitization and challenge could significantly attenuate airway inflammation in a mouse asthma model. We will optimize the use of the antibody and further test whether TSLP neutralization could reverse pre-established airway inflammation and airway hyperresponsiveness in a chronic mouse asthma model, a study with clinical significance. Project Narrative: Asthma is an increasingly common disease that remains poorly understood and difficult to manage. Currently available treatments are palliative and require daily administration for life by some patients. Our goal is to elucidate the roles of thymic stromal lymphopoietin (TSLP) in the pathogenesis of asthma and explore TSLP as a novel therapeutic target to prevent and/or control the disease.