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

描述（由申请人提供）：哮喘是一种越来越常见的疾病，仍然知之甚少，难以管理。目前可用的治疗是姑息性的，并且需要一些患者终身每日施用。本研究旨在阐明胸腺基质淋巴细胞生成素（TSLP）在哮喘发病机制中的作用，并探索TSLP作为预防和/或控制哮喘的新靶点。基于以下事实，我们推测TSLP是过敏性疾病发病机制中的关键因素，因此可以作为过敏和哮喘的候选治疗靶点。(1)TSLP激活CD 11 c+树突状细胞（DC），这反过来又引发幼稚CD 4 + T细胞分化为Th 2细胞。(2)TSLP在特应性皮炎患者的皮损皮肤上皮细胞以及哮喘患者的气道上皮细胞中上调。(3)肺特异性TSLP表达导致哮喘样疾病，而皮肤特异性表达导致特应性皮炎。(4)TSLP受体缺陷（Tslpr-/-）小鼠在小鼠哮喘模型中未能发展成哮喘样疾病。在此基础上，本研究设计了以下实验：1.明确急性哮喘小鼠模型肺TSLP表达的调控。我们将确定Th 2极化的OVA特异性CD 4 + T细胞和/或负载OVA的DC的存在是否能上调OVA攻击后气道上皮细胞中TSLP的表达。2.通过骨髓嵌合体技术明确OVA诱导哮喘模型中Tslpr-/- DCs的功能损害。我们还将确定树突状细胞和CD 4 + T细胞在TSLP诱导的气道炎症发病机制中的相对贡献。3.探索TSLP作为哮喘治疗的新靶点。我们最近的数据显示，在致敏和激发时给予抗TSLP中和抗体可以显著减轻小鼠哮喘模型中的气道炎症。我们将优化抗体的使用，并进一步测试TSLP中和是否可以逆转慢性小鼠哮喘模型中预先建立的气道炎症和气道高反应性，这是一项具有临床意义的研究。项目叙述：哮喘是一种越来越常见的疾病，但仍然知之甚少，难以管理。目前可用的治疗是姑息性的，并且需要一些患者终身每日施用。本研究旨在阐明胸腺基质淋巴细胞生成素（TSLP）在哮喘发病机制中的作用，并探索TSLP作为预防和/或控制哮喘的新靶点。

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.