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

描述(申请人提供)：哮喘是一种越来越常见的疾病，人们对其了解很少，也很难管理。目前可用的治疗方法是姑息性的，一些患者需要终生服用。我们的目标是阐明胸腺间质淋巴生成素(TSLP)在哮喘发病机制中的作用，并探索TSLP作为预防和/或控制疾病的新的治疗靶点。基于以下事实，我们假设TSLP是变态反应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可激活CD11c+树突状细胞(DCs)，使CD11c+树突状细胞(DCs)分化为Th2细胞。(2)TSLP在特应性皮炎患者皮损上皮细胞和哮喘患者呼吸道上皮细胞中表达上调。(3)肺组织特异性TSLP表达导致哮喘样疾病，皮肤特异性表达导致特应性皮炎。(4)TSLP受体缺陷(Tslpr-/-)小鼠未能在小鼠哮喘模型中发生哮喘样疾病。基于这些数据，本方案设计的实验旨在：1.明确急性哮喘模型小鼠肺组织TSLP表达的调节。我们将确定是否存在Th2极化的OVA特异的CD4+T细胞和/或OVA负载的DC在OVA攻击时上调气道上皮细胞TSLP的表达。2.应用骨髓嵌合体技术检测TslPr-/-DC在OVA诱导的哮喘模型中的功能损害。我们还将确定DC和CD4+T细胞在TSLP诱导的呼吸道炎症发病机制中的相对作用。3.探索TSLP作为治疗哮喘的新靶点。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的呼吸道炎症。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。项目简介：哮喘是一种越来越常见的疾病，人们对此仍知之甚少，也很难管理。目前可用的治疗方法是姑息性的，一些患者需要终生服用。我们的目标是阐明胸腺间质淋巴生成素(TSLP)在哮喘发病机制中的作用，并探索TSLP作为预防和/或控制疾病的新的治疗靶点。

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.