TSLP in Th2 Immunity and Allergic Airway Inflammation

描述（由申请人提供）：哮喘是一种越来越常见的疾病，但人们对其了解甚少且难以控制。在了解环境因素如何与遗传易感性协同作用，导致哮喘和过敏个体中过敏原优先发育和激活Th2细胞方面存在根本差距。我们的长期目标是更好地了解过敏原特异性Th2反应的启动和维持，并确定治疗和预防过敏性疾病的潜在治疗靶点。该应用程序的总体目标是确定tslp介导的Th2敏化和Th2记忆的机制。TSLP在哮喘和特应性皮炎的发病机制中起着至关重要的作用，我们实验室的研究表明，缺乏TSLP受体的小鼠在变应性炎症中受到严重损害，而其他研究也确立了TSLP在人类哮喘和特应性皮炎发病机制中的重要性。根据我们的初步研究，我们的中心假设是树突状细胞和粘膜上皮细胞产生的TSLP作用于dc和CD4+ T细胞，破坏气道粘膜耐受，启动和维持Th2免疫，因此是过敏性疾病的关键调节因子。我们将通过三个具体目标来检验这一假设：1)确定TSLP在气道耐受性破坏中的作用；2)明确树突状细胞产生的TSLP在Th2极化中的作用；3)明确TSLP在Th2记忆细胞产生和维持中的作用。在第一个目标中，我们将研究TSLP如何抑制抗原诱导的调节性T细胞并促进对吸入无害抗原的Th2致敏。在第二个目标中，我们将在骨髓源树突状细胞中使用已经证实的逆转录病毒介导的基因敲低和过表达来研究抗原启动期间TSLP在Th2致敏中的作用。在第三个目标中，我们将过继性转移体外极化Th2细胞，研究TSLP如何影响Th2记忆的产生和维持。我们还将测试TSLP阻断是否能够抑制已经建立的抗原特异性Th2记忆，这是一项具有临床意义的研究。这些问题都没有被探究过。我们提出的研究旨在探索tslp介导的气道耐受性破坏、Th2致敏的启动和Th2记忆的维持，这将有助于更好地了解人类过敏性疾病的发病机制。这项研究的结果不仅对变态反应性疾病病因的科学认识，而且对变态反应性疾病预防和/或治疗的新干预措施的发展具有重要的积极影响。

DESCRIPTION (provided by applicant): Asthma is an increasingly common disease that remains poorly understood and difficult to manage. There is a fundamental gap in understanding how environmental factors acting in concert with genetic predisposition leading to the preferential development and activation of Th2 cells by allergens in asthma and allergic individuals. Our long term goal is to better understand the initiation and maintenance of allergen-specific Th2 responses, and to identify potential therapeutic targets for treatment and prevention of allergic diseases. The overall objective of this application is to determine the mechanism of TSLP-mediated Th2 sensitization and Th2 memory. TSLP is critical in the pathogenesis of asthma and atopic dermatitis as studies in our lab demonstrated that mice deficient in TSLP receptor is greatly impaired in allergic inflammation while others established the importance of TSLP in the pathogenesis of human asthma and atopic dermatitis. Based upon our preliminary study, our central hypothesis is that TSLP produced by dendritic cells and mucosal epithelial cells acts on DCs and CD4+ T cells to breakdown airway mucosal tolerance, initiate and maintain Th2 immunity and is thus a key regulator of allergic diseases. We will test the hypothesis by pursuing three Specific Aims: 1) Define the role of TSLP in the breakdown of airway tolerance; 2) Define the role of dendritic cell produced TSLP in Th2 polarization; and 3) Define the role of TSLP in generation and maintenance of Th2 memory cells. In the first aim, we will study how TSLP suppresses antigen induced regulatory T cells and promotes Th2 sensitization against inhaled harmless antigens. In the second aim, we will use an already proven retrovirus mediated gene knockdown and overexpression in bone marrow derived dendritic cells to study role of TSLP in Th2 sensitization during antigen priming. In the third aim, we will adoptively transfer in vitro polarized Th2 cells to study how TSLP affects the generation and maintenance of Th2 memory. We will also test whether TSLP blockade is able to dampen already established antigen-specific Th2 memory, a study with clinical significance. None of these questions have been explored. Our proposed research to explore TSLP-mediated breakdown of airway tolerance, initiation of Th2 sensitization, and maintenance of Th2 memory will lead to a better understanding of the pathogenesis of human allergic diseases. The results of this study are expected to have an important positive impact not only on the scientific understanding of the etiology of allergic disorders but also on the development of new interventions for the prevention and/or treatment of allergic diseases. PUBLIC HEALTH RELEVANCE: Our proposed research mainly deals with the early steps of allergen sensitization that will advance our understanding of the pathogenesis of asthma and allergy. Studies on the generation and maintenance of Th2 memory, and using antibody blockade to dampen Th2 memory are of clinical relevance which might be translatable to control and/or prevent asthma in humans.