TSLP in Th2 Immunity and Allergic Airway Inflammation

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。在理解环境因素如何与遗传易感性共同作用导致哮喘和过敏性个体中变应原优先发展和激活Th2细胞方面，存在着根本的差距。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。这项应用的总体目标是确定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关键作用，因为我们实验室的研究表明，TSLP受体缺陷的小鼠在过敏性炎症中受到严重损害，而其他研究证实了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CD4T细胞，破坏呼吸道粘膜耐受，启动和维持Th2免疫，因此是变态反应性疾病的关键调节因子。我们将通过三个具体的目标来验证这一假说：1)确定TSLP在气道耐受性崩溃中的作用；2)确定树突状细胞产生的TSLP在Th2极化中的作用；以及3)确定TSLP在Th2记忆细胞的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Th2对吸入无害抗原的敏化。在第二个目标中，我们将利用已经证实的逆转录病毒介导的基因敲除和在骨髓来源的树突状细胞中过表达来研究TSLP在抗原启动过程中Th2增敏中的作用。在第三个目标中，我们将通过体外过继转移极化的Th2细胞来研究TSLP如何影响Th2记忆的产生和维持。我们还将测试阻断TSLP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讨过。我们提出的探索TSLP介导的气道耐受破坏、启动Th2敏化和维持Th2记忆的研究将有助于更好地理解人类变态反应性疾病的发病机制。预计这项研究的结果不仅将对科学理解过敏性疾病的病因产生重要的积极影响，而且将对开发预防和/或治疗过敏性疾病的新干预措施产生重要的积极影响。 公共卫生相关性：我们建议的研究主要涉及过敏原致敏的早期步骤，这将促进我们对哮喘和过敏发病机制的理解。关于Th2记忆的产生和维持，以及利用抗体阻断抑制Th2记忆的研究具有临床意义，可能对控制和/或预防人类哮喘具有临床意义。

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.