TSLP in Th2 Immunity and Allergic Airway Inflammation

TSLP 在 Th2 免疫和过敏性气道炎症中的作用

• 批准号: 8416424
• 负责人: BAOHUA ZHOU
• 金额: $ 35.83万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416424
• 关键词: Affect; Allergens; Allergic; Allergic Disease; Allergic inflammation; Allergic rhinitis; Animals; Antibodies; Antigens; Asthma; Atopic Dermatitis; Bone Marrow; Breathing; CD4 Positive T Lymphocytes; Cells; Data; Dendritic Cells; Development; Disease; Dose; Environmental Risk Factor; Epithelial Cells; Etiology; Extrinsic asthma; Generations; Genes; Genetic Predisposition to Disease; Goals; Health; Human; Hypersensitivity; Immune response; Immunity; In Vitro; Individual; Laboratories; Lead; Maintenance; Mediating; Memory; Modeling; Mus; Pathogenesis; Play; Prevalence; Prevention; Preventive Intervention; Regulatory T-Lymphocyte; Research; Retroviridae; Role; Signal Transduction; Societies; TNFSF5 gene; TSLP gene; Testing; Th2 Cells; Wild Type Mouse; Work; allergic airway inflammation; allergic response; base; clinically relevant; clinically significant; cytokine; human TSLP protein; in vivo; innovation; memory recall; overexpression; prevent; public health relevance; receptor; response; therapeutic target

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.

描述（由申请人提供）：哮喘是一种日益常见的疾病，人们对其了解甚少且难以治疗。对于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 细胞的理解存在根本性差距。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。本申请的总体目标是确定 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至关重要，因为我们实验室的研究表明，缺乏 TSLP 受体的小鼠在过敏性炎症中受到极大损害，而其他人则确立了 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，破坏气道粘膜耐受性，启动和维持Th2免疫，因此是过敏性疾病的关键调节因子。我们将通过追求三个具体目标来检验这一假设：1）定义 TSLP 在气道耐受性崩溃中的作用； 2）定义树突状细胞产生的TSLP在Th2极化中的作用； 3) 定义 TSLP 在 Th2 记忆细胞的生成和维持中的作用。第一个目标是，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 对吸入的无害抗原的敏化。在第二个目标中，我们将使用已被证实的逆转录病毒介导的骨髓源性树突状细胞中的基因敲低和过度表达来研究 TSLP 在抗原引发过程中 Th2 致敏中的作用。第三个目标，我们将通过体外极化的Th2细胞过继转移来研究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讨过。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。这项研究的结果预计不仅会对过敏性疾病病因学的科学理解产生重要的积极影响，而且还会对预防和/或治疗过敏性疾病的新干预措施的开发产生重要的积极影响。