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

基本信息

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
项目类别：
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

项目摘要

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，仍然很难理解且难以管理。在理解环境因素如何与遗传易感性一起起作用的环境因素如何导致过敏原对哮喘和过敏个体中Th2细胞的优先发展和激活。我们的长期目标是更好地了解过敏原特异性TH2反应的启动和维护，并确定潜在的治疗靶标，以治疗和预防过敏性疾病。该应用的总体目的是确定TSLP介导的TH2敏化和TH2记忆的机制。 TSLP在我们实验室的研究中表明，TSLP受体缺乏的小鼠在过敏性炎症中严重损害，而其他人则确立TSLP在人类哮喘和特应性皮炎的发病机构中的重要性。基于我们的初步研究，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DCS和CD4+ T细胞上，可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剂。我们将通过追求三个具体目标来检验假设：1）定义TSLP在气道耐受性崩溃中的作用； 2）定义树突状细胞在Th2极化中产生的TSLP的作用； 3）定义TSLP在TH2存储单元的生成和维护中的作用。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，我们将使用已经经过验证的逆转录病毒介导的基因敲低和骨髓衍生的树突状细胞过表达来研究TSLP在抗原启动过程中TSLP在Th2敏化中的作用。在第三个目标中，我们将在体外极化Th2细胞中传递，以研究TSLP如何影响TH2记忆的产生和维持。我们还将测试TSLP阻滞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。这些问题都没有得到探讨。我们提出的研究旨在探索TSLP介导的气道耐受性，TH2敏化的启动和TH2记忆的维持，将使人们更好地了解人类过敏性疾病的发病机理。预计这项研究的结果不仅对对过敏性疾病的病因的科学理解产生重要的积极影响，而且对预防和/或治疗过敏性疾病的新干预措施的发展也产生了重要的积极影响。