IL-13 Atopic Dermatitis and Its Relationship with the Development of Asthma

IL-13 特应性皮炎及其与哮喘发生的关系

• 批准号: 8072580
• 负责人: TAO ZHENG
• 金额: $ 40.18万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8072580
• 关键词: Allergens; Allergic; Allergic inflammation; Allergic rhinitis; Animal Model; Antigen-Presenting Cells; Asthma; Atopic Dermatitis; Biological Models; Breathing; Breeding; Cancer Center; Characteristics; Chronic; Clinical; Collaborations; Cutaneous; Data; Dermal; Dermatitis; Development; Disease; Disease susceptibility; Dose; Environment; Eosinophilia; Epithelial; Extrinsic asthma; Functional disorder; Genes; Genetic; Human; IL13 gene; IgE; Immune response; Immunity; Immunoglobulins; Immunologics; In Vitro; Inflammation; Inflammatory; Interleukin-13; Interleukin-13 Overexpression; Interleukin-17; Interleukin-4; Interleukin-5; Kinetics; Knock-out; Longitudinal Studies; Lung; Lung Inflammation; Lymphoid Tissue; Mediating; Mediator of activation protein; Metaplasia; Modeling; Molecular; Mucous body substance; Mus; Ovum; Pathogenesis; Pathology; Patients; Peripheral; Phase; Phenotype; Play; Pneumonia; Predisposition; Process; Protocols documentation; Regulation; Role; Site; Skin; Symptoms; T-Lymphocyte; TSLP gene; Testing; Th2 Cells; Tissues; Transgenes; Transgenic Mice; Transgenic Model; United States National Institutes of Health; airway hyperresponsiveness; allergic response; base; cell type; chemokine; cytokine; functional status; genetic variant; intraperitoneal; keratinocyte; mast cell; mouse model; neutralizing antibody; overexpression; peripheral blood; promoter; public health relevance; receptor; research study; response; selective expression; skin disorder; trait

DESCRIPTION (provided by applicant): Atopic dermatitis (AD) has been proposed as the cutaneous manifestation of a systemic disorder that also gives rise to asthma and allergic rhinitis, the so-called "atopic march". AD and other atopic disorders have an overlapping pathogenesis and genetic basis. In addition, AD and asthma share some common immunological features, including elevated IgE, peripheral and lesional eosinophilia, Th2 cytokine elevation, epithelial dysfunction and similar allergenic triggers. Th2 inflammation is an important component in the pathogenesis of both asthma and AD. Interleukin-13, a major Th2 cytokine, is believed to be involved in the pathogenesis of AD. However the precise molecular mechanisms underlying AD still remain elusive and the relationship between AD and asthma is poorly understood. We have recently developed an externally regulatable overexpression transgenic model system in which IL-13 is selectively expressed in the murine skin. In our preliminary studies, expression of IL-13 in the skin causes a chronic pruritic inflammatory skin disease with many characteristics closely resembling those of human atopic dermatitis. Many proinflammatory cytokines are highly upregulated, including IL-17 and TSLP, in the skin. IL-13-induced chronic dermatitis causes a systemic Th2-prone environment. Moreover, IL-13-induced dermatitis is associated with increased pulmonary inflammation, mucus metaplasia and airway hyperresponsiveness to allergen challenges, suggesting that IL-13 induced AD predisposes to an asthma phenotype. From these studies, we hypothesized that IL-13 plays an important role in the pathogenesis of atopic dermatitis and IL-13-induced atopic dermatitis leads to the development of asthma. In this application, we propose to: (1) Further characterize the skin-specific IL-13 transgenic model of AD and define the downstream cellular, molecular, and immunological mechanisms of IL-13-induced AD; (2) Determine if IL-13-induced AD leads to increased susceptibility to the development of allergic phenotype in the lung and the immunological mechanisms that underlie the progression from AD to asthma; and (3) Define the role of TSLP in IL-13 induced AD and in increased susceptibility to the development of allergic response to allergens in the lung. These studies will provide better understanding of the role of IL-13 in the pathogenesis of AD and its relationship with the development of asthma and the cellular and molecular mechanisms underlying these related disorders. PUBLIC HEALTH RELEVANCE Narrative: Atopic dermatitis and asthma are closely related allergic disorders that share many immunological features, including Th2-dominated immunity during the course of the disease. We have developed a mouse model of atopic dermatitis in which IL-13 is targeted to the skin and expression of this major Th2 cytokine causes both atopic dermatitis and asthma-like phenotypes in mice. We propose in this project to utilize this model of "atopic march" to explore the molecular, cellular, and immunological mechanisms that underlie the pathogenesis of atopic dermatitis and its relationship with the development of asthma.

描述（由申请人提供）：特应性皮炎（AD）被认为是一种全身性疾病的皮肤表现，也会引起哮喘和过敏性鼻炎，即所谓的“特应性进行曲”。AD与其他特应性疾病具有重叠的发病机制和遗传基础。此外，AD和哮喘具有一些共同的免疫学特征，包括IgE升高、外周和病灶嗜酸性粒细胞增多、Th2细胞因子升高、上皮功能障碍和类似的过敏原触发因素。Th2炎症是哮喘和AD发病机制的重要组成部分。白细胞介素-13是一种主要的Th2细胞因子，被认为参与了AD的发病机制。然而，阿尔茨海默病的确切分子机制仍然难以捉摸，阿尔茨海默病与哮喘之间的关系也知之甚少。我们最近开发了一种外部可调节的过表达转基因模型系统，其中IL-13在小鼠皮肤中选择性表达。在我们的初步研究中，IL-13在皮肤中的表达引起一种慢性瘙痒性炎症性皮肤病，其许多特征与人类特应性皮炎非常相似。许多促炎细胞因子在皮肤中高度上调，包括IL-17和TSLP。il -13诱导的慢性皮炎导致系统性th2易感环境。此外，IL-13诱导的皮炎与肺部炎症、粘液化生和气道对过敏原的高反应性增加有关，这表明IL-13诱导的AD易患哮喘表型。从这些研究中，我们推测IL-13在特应性皮炎的发病机制中起重要作用，IL-13诱导的特应性皮炎可导致哮喘的发生。在本应用中，我们建议：(1)进一步表征皮肤特异性IL-13转基因AD模型，明确IL-13诱导AD的下游细胞、分子和免疫机制；(2)确定il -13诱导的AD是否会增加肺部过敏表型的易感性，以及AD向哮喘发展的免疫学机制；(3)明确TSLP在IL-13诱导的AD以及对肺部过敏原过敏反应易感性增加中的作用。这些研究将有助于更好地了解IL-13在AD发病机制中的作用及其与哮喘发展的关系，以及这些相关疾病的细胞和分子机制。