Mechanisms of Endotoxin-induced Breakdown of Tolerance in the Lung

内毒素引起的肺耐受性破坏的机制

• 批准号: 8202694
• 负责人: Timothy J. Chapman
• 金额: $ 5.01万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8202694
• 关键词: Address; Adjuvant; Adult; Allergens; Allergic; Allergic inflammation; American; Animal Model; Animals; Antigens; Area; Asthma; Blocking Antibodies; Breathing; Chickens; Child; Chronic; Data; Dendritic Cells; Development; Disease; Dose; Effector Cell; Endotoxins; Eragrostis; Failure; Fostering; Generations; Genetic; Human; Hypersensitivity; Immune Tolerance; Immune response; Immune system; Immunology; Inflammation; Inflammatory; Inflammatory Response; Intranasal Administration; Lead; Lipopolysaccharides; Lung; Lung diseases; Maintenance; Methods; Modeling; Mouse Strains; Mus; Ovalbumin; Pathologic; Pneumonia; Population; Process; Publishing; Regulatory T-Lymphocyte; Respiratory Tract Diseases; Risk; Role; Staging; Surface; T cell response; T-Lymphocyte; Testing; Tissues; airway inflammation; allergic response; cytokine; interest; novel; prevent; research study; respiratory; response; therapy development

DESCRIPTION (provided by applicant): Asthma is a debilitating inflammatory disease of the respiratory tract that impacts millions of Americans. Animal models have been useful in defining some of the key mechanisms involved in the development of allergen-specific airway inflammation. While much is currently known about initiation of allergic inflammation in naive animals, it is largely unknown how tolerance is established or breaks down in susceptible hosts. This may be particularly important for understanding late-onset asthma in older children and adults where it is likely that tolerance to allergens pre-dates the initiation of allergic inflammation. We therefore propose to study allergic sensitization in tolerized animals, building on novel preliminary data that shows a dose-dependent effect of LPS in breaking tolerance for the induction of pulmonary inflammation. The breakdown of tolerance in mice after administration of high-dose LPS correlates with a failure of regulatory T cells (Tregs) to accumulate in the lung. We plan to use an established model of inhaled tolerance to characterize both the effector T cell (Teff) and Treg responses in lungs after administration of LPS and model allergen. We then will use blocking antibodies and genetically modified mouse strains to examine the importance of lung accumulation of Tregs to the maintenance of tolerance. Furthermore, we will examine how changes in the composition and magnitude of the inflammatory response to differing doses of LPS alters the ability of adaptive Tregs to counteract ongoing inflammation and prevent generation of a Teff response that promotes allergic inflammation. Results from these studies will increase our understanding of the initiation of allergic responses, and may lead to the development of therapies aimed at the avoidance of early stage processes of asthmatic disease. PUBLIC HEALTH RELEVANCE: Asthma is a chronic inflammatory disease of the lung that is initiated through the failure of immunologic tolerance and induction of an inappropriate immune response to otherwise innocuous allergens. Regulatory T cells (Tregs) that migrate to inflamed tissues have been shown to be important in the maintenance of tolerance, but little is known about the importance of lung Tregs in maintaining tolerance to inhaled allergen exposure, or how this process breaks down in asthma. We propose to study the importance of lung Treg accumulation in the maintenance of tolerance, and hope to discover novel mechanisms involved in allergic sensitization that are translational and beneficial to at-risk human populations.

描述（由申请人提供）：哮喘是一种影响数百万美国人的呼吸道炎症性疾病。动物模型对于定义与过敏原特异性气道炎症发展有关的一些关键机制很有用。虽然目前对幼稚动物的过敏性炎症的开始知之甚少，但在易感宿主中如何建立或分解了耐受性。这对于理解年龄较大的儿童和成年人的晚期哮喘尤其重要，在这种情况下，对过敏原的耐受性可能会预先开始过敏性炎症。 因此，我们建议研究耐受性动物中的过敏敏化，这是基于新的初步数据的基础，该数据显示了LPS在破坏肺部炎症诱导的耐受性方面的剂量依赖性作用。给药高剂量LPS​​后，小鼠耐受性的分解与调节T细胞（Tregs）在肺中积聚的失败相关。我们计划使用已建立的吸入耐受性模型来表征LPS和模型过敏原后肺中肺的效应T细胞（TEFF）和TREG反应。然后，我们将使用阻断抗体和转基因的小鼠菌株来检查Tregs肺积累对维持耐受性的重要性。此外，我们将研究炎症反应对不同剂量LPS​​的组成和幅度的变化如何改变自适应Treg抵消正在进行的炎症并防止产生促进过敏性炎症的TEFF反应的能力。这些研究的结果将提高我们对过敏反应的开始的理解，并可能导致旨在避免早期哮喘疾病过程的疗法的发展。 公共卫生相关性：哮喘是一种肺部的慢性炎症性疾病，是由于免疫耐受性的失败和对其他无害过敏原的不当免疫反应而引发的。已证明迁移到发炎组织的调节性T细胞（Tregs）在维持耐受性中很重要，但是对于肺Treg在维持吸入过敏原暴露的耐受性方面的重要性知之甚少，或该过程如何在哮喘中破裂。我们建议研究肺Treg积累在维持耐受性中的重要性，并希望发现参与过敏性敏化的新型机制，这些机制是转化和对高危人群有益的。