Regional B Cells Modulate Airway Th2 Responses

区域 B 细胞调节气道 Th2 反应

基本信息

批准号：
7847633
负责人：
Craig Michael Schramm
金额：
$ 19.13万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847633
关键词：
Acute Address Allergic Allergic Reaction Allergic inflammation Animal Diseases Animals Anti-Inflammatory Agents Anti-inflammatory Antigen-Presenting Cells Antigens Asthma B-Lymphocyte Subsets B-Lymphocytes Bone Marrow Bronchoalveolar Lavage Bystander Suppression CD8B1 gene Cell physiology Cell surface Cells Characteristics Chronic Coculture Techniques Complex Confocal Microscopy Cultured Cells Data Dependence Development Disease Eosinophilia Eragrostis Extrinsic asthma Fc Receptor Generations Hilar Human IgE Immunoglobulins Immunologics In Vitro Inflammation Inflammatory Inflammatory Response Interleukin-10 Interleukin-13 Interleukin-4 Interleukin-5 Label Learning Location Lung Lung Inflammation Lymphocyte Lymphocytosis Maintenance Mediating Modeling Mus Nose Organ Ovalbumin Phenotype Play Population Process Production Receptors, Antigen, B-Cell Recovery Regulation Regulatory T-Lymphocyte Research Resolution Role Staging Staining method Stains Structure of parenchyma of lung T-Lymphocyte Th2 Cells Tissues aerosolized airborne allergen airway hyperresponsiveness airway inflammation allergic airway disease allergic airway inflammation base cell type cytokine eosinophil in vivo insight interest lymph nodes mast cell novel prevent public health relevance reconstitution research study response subcutaneous

项目摘要

DESCRIPTION (provided by applicant): Asthma is an inflammatory disease of the airways, involving antigen-presenting cells, T lymphocytes, mast cells and eosinophils. B lymphocytes have traditionally been viewed as target cells for Th2 cytokines; however, emerging evidence suggests that regulatory types of B cells (Breg) can be induced under inflammatory conditions and that these Breg cells can suppress inflammation and/or enhance tolerance. Sensitized mice demonstrate a biphasic response to antigen, with acute exposure eliciting allergic airway disease but chronic exposure resulting in local inhalational tolerance (LIT), with resolution of airway and lung inflammation but persistence of systemic allergic sensitization. A consistent feature of LIT is the persistence of lymphocytes in bronchoalveolar lavage, lung tissue, and hilar lymph nodes (HLN). Some of these lymphocytes are regulatory T cells (Treg), but others are B cells. Based on our preliminary data, we hypothesize that a novel regulatory B-cell phenotype differentiates during the development of LIT in regional tissues, and that this cell regulates local immunologic responses. We propose to identify the B cell subset(s) and their mechanisms that contribute to the development of LIT with the following Specific Aims: 1) Assess phenotypic and functional characteristics of suppressive HLN LIT B cell subset(s); 2) Determine the mechanism(s) underlying LIT HLN B-cell-mediated induction of Treg cells; and 3) Determine if this inhibitory Breg represents recruitment of a pre-existing cell type into the HLNs or conversion from a pre-existing B cell subset. Insights gained from our proposed studies may elucidate important mechanisms underlying LIT and, ultimately, may help us learn how to similarly turn off airway inflammation in human asthmatics. Moreover, results of the above studies will yield new fundamental immunologic insights regarding B-cell regulation of T-cell function, which may have ramifications that extend well beyond asthma. PUBLIC HEALTH RELEVANCE: Allergic mice are able to turn off their asthma. They appear to make a specific type of B lymphocyte that is capable of creating regulatory T lymphocytes, which inhibit airway inflammation. Better understanding of this process in mice may help us to learn how to similarly turn off airway inflammation in human asthmatics.

描述（申请人提供）：哮喘是一种气道炎症性疾病，涉及抗原呈递细胞、T淋巴细胞、肥大细胞和嗜酸性粒细胞。 B 淋巴细胞传统上被视为 Th2 细胞因子的靶细胞；然而，新出现的证据表明，在炎症条件下可以诱导调节类型的 B 细胞 (Breg)，并且这些 Breg 细胞可以抑制炎症和/或增强耐受性。致敏小鼠表现出对抗原的双相反应，急性暴露引起过敏性气道疾病，但慢性暴露导致局部吸入耐受（LIT），气道和肺部炎症消退，但全身过敏致敏持续存在。 LIT 的一个一致特征是支气管肺泡灌洗液、肺组织和肺门淋巴结 (HLN) 中持续存在淋巴细胞。其中一些淋巴细胞是调节性 T 细胞 (Treg)，但其他则是 B 细胞。根据我们的初步数据，我们假设一种新的调节性 B 细胞表型在区域组织中 LIT 的发展过程中分化，并且该细胞调节局部免疫反应。我们建议确定有助于 LIT 发展的 B 细胞亚群及其机制，具体目标如下： 1) 评估抑制性 HLN LIT B 细胞亚群的表型和功能特征； 2) 确定 LIT HLN B 细胞介导的 Treg 细胞诱导机制； 3) 确定这种抑制性 Breg 是否代表将预先存在的细胞类型招募到 HLN 中或从预先存在的 B 细胞亚群进行转化。从我们提出的研究中获得的见解可能会阐明 LIT 的重要机制，并最终可能帮助我们了解如何以类似的方式关闭人类哮喘患者的气道炎症。此外，上述研究的结果将产生关于 B 细胞调节 T 细胞功能的新的基本免疫学见解，其影响可能远远超出哮喘范围。公共卫生相关性：过敏小鼠能够停止哮喘。它们似乎产生一种特定类型的 B 淋巴细胞，能够产生调节性 T 淋巴细胞，从而抑制气道炎症。更好地了解小鼠的这一过程可能有助于我们学习如何类似地关闭人类哮喘患者的气道炎症。