Immune Dysregulation in Allergic Asthma

(申请人摘要)此次续签SCOR的指导性假设是 过敏性哮喘是由对过敏原的免疫反应失调引起的。这个 失调的免疫反应启动了一系列级联反应，导致 IgE致敏的肥大细胞和变应原特异性Th2细胞在 气道黏膜、气道高反应性、嗜酸性炎症与气道 粘液细胞化生的重塑。该提案由四个部分组成 项目，每个项目都有一个临床部分和三个支持核心， 包括一个临床核心。利普斯库姆博士的项目建议研究 肺抗原提呈细胞，特别是肺树突状细胞(DC)，在 肺对过敏原的免疫反应。Lipscomb将采用转移T 小鼠变态反应性肺部炎症模型中的细胞克隆和肺树突状细胞 使用人单核细胞来源的DC、人支气管肺泡灌洗液和 这些研究中的支气管镜活检。奥利弗博士的项目将利用她 实验室观察表明，不释放组胺的嗜碱性细胞 继高亲和力IgE受体(FceRI)后，交联性缺乏 酪氨酸激酶，赛克。奥利弗建议确定患有这种疾病的人 这样的“非释放型”嗜碱性粒细胞可以预防哮喘。她还将探索 非释放型嗜碱性粒细胞Syk活性丧失的机制及评估 抗-IgE治疗引起的血清IgE降低是否会导致 FceRI在人肺肥大细胞的表达。斯克拉尔博士的项目将研究 嗜酸性粒细胞优先募集的分子机制 和嗜碱性粒细胞进入哮喘的支气管粘膜。斯克拉尔将使用小说 量化分子亲和力和亲和力变化的技术 参与了细胞间的相互作用，该作用模拟了白细胞与 内皮细胞。Tesfaigzi博士的项目建议研究调解人的角色 在哮喘肺中产生，导致粘液细胞化生。具体来说， Tesfaigzi Win寻求通过抑制正常细胞凋亡发挥作用 促凋亡调节因子Bax在粘液细胞化生中的作用。他将使用一个 创新的小鼠细支气管外植体模型、细胞因子受体和Bax基因敲除 小鼠，人类支气管刷，以及来自哮喘患者和 控制。这四个项目将共同确定涉及 导致哮喘、肺部炎症和支气管哮喘的关键途径 重塑，目标是确定可能的预防或 治疗哮喘。

(Applicant's Abstract) The guiding hypothesis of this SCOR renewal is that allergic asthma results from a dysregulated immune response to allergens. The dysregulated immune response sets in motion a cascade resulting in the accumulation of IgE-sensitized mast cells and allergen-specific Th2 cells in airway mucosa, airway hyperreactivity, eosinophilic inflammation and airway remodeling with mucous cell metaplasia. The proposal consists of four projects, each with a clinical component, and three supporting cores, including a clinical core. Dr. Lipscomb's project proposes to study the role of lung antigen presenting cells, particularly lung dendritic cells (DCs), in pulmonary immune responses to allergens. Lipscomb will adoptively transfer T cell clones and lung DCs in a murine allergic pulmonary inflammation model and use human monocyte-derived DCs, human bronchoalveolar lavage fluids and bronchial biopsies in these studies. Dr. Oliver's project will exploit her laboratory's observation showing that basophils that don't release histamine following high affinity IgE receptor (FceRI) crossing-linking are deficient in the tyrosine kinase, Syk. Oliver proposes to determine whether people with such "non-releaser" basophils are protected from asthma. She will also explore the mechanisms for loss of Syk activity in non-releaser basophils and assess whether decreased serum IgE induced by anti-IgE therapy leads to a decrease in FceRI expression on human lung mast cells. Dr. Sklar's project will examine the molecular mechanisms involved in the preferential recruitment of eosinophils and basophils into the bronchial mucosa in asthma. Sklar will use novel technology to quantify changes in affinity and avidity of the molecules involved in the cell-cell interactions that model leukocyte adhesion to the endothelium. Dr. Tesfaigzi's project proposes to study the role of mediators generated in asthmatic lungs in causing mucous cell metaplasia. Specifically, Tesfaigzi win seek a role for suppression of normal apoptosis by the pro-apoptotic regulator, Bax, in mucous cell metaplasia. He will use an innovative mouse bronchiolar explant model, cytokine receptor and Bax knockout mice, human bronchial brushings, and autopsy tissues from asthmatics and controls. Collectively, the four projects will identify mechanisms involved in critical pathways that lead to asthmatic lung inflammation and bronchial remodeling with the goal of identifying possible targets for prevention or treatment of asthma.