Immune Dysregulation in Allergic Asthma

（申请人的摘要）该SCOR更新的指导假设是， 过敏性哮喘是由对过敏原的免疫应答失调引起的。的 失调的免疫反应启动级联反应，导致 IgE致敏的肥大细胞和变应原特异性Th 2细胞在 气道粘膜、气道高反应性、嗜酸性粒细胞炎症和气道 重塑伴粘液细胞化生。该提案包括四个 项目，每个项目都有一个临床组成部分，和三个支持核心， 包括临床核心。Lipscomb博士的项目提议研究 肺抗原呈递细胞，特别是肺树突状细胞（DC）， 肺部对过敏原的免疫反应利普斯科姆将采用转移T 细胞克隆和肺DC在鼠过敏性肺部炎症模型中的作用， 使用人单核细胞衍生的DC、人支气管肺泡灌洗液和 在这些研究中支气管活检。奥利弗博士的项目将利用她 实验室观察显示不释放组胺的嗜碱性粒细胞 在高亲和力IgE受体（FceRI）交联后， 酪氨酸激酶Syk。奥利弗建议， 这样的“非趋化”嗜碱性粒细胞被保护免于哮喘。她还将探索 非嗜碱性粒细胞中Syk活性丧失的机制， 抗IgE治疗诱导的血清IgE降低是否导致 人肺肥大细胞上的FceRI表达。Sklar博士的项目将检查 嗜酸性粒细胞优先募集的分子机制 和嗜碱性粒细胞进入支气管粘膜。Sklar将使用小说 量化分子亲和力和亲合力变化的技术 参与细胞-细胞相互作用，模拟白细胞粘附到 内皮细胞Tesfaigzi博士的项目建议研究调解人的作用 在哮喘的肺中产生，引起粘液细胞化生。具体地说， Tesfaigzi没有寻求抑制正常细胞凋亡的作用， 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 创新小鼠细支气管移植模型、细胞因子受体和Bax基因敲除 小鼠，人支气管刷，以及来自哮喘患者的尸检组织， 对照总的来说，这四个项目将确定涉及以下方面的机制： 导致哮喘性肺部炎症和支气管炎的关键途径 重塑，目的是确定可能的预防目标， 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.