IMMUNE DYSREGULATION AND ALLERGIC ASTHMA

SCOR提议的中心假设是，最初的事件 在过敏性哮喘中是一种不适当的调节(失调) 肺对吸入性抗原的免疫反应，这依赖于 遗传学的结合，免疫的发育阶段 反应、环境影响和当地的细胞因子环境 初始变应原挑战的时间。这种失调的免疫反应 导致局部过敏原特异性IL-4和IL-5的积聚 分泌T细胞(Th2反应)。IL-4和IL-5促进发育 分别是特异性IgE抗体和嗜酸性粒细胞增多症，其次是 支气管炎，局部嗜酸性粒细胞、肥大细胞和 嗜碱性粒细胞；支气管高反应性；以及 哮喘。该提案包括五个项目，这些项目将审查 哮喘的免疫调节和炎症的不同方面。每个人 项目是校长正在进行的研究的直接延伸 调查人员都是经验丰富的资深科学家。项目1(Lipscomb) 将研究是什么调节T细胞亚群的发育和运输 在OVA T细胞受体转基因小鼠模型中肺的相对含量 IgE和嗜酸性粒细胞在慢性支气管炎中的作用 非转基因小鼠模型的建立及类固醇和色甘露的影响 改善两种模型的肺免疫和炎症。项目2 (奥利弗)将剖析人类肥大细胞内的信号通路 细胞和嗜碱性粒细胞，并检验肺内 哮喘患者暴露变应原改变外周血嗜碱粒细胞 信号和粘合剂特性。项目3(Schuyler)，临床 项目，将确定哮喘患者的局部肺环境 影响对新的航空抗原的反应。该项目还提出了 确定抑制局部炎症是否会改变免疫系统 对局部灌输或系统管理的反应 新抗原。免疫学核心实验室(Lewis)将集中大部分 需要进行大量的免疫检测，以满足拟议的 学习。总的来说，这些研究应该提供重要的信息。 关于哮喘的细胞和分子机制，并建议 可能有新的干预措施来治疗这种疾病。

The central hypothesis for this SCOR proposal is that the initial event in allergic asthma is an inappropriately regulated (dysregulated) pulmonary immune response to an inhaled antigen, which is dependent on a combination of genetics, the developmental stage of the immune response, environmental effects, and the local cytokine milieu at the time of initial allergen challenge. This dysregulated immune response results in the local accumulation of allergen-specific IL-4 and IL-5 secreting T cells (a Th2 response). IL-4 and IL-5 enhance the development of specific IgE antibodies and eosinophilia, respectfully, followed by bronchial inflammation with increased local eosinophils, mast cells, and basophils; bronchial hyperresponsiveness; and the clinical expression of asthma. This proposal consists of five projects, which will examine different aspects of immune regulation and inflammation in asthma. Each project is a direct extension of ongoing research by principal investigators who are seasoned senior scientists. Project 1(Lipscomb) will examine what regulates T cell subset development and traffic to lungs in an OVA T cell receptor transgenic mouse model, the relative importance of IgE and eosoinphils on bronchial inflammation in a nontransgenic mouse model, and the effects of steroids and cromolyn on modifying pulmonary immunity and inflammation in both models. Project 2 (Oliver) will dissect intracellular signaling pathways in human mast cells and basophils and examine the hypothesis that intrapulmonary allergen exposure in asthmatics alters peripheral blood basophil signaling and adhesive properties. Project 3 (Schuyler), the clinical project, will determine whether the local lung environment in asthmatics influences the response to new aeroantigens. This project also proposes to determine whether suppressing local inflammation may alter an immune response to either locally instilled or systemically administered neoantigens. An Immunology Core laboratory (Lewis) will centralize most of the large numbers of immunologic assays required for the proposed studies. Collectively, these studies should provide important information about the cellular and molecular mechanisms of asthma and suggest possible new interventions in treating the disease.