IMMUNE DYSREGULATION AND ALLERGIC ASTHMA

SCOR建议的中心假设是， 在过敏性哮喘中， 肺免疫反应吸入抗原，这是依赖于 结合了遗传学、免疫系统的发育阶段 反应，环境影响，和当地的细胞因子环境中， 过敏原初始激发时间。这种失调的免疫反应 导致变应原特异性IL-4和IL-5的局部积累 分泌T细胞（Th 2应答）。IL-4和IL-5促进了 特异性IgE抗体和嗜酸性粒细胞增多症，分别，其次是 支气管炎症伴局部嗜酸性粒细胞、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，将审查 哮喘中免疫调节和炎症的不同方面。每个 项目是一个正在进行的研究的直接延伸，由校长 调查人员都是经验丰富的资深科学家项目1（利普斯科姆） 将研究是什么调节T细胞亚群的发展和交通， 肺中的OVA T细胞受体转基因小鼠模型，相对 IgE和嗜酸性粒细胞在支气管炎症中作用 非转基因小鼠模型，以及类固醇和克罗宁对 改变两种模型中的肺免疫和炎症。计划2 （奥利弗）将剖析细胞内信号通路在人类肥大细胞 细胞和嗜碱性粒细胞，并检查肺内 哮喘患者变应原暴露改变外周血嗜碱性粒细胞 信号和粘合性能。项目3（斯凯勒），临床 该项目将确定哮喘患者的局部肺环境是否 影响对新的空气抗原的反应。该项目还建议 以确定抑制局部炎症是否会改变免疫系统， 对局部滴注或全身给药的反应 新抗原免疫学核心实验室（刘易斯）将集中大多数 所需的大量免疫学检测的建议， 问题研究总的来说，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， 治疗这种疾病的可能的新干预措施。

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.