HUMORAL & CELL-MEDIATED IMMUNITY IN DEVELOPMENT OF BRONCHIAL HYPERRESPONSIVENESS

幽默

• 批准号: 3844514
• 负责人: ERWIN W GELFAND
• 金额: --
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3844514
• 关键词: T cell receptor; asthma; athymic mouse; cellular immunity; disease /disorder model; histopathology; humoral immunity; immunoglobulin E; inflammation; laboratory mouse; pathology; plethysmography; respiratory airflow disorder; species difference; tissue /cell culture

Asthma is a disease of the airways, where most patients demonstrate bronchial hyperresponsiveness (BHR) to a range of triggers including drugs such as methacholine. Asthma is most often associated with airway inflammation but the evidence associating asthma with inflammation, albeit compelling, is circumstantial. The long term objectives of this project are to delineate the role of humoral and cell-mediated immunity in the development of BHR, especially the role of IgE antibody and specific T- lymphocyte subsets. Knowledge of the murine immune system, its functional compartmentalization and defined genetic differences in the ability to generate IgE antibodies offers distinct advantages for using this species over other animal models of BHR. We have now developed an experimental model of BHR in mice following exposure to inhaled antigen. In the absence of adjuvant, BALB/c mice develop a brisk IgE antibody response associated with a marked increase in the peri-bronchial associated lymph nodes (PBLN) and numbers of antigen-reactive T cells. Moreover using in vivo (body plethysmography) and in vitro (tracheal smooth muscle contraction) assays, we demonstrate that mice sensitized by inhalation of antigen develop BHR. In this project we will determine the role of local and systemic immunity in the pathogenesis of BHR. We will study the development of BHR in high and low IgE responding mice, in athymic (nude) mice, as well as following adoptive transfer of distinct lymphocyte subsets from previously sensitized animals or antigen-specific T-cell clones of different phenotypes. We will directly delineate the role for IgE antibody in passive transfer experiments as well as determining whether T-cell receptor Vbeta usage is restricted in sensitized or IgE-producing animals. These studies will provide new and important information concerning the role of T-B interactions and IgE in the pathogenesis of BHR.

哮喘是一种呼吸道疾病，大多数患者表现为 支气管高反应性（BHR）对一系列触发因素，包括药物 例如乙酰甲胆碱。 哮喘最常与气道 炎症，但哮喘与炎症有关的证据，尽管 很有说服力是间接证据 该项目的长期目标 是为了描述体液和细胞介导的免疫在免疫系统中的作用。 BHR的发展，特别是IgE抗体和特异性T- 淋巴细胞亚群 了解小鼠免疫系统，其功能 划分和定义的遗传差异的能力， 产生IgE抗体为使用该物种提供了明显的优势 比其他BHR动物模型更好。 我们现在已经开发出一种实验性的 暴露于吸入抗原后小鼠中的BHR模型。 在没有 BALB/c小鼠产生了与佐剂相关的活跃的IgE抗体应答， 支气管周围相关淋巴结（PBLN）显著增加 和抗原反应性T细胞的数量。 此外，使用体内（身体 体积描记法）和体外（气管平滑肌收缩）测定， 我们证明了通过吸入抗原致敏的小鼠发展BHR。 在这个项目中，我们将确定局部和全身免疫的作用， BHR的发病机制。 我们将研究BHR的发展， 和低IgE应答小鼠，无胸腺（裸）小鼠，以及以下 从先前致敏的不同淋巴细胞亚群过继转移 动物或不同表型的抗原特异性T细胞克隆。 我们将 直接描述IgE抗体在被动转移中的作用 实验以及确定T细胞受体V β的使用是否 仅限于致敏或产生IgE的动物。 这些研究将 提供有关T-B作用的新的重要信息 BHR发病机制中的相互作用和IgE。