ASTHMA, ALLERGIC AND IMMUNOLOGIC DISEASES COOP RES CTR

描述（改编自申请人的摘要）：细胞因子作用于 调节免疫和炎症细胞在所有阶段的活动 免疫系统的反应。 调查人员的总体目标是 了解促炎和特应性细胞因子 调节宿主对病原体和环境抗原的反应。 这 该项目特别关注细胞因子调节的两个领域， 与超敏反应的发生和表达有关。 的 第一个问题涉及在小鼠中超敏反应的初始诱导， 表皮和促炎细胞因子IL-1-β（IL-1b）的作用 和作为致敏介质的光敏素-α（LTa）。 第二 涉及Th 1和Th 2细胞协同作用以建立 实验性小鼠气道嗜酸性粒细胞炎症反应 超敏反应 这些调查建立在校长的基础上， 研究者长期以来对分子生物学 IL-1和LT的遗传学和细胞生理学，以及他强大的临床 作为该司司长， 华盛顿大学过敏和免疫学教授。 目标1建立在 初步数据表明，接触性超敏反应是 在携带IL-1b和LTa基因靶向无效突变的小鼠中消融 并研究了这些细胞因子在细胞活化过程中的表达， 接触性超敏反应以及它们如何反过来调节额外的下游 反应中的效应器机制。 它特别面向 了解表皮细胞凋亡作为一个触发因素的作用， 暴露于致敏剂后IL-1b的释放。 目标2如下 根据申请人使用卵清蛋白的鼠模型的初始数据 （OVA）诱导的气道超敏反应，已经证明， Th 2细胞在这种超敏反应的早期进入肺部， 表明这些 细胞类型在病理性嗜酸性粒细胞的募集中协同作用 气道炎症反应。 Th 1和Th 2在传统上 被认为是反调节和对抗性的。 申请人 我建议研究这两种细胞 在超敏反应的发展中起协同作用。 项目互动：这些目标将通过持续的 与AAIDCRC其他成员的互动。 尤其是墨菲医生 （项目2）是Th 1领域国际公认的学者， Th 2表型发育。 他在这方面的经验和许多 他开发的试剂和方法将证明表型的发展。 他 他在这一领域的经验以及他开发的许多试剂和方法 将被证明对目标2非常有用。 Unanue博士（项目3）和Dr. 卓别林和他的同事一起工作了近10年，研究了 IL-1和Unanue博士使用中和抗细胞因子的经验 研究抗体在体内的生理功能将加强 这类实验的应用。 横山博士的加入 （项目4）将支持努力确定纳戈尔诺-卡拉巴赫的作用 细胞作为这些超敏反应的调节器。

Description (adapted from the applicant's Abstract): Cytokines act to modulate the activities of immune and inflammatory cells during all stages of the immune response. The overall goal of the investigators is to understand the mechanisms by which proinflammatory and atopic cytokines modulate the host response to pathogens and environmental antigens. This project focuses particularly on two areas of cytokine regulation as they relate to development and expression of hypersensitivity responses. The first concerns the initial induction of hypersensitivity responses in the epidermis and the role of the proinflammatory cytokines IL-1-beta (IL-1b) and lymphotoxin-alpha (LTa) as mediators of sensitization. The second concerns the mechanism by which Th1 and Th2 cells synergize to establish eosinophilic inflammatory responses in experimental murine airway hypersensitivity. These investigations build on the Principal Investigator's long standing productive investigations of the molecular genetics and cellular physiology of IL-1 and LT, and on his strong clinical interest in asthma and hypersensitivity diseases as Director of the Division of Allergy and Immunology at Washington University. Aim 1 builds on preliminary data indicating that the contact hypersensitivity response is ablated in mice carrying targeted null mutations in the IL-1b and LTa genes and investigates the expression of these cytokines during activation of contact hypersensitivity and how they in turn modulate additional downstream effector mechanisms in the response. It is particularly oriented to understanding the role of epidermal cell apoptosis as a trigger for the release of IL-1b following exposure to sensitizing agents. Aim 2 follows from the applicants initial data using the murine model of ovalbumin (OVA)-induced airway hypersensitivity which have demonstrated that both Th1 and Th2 cells enter the lung early in this hypersensitivity response, and suggest that these cell types synergize in the recruitment of the pathological eosinophilic inflammatory response in the airway. The Th1 and Th2 have traditionally been thought to be counter-regulatory and antagonistic. The applicants propose to investigate the mechanisms by which these two types of cells synergize in the development of the hypersensitivity response. Program Interactions: These Aims will be facilitated by sustained interactions with other members of the AAIDCRC. In particular, Dr. Murphy (Project 2) is an internationally recognized scholar in the field of Th1 and Th2 phenotype development. His experience in this area and the many reagents and methods he has developed will prove phenotype development. His experience in this area and the many reagents and methods he has developed will prove exceptionally useful for Aim 2. Dr. Unanue (Project 3) and Dr. Chaplin have worked together for nearly 10 years studying the physiology of IL-1, and Dr. Unanue's experience in the use of neutralizing anti-cytokine antibodies to study physiological functions in vivo will strengthen the application of these types of experiments. The addition of Dr. Yokoyama (Project 4) to the AAIDCRC will support efforts to determine the role of NK cells as regulators of these hypersensitivity responses.