ASTHMA, ALLERGIC AND IMMUNOLOGIC DISEASES COOP RES CTR

描述(改编自申请者摘要)：细胞因子作用于 在各个阶段调节免疫细胞和炎症细胞的活动 对免疫反应的影响。调查人员的总体目标是 了解促炎性和特应性细胞因子的作用机制 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，因为它们 与超敏反应的发展和表达有关。这个 第一个涉及的是在体内最初诱导的过敏反应。 表皮与促炎细胞因子IL-1-β的作用 淋巴毒素-α(LTA)作为致敏介质。第二 涉及Th1和Th2细胞协同建立的机制 实验性小鼠气道嗜酸性炎症反应的研究 过敏症。这些调查是建立在主要的 研究人员对分子的长期富有成效的研究 IL-1和LT的遗传学和细胞生理学及其强大的临床 作为该司司长，对哮喘和过敏性疾病感兴趣 华盛顿大学过敏和免疫学教授。AIM 1建立在 初步数据表明，接触过敏反应是 携带IL-1b和LTA基因靶向零突变的小鼠的消融 并研究了这些细胞因子在活化过程中的表达。 接触性过敏性及其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触发因素的作用 暴露于致敏剂后IL-1b的释放。接下来是目标2 从申请者使用卵白蛋白小鼠模型的初始数据 (OVA)诱导的呼吸道超敏反应，已证明Th1 在这种超敏反应中，Th2细胞很早就进入了肺部， 这表明这些 不同细胞类型在病理性嗜酸性粒细胞募集中的协同作用 呼吸道的炎症反应。Th1和Th2传统上 被认为是反监管和对抗性的。申请者 建议研究这两种类型的细胞的机制 在超敏反应的发展中发挥协同作用。 计划互动：这些目标将通过持续的 与AAIDCRC其他成员的互动。特别是，墨菲博士 (项目2)是Th1领域的国际公认学者， Th2表型发育。他在这一领域和许多方面的经验 他开发的试剂和方法将证明表型发育。他的 在这一领域的经验以及他开发的许多试剂和方法 Unanue博士(项目3)和Dr Unanue博士将被证明对Aim 2特别有用。 卓别林合作了近10年，研究人体的生理学。 IL-1和Unanue博士使用中和抗细胞因子的经验 研究体内生理功能的抗体将增强 这些类型的实验的应用。横山博士的加盟 (项目4)AAIDCRC将支持确定自然资源中心作用的努力 细胞作为这些过敏性反应的调节器。

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.