Mechanisms of Human Basophil-Mediated Allergic Inflammation

人类嗜碱性粒细胞介导的过敏性炎症的机制

• 批准号: 8631752
• 负责人: David P Huston
• 金额: $ 40.36万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631752
• 关键词: Allergic; Allergic Disease; Allergic inflammation; Antigen Presentation; Antigens; Atopic Dermatitis; Autoantibodies; Autoimmune Diseases; Autologous; Basophils; Biological Assay; Blood Circulation; CD28 gene; CD3 Antigens; Cell Separation; Cell surface; Cells; Characteristics; Chronic; Clinical assessments; Development; Diagnosis; Disease; Flow Cytometry; Goals; Health; Hematopoietic; Human; IL3RA gene; IgE; Immune response; In Vitro; Interleukin-3; Investigation; Laboratories; Lead; Leukocytes; Mediating; Messenger RNA; Minor; Modeling; Molecular; Mus; Natural Immunity; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Population; Receptor Signaling; Regulation; Signal Pathway; T-Lymphocyte; TSLP gene; Techniques; Testing; Urticaria; adaptive immunity; atopy; crosslink; cytokine; effective therapy; granulocyte; human TSLP protein; immunoregulation; in vivo; insight; novel; polarized cell; research clinical testing; response

DESCRIPTION (provided by applicant): The overall goal of this laboratory over the past 20 years has been the elucidation of mechanisms regulating allergic inflammation and thereby identification of novel targets for treating allergic diseases. This proposal will focus on mechanisms regulating human basophil activation and effector function in allergic diseases. Basophils are the least abundant granulocytes in the circulation, and only recently has evidence demonstrated that basophils have potent effector functions that bridge innate and adaptive immunity and contribute to the pathogenesis of both allergic and autoimmune diseases. Preliminary studies demonstrate that IL-3 is a key cytokine for polarizing basophils for effector functions that include degranulation in response to FcεR1 crosslinking, regulation of cell surface molecule expression, cytokine expression, and immune modulation. Key preliminary findings include: 1) detailed analysis of IL-3 activation of human basophils that demonstrates IL-3-inducible phenotypic subsets of basophils with distinct functional characteristics; 2) the first direct evidence for human basophil expression of the thymic stromal lymphopoietin receptor (TSLPR) and signaling in response to TSLP, which is regulated by IL-3 and IL-33; and 3) evidence for basophil "functional tolerance' regulated by IL-3. This proposal will investigate the central hypothesis that targeting IL-3 activation of basophils is an effective strategy for treatin basophil-mediated allergic diseases. Studies will use human basophils from healthy controls and patients with allergic diseases, as well as murine basophils from IL-3 deficient and control mice, and state-of-the-art cellular and molecular techniques. The central hypothesis will be investigated by testing the following four corollary hypotheses: Aim 1: Investigate the hypothesis that in the absence of IL-3, basophils are in a state of "functional tolerance", and that IL-3 activation of basophils breaks "functional tolerance" and results in heterogeneous subpopulations which may be either in sequential states of activation or stochastically distinct subpopulations; Aim 2: Investigate the hypothesis that IL-3 activated basophils respond to TSLP and acquire a functional phenotype that is polarized for inducing Th2 immune responses; Aim 3: Investigate the hypothesis that the IL-3 activation state of basophils determines the sensitivity o basophil activation testing for assessment of clinical atopy versus "functional tolerance"; and Aim 4: Investigate the hypothesis that antagonism, or lack, of IL-3 will result in basophil "functional tolerance" in [a murine model of atopy and a novel in vitro human model of atopy.] These studies have the potential to delineate the mechanisms by which basophils are activated for distinct effector functions, lead to novel assays for clinical evaluation of basophil activatio, and provide proof-of- concept for potentially targeting IL-3 as a novel treatment of allergic disorders.

描述（由申请人提供）：该实验室过去20年的总体目标是阐明调节过敏性炎症的机制，从而确定治疗过敏性疾病的新靶点。本提案将重点关注调节人类嗜碱性粒细胞激活和效应子的机制。嗜碱性粒细胞颗粒是循环系统中数量最少的免疫细胞，直到最近才有证据表明嗜碱性粒细胞具有强大的效应功能，可以连接先天性和适应性，并有助于过敏性和慢性疾病的发病机制。初步研究表明，IL-3 是极化嗜碱性粒细胞的关键细胞因子，可实现效应功能，包括响应 FcεR1 交联的脱颗粒、细胞表面分子表达的调节、细胞因子表达和免疫调节。对人类嗜碱性粒细胞 IL-3 激活的详细分析，证明嗜碱性粒细胞的 IL-3 诱导表型子集具有不同的功能特征；2) 人类嗜碱性粒细胞的第一个直接证据；胸腺基质淋巴细胞生成素受体 (TSLPR) 的嗜碱性粒细胞表达以及响应 TSLP 的信号传导，受 IL-3 和 IL-33 调节；3) 嗜碱性粒细胞“功能耐受”受 IL-3 调节的证据。中心假设是，针对嗜碱性粒细胞的 IL-3 激活是治疗嗜碱性粒细胞介导的过敏性疾病的有效策略。研究也将使用来自健康对照者和过敏性疾病患者的人类嗜碱性粒细胞。中心假设将通过测试以下四个推论假设进行研究：目标 1：研究在缺乏 IL-3 的情况下的假设。 IL-3、嗜碱性粒细胞在“功能耐受”状态下被破坏，IL-3 激活嗜碱性粒细胞“功能耐受”并导致异质亚群，这些亚群可能处于连续激活状态或目标 2：研究 IL-3 激活的嗜碱性粒细胞对 TSLP 做出反应并获得极化以诱导 Th2 免疫反应的功能表型的假设；目标 3：研究嗜碱性粒细胞的 IL-3 激活状态决定的假设敏感性 o 嗜碱性粒细胞激活测试，用于评估临床特应性与“功能耐受性”；目标 4：研究拮抗或缺乏的假设； IL-3 将在[小鼠特应性模型和新型体外人类特应性模型]中产生嗜碱性粒细胞“功能耐受”。这些研究有可能描述嗜碱性粒细胞被激活以实现不同效应功能的机制，从而导致嗜碱性粒细胞活化临床评估的新测定方法，并为潜在靶向 IL-3 作为过敏性疾病的新治疗方法提供了概念验证。