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
基本信息
- 批准号:8966613
- 负责人:
- 金额:$ 36.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AllergicAllergic DiseaseAllergic inflammationAntigen PresentationAntigensAtopic DermatitisAutoantibodiesAutoimmune DiseasesAutologousBasophilsBiological AssayBlood CirculationCD28 geneCD3 AntigensCell SeparationCell surfaceCellsCharacteristicsChronicClinical assessmentsDevelopmentDiagnosisDiseaseFlow CytometryGoalsHealthHematopoieticHumanIL3RA geneIgEImmune responseIn VitroInterleukin-3InvestigationLaboratoriesLeadLeukocytesMediatingMessenger RNAMinorModelingMolecularMusNatural ImmunityPathogenesisPatientsPeripheral Blood Mononuclear CellPhenotypePopulationReceptor SignalingRegulationSignal PathwayT-LymphocyteTSLP geneTechniquesTestingUrticariaadaptive immunityatopycrosslinkcytokineeffective therapygranulocyteimmunoregulationin vivoinsightmouse modelnovelpolarized cellresearch clinical testingresponse
项目摘要
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 Fc¿R1 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 Fc 的脱粒作用。 R1 交联、细胞表面分子表达的调节、细胞因子表达和免疫调节包括:1) 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 诱导表型亚群具有不同的功能特征; 2) 第一个直接证据表明人类嗜碱性粒细胞表达胸腺基质淋巴细胞生成素受体 (TSLPR) 以及响应 TSLP 的信号传导,该信号受 IL-3 调节和 IL-33;3) 嗜碱性粒细胞“功能耐受”受 IL-3 调节的证据。该提案将研究以下中心假设:靶向嗜碱性粒细胞的 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。使用来自健康对照和过敏性疾病患者的人类嗜碱性粒细胞,以及来自 IL-3 缺陷和对照小鼠的鼠嗜碱性粒细胞,以及最先进的细胞和分子技术,将通过测试以下内容来研究中心假设。四个推论假设: 目标 1:研究这样的假设:在没有 IL-3 的情况下,嗜碱性粒细胞处于“功能耐受”状态,并且嗜碱性粒细胞的 IL-3 激活破坏了“功能耐受”并导致异质亚群,这可能处于连续激活状态或随机不同的亚群;目标 2:研究 IL-3 激活的嗜碱性粒细胞响应 TSLP 并获得极化的功能表型的假设;诱导 Th2 免疫反应;目标 3:研究嗜碱性粒细胞的 IL-3 激活状态决定嗜碱性粒细胞激活测试的敏感性,以评估临床特应性与“功能耐受性”;目标 4:研究拮抗作用或功能性耐受性的假设; IL-3 的缺乏将导致嗜碱性粒细胞在[小鼠特应性模型和新型体外人类特应性模型]中出现“功能耐受”。这些研究有可能描述了嗜碱性粒细胞被激活以实现不同效应器功能的机制,导致嗜碱性粒细胞激活的临床评估的新测定法,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。
项目成果
期刊论文数量(0)
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David P Huston其他文献
Finding new mineral prospects with HYMAP : early results from a hyperspectral remote-sensing case study in the west Pilbara
使用 HYMAP 寻找新的矿产前景:皮尔巴拉西部高光谱遥感案例研究的早期结果
- DOI:
- 发表时间:
1999 - 期刊:
- 影响因子:0
- 作者:
P. Bierwirth;R. Blewett;David P Huston - 通讯作者:
David P Huston
David P Huston的其他文献
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{{ truncateString('David P Huston', 18)}}的其他基金
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 - 财政年份:2013
- 资助金额:
$ 36.38万 - 项目类别:
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:
8514186 - 财政年份:2012
- 资助金额:
$ 36.38万 - 项目类别:
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