The differentiation and function of CD4+ Th2 cells during allergen-induced asthma
过敏原诱发哮喘过程中CD4 Th2细胞的分化和功能
基本信息
- 批准号:8910831
- 负责人:
- 金额:$ 5.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-02-01 至 2019-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAffectAllergensAllergic inflammationAnaphylaxisAntigensAsthmaB-LymphocytesBCL6 geneBindingCD4 Positive T LymphocytesCell physiologyCellsCuesCytokine SignalingDermatophagoides pteronyssinusDevelopmentDiseaseDisease modelEffector CellExposure toExtrinsic asthmaGoalsHealthHelper-Inducer T-LymphocyteHeterogeneityIgEImmunotherapyIncidenceInflammationInflammatoryInterleukin-10Interleukin-13Interleukin-4Interleukin-5KineticsKnowledgeLeadLigandsLungLymphoidMaintenanceMemoryMethodsModelingMolecularMusOrganPathogenesisPathologyPeptidesPopulationPopulation HeterogeneityProcessProductionProteinsPyroglyphidaeRecurrenceRegulatory T-LymphocyteRelative (related person)ResearchResolutionRoleSTAT6 Transcription FactorSymptomsT memory cellT-Cell ReceptorT-LymphocyteT-Lymphocyte SubsetsTestingTh2 CellsTherapeuticTherapeutic EffectWorkairway inflammationallergic airway inflammationasthmatic patientbasecytokinedesignhigh riskimmunopathologyimmunoregulationinnovationmagnetic beadsmemory CD4 T lymphocytenovelpreventreceptorresponsetherapeutic developmenttherapy developmenttooltranscription factor
项目摘要
DESCRIPTION (provided by applicant): Asthma is an inflammatory disease of the airways characterized by acute, intermittent and recurrent episodes of inflammation that can be induced by a specific allergen. CD4+ T cells contribute to this process by producing the Type 2 cytokines IL-4, IL-5, and IL-13 and inducing B cell production of IgE in response to T cell receptor (TCR) recognition of allergen peptides bound to MHCII molecules on host cells. In both murine models of disease and asthmatic patients, quiescent allergen peptide:MHCII (pMHCII)-specific CD4+ memory T cells can persist in lungs and lymphoid organs long after resolution of inflammation. Upon subsequent exposure to allergen, CD4+ memory T cells rapidly drive asthma-induced immunopathology making these cells attractive targets for allergen-specific immune modulation. Little is known, however, about the differentiation and maintenance of Th2 cells that orchestrate the asthmatic response due to the challenge of tracking small populations of CD4+ T cells that express allergen pMHCII: specific TCRs. To address this lack of knowledge, we produced an MHCII tetramer containing a peptide from the Der p1 protein of the house dust mite (HDM), Dermatophagoides pteronyssinus, the most common cause of atopic asthma. Using this tetramer and a novel magnetic bead-based cell enrichment method of our design, we have found three allergen- specific CD4+ T cell subsets that develop after the induction of allergic airway inflammation. The central hypothesis of this application is that functionally heterogeneous yet synergistic populations of Th2 effector and memory cells develop in response to competition between lineage-defining transcription factors and underlies asthma pathogenesis. The goals of this proposal are to identify the molecular and cellular mechanisms that lead to Th2 effector cell heterogeneity and determine how these cells persist and contribute to asthma pathogenesis in the lung so they can be modified by immunotherapy. This innovative approach could provide the means for preventing allergenic priming of memory Th2 cells or eliminating them through antigen-specific therapies.
描述(由申请人提供):哮喘是一种气道炎症性疾病,其特征是可由特定过敏原诱发的急性、间歇性和复发性炎症发作。 CD4+ T 细胞通过产生 2 型细胞因子 IL-4、IL-5 和 IL-13 并诱导 B 细胞产生 IgE 来响应 T 细胞受体 (TCR) 识别与 MHCII 分子结合的过敏原肽,从而促进这一过程。宿主细胞。在小鼠疾病模型和哮喘患者中,静止的过敏原肽:MHCII (pMHCII) 特异性 CD4+ 记忆 T 细胞在炎症消退后很长时间内可以在肺部和淋巴器官中持续存在。随后暴露于过敏原后,CD4+记忆T细胞迅速驱动哮喘诱发的免疫病理学,使这些细胞成为过敏原特异性免疫调节的有吸引力的靶标。然而,由于追踪表达过敏原 pMHCII(特定 TCR)的小群 CD4+ T 细胞的挑战,人们对协调哮喘反应的 Th2 细胞的分化和维持知之甚少。为了解决这一知识的缺乏,我们生产了一种 MHCII 四聚体,其中含有来自屋尘螨 (HDM)、屋尘螨 (Dermatophagoides pteronyssinus)(特应性哮喘最常见原因)的 Der p1 蛋白的肽。使用这种四聚体和我们设计的新型基于磁珠的细胞富集方法,我们发现了三种过敏原特异性 CD4+ T 细胞亚群,它们在过敏性气道炎症诱导后形成。本申请的中心假设是,功能异质但协同的 Th2 效应细胞和记忆细胞群体是响应谱系定义转录因子之间的竞争而发展的,是哮喘发病机制的基础。该提案的目标是确定导致 Th2 效应细胞异质性的分子和细胞机制,并确定这些细胞如何持续存在并促进肺部哮喘发病机制,以便可以通过免疫疗法对其进行修改。这种创新方法可以提供预防记忆 Th2 细胞过敏引发或通过抗原特异性疗法消除它们的方法。
项目成果
期刊论文数量(0)
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{{ truncateString('MARION PEPPER', 18)}}的其他基金
The Development and Function of Plasmodium-specific memory B cells
疟原虫特异性记忆 B 细胞的发育和功能
- 批准号:
10062845 - 财政年份:2016
- 资助金额:
$ 5.78万 - 项目类别:
The Development and Function of Plasmodium-specific memory B cells
疟原虫特异性记忆 B 细胞的发育和功能
- 批准号:
9235529 - 财政年份:2016
- 资助金额:
$ 5.78万 - 项目类别:
The differentiation and function of CD4+ Th2 cells during allergen-induced asthma
过敏原诱发哮喘过程中CD4 Th2细胞的分化和功能
- 批准号:
8994262 - 财政年份:2014
- 资助金额:
$ 5.78万 - 项目类别:
The differentiation and function of CD4+ Th2 cells during allergen-induced asthma
过敏原诱发哮喘过程中CD4 Th2细胞的分化和功能
- 批准号:
8719697 - 财政年份:2014
- 资助金额:
$ 5.78万 - 项目类别:
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