Differential regulation of mast cell-mediated allergic responses by IL-10
IL-10 对肥大细胞介导的过敏反应的差异调节
基本信息
- 批准号:10584859
- 负责人:
- 金额:$ 40.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-01 至 2027-12-31
- 项目状态:未结题
- 来源:
- 关键词:Adoptive TransferAllergensAllergicAllergic inflammationAnaphylaxisAntiinflammatory EffectAntiparasitic AgentsAttenuatedAutomobile DrivingBone MarrowCD4 Positive T LymphocytesCell Culture TechniquesCell LineCell LineageCell physiologyCellsCellular ImmunityChymaseConnective TissueDataDevelopmentDiseaseEnhancersEventExhibitsFood HypersensitivityGoalsHeterogeneityHomeostasisHumanHypersensitivityIgEImmuneImmune responseImmunodeficient MouseInflammationInflammatoryInflammatory ResponseIngestionInterleukin-10Interleukin-13Interleukin-4Interleukin-6Interleukin-9IntestinesInvestigationLightMapsMediatingMissionModelingMucous MembraneMusNational Institute of Allergy and Infectious DiseaseNatureOutcomePathologicPathway interactionsPeritonealPharmaceutical PreparationsPhenotypePhysiologicalPlayPopulationProductionProliferatingReactionRegulationRegulatory T-LymphocyteReportingRheumatoid ArthritisRoleShapesSignal PathwaySignal TransductionSkin TissueSourceStem Cell FactorStimulusT-LymphocyteT-Lymphocyte SubsetsTestingTh2 CellsTherapeuticTherapeutic InterventionTissuesTransforming Growth Factor betaallergic responseautocrinecell behaviorcell mediated immune responsecell typeconditioningcytokineeggfood allergenfood antigenimmunoregulationinsightmast cellmastocytosisnovelparacrineprototypereceptorresponsetranscriptomicstumor-immune system interactions
项目摘要
PROJECT SUMMARY
This project focuses on the mechanisms by which IL-10 differentially regulates and promotes
mast cell (MC) hyperplasia, heterogeneity, activation and cellular functions during the
development of IgE and non-IgE-mediated allergic responses to food antigens.
We have demonstrated a key role for the immunomodulatory cytokine IL-10 in driving MC
expansion, activation, and cytokine production during food allergy. IL-10-primed MCs exhibited
enhanced proliferation, IgE-mediated passive anaphylaxis, and the production of TH2-type
cytokines. This suggests a novel role for IL-10 in the homeostasis and function of MCs. However,
the mechanisms by which IL-10 promotes MC activation are not very clear and remain to be
determined. Furthermore, whether these proinflammatory effects of IL-10 on MCs extend to
specific MC lineages, are global in nature, or context-dependent also remain to be examined. This
project combines hypothesis testing and targeted mechanistic approaches to further probe the
mechanisms by which IL-10 regulates MC functions. These include understanding whether IL-10
differentially regulates MC responses to distinct antigenic stimuli, assessment of its effects on
heterogeneous MC subsets, and determination of whether its effects are controlled by the source
cell type. The long-term overall goals are to: 1) identify cell-intrinsic and extrinsic factors by
which IL-10 promotes or suppresses distinct MC populations and regulates their effector function
during type 2 inflammatory responses; and 2) examine the systemic and functional local tissue
consequences of regulation of MC expansion and activation by IL-10. Aim 1 will elucidate whether
IL-10 promotes IgE-mediated mucosal MC responses to physiological food antigens such as
peanut and egg allergen and examine its effects on non-IgE-mediated pathways of allergic
sensitization including IL-33-induced anaphylaxis. Whether the effects of IL-10 also extend to
connective tissue MCs will be assessed and the phenotypic and transcriptomic profiles of both
MC subsets will be mapped. Aim 2 will assess the contributions of cell-intrinsic and paracrine IL-
10 to MC hyperplasia and effector function. Aim 3 will identify the effects of source-dependent IL-
10 and determine whether TH2 or non-TH2-derived IL-10 can differentially regulate MC function.
Given the known pleiotropic pathologic and regulatory effects of IL-10 during various T and MC-
mediated immune responses including anti-parasitic responses and allergy, and considering its
status as a canonical immunoregulatory cytokine, it is important to further identify the mechanisms
underlying the proinflammatory effects of IL-10 and its ability to promote rather than suppress
MC-dependent responses. As such, these studies are not only relevant to the mission of NIAID
but may also serve to identify precision-based approaches for therapeutic interventions.
项目概要
该项目重点研究 IL-10 差异调节和促进的机制
肥大细胞(MC)增生、异质性、激活和细胞功能
对食物抗原产生 IgE 和非 IgE 介导的过敏反应。
我们已经证明了免疫调节细胞因子 IL-10 在驱动 MC 中的关键作用
食物过敏期间的扩张、激活和细胞因子的产生。 IL-10 引发的 MC 展示
增殖增强、IgE 介导的被动过敏反应以及 TH2 型的产生
细胞因子。这表明 IL-10 在 MC 的稳态和功能中具有新的作用。然而,
IL-10促进MC激活的机制尚不十分清楚,有待进一步研究
决定。此外,IL-10 对 MC 的促炎作用是否会延伸至
特定的 MC 谱系、本质上是全球性的还是依赖于环境的也有待研究。这
该项目结合了假设检验和有针对性的机制方法来进一步探讨
IL-10 调节 MC 功能的机制。其中包括了解 IL-10 是否
差异调节 MC 对不同抗原刺激的反应,评估其对
异构 MC 子集,并确定其影响是否受源控制
细胞类型。长期总体目标是:1)通过以下方式识别细胞内在和外在因素:
IL-10 促进或抑制不同的 MC 群体并调节其效应功能
2 型炎症反应期间; 2)检查全身和功能性局部组织
IL-10 调节 MC 扩张和激活的后果。目标 1 将阐明是否
IL-10 促进 IgE 介导的粘膜 MC 对生理性食物抗原的反应,例如
花生和鸡蛋过敏原并检查其对非 IgE 介导的过敏途径的影响
致敏,包括 IL-33 诱导的过敏反应。 IL-10 的作用是否也延伸至
将评估结缔组织 MC 以及两者的表型和转录组特征
MC 子集将被映射。目标 2 将评估细胞内在和旁分泌 IL-的贡献
10.MC增生与效应器功能。目标 3 将确定来源依赖性 IL-的影响
10并确定TH2或非TH2衍生的IL-10是否可以差异调节MC功能。
鉴于 IL-10 在各种 T 和 MC 过程中已知的多效性病理和调节作用
介导的免疫反应,包括抗寄生虫反应和过敏,并考虑其
作为一种典型的免疫调节细胞因子,进一步确定其机制非常重要
IL-10 的促炎作用及其促进而非抑制能力的基础
MC 依赖性反应。因此,这些研究不仅与 NIAID 的使命相关
但也可能有助于确定基于精确的治疗干预方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Clinton B Mathias其他文献
IL-10 Neutralization Attenuates Mast Cell Responses in a Murine Model of Experimental Food Allergy
IL-10 中和可减弱实验性食物过敏小鼠模型中肥大细胞的反应
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
D. Krajewski;Saurav Ranjitkar;Caitlin Tedeschi;Nicole Maldonado Perez;Nathan Jordan;Mohamed M. Mire;Sallie S Schneider;Clinton B Mathias - 通讯作者:
Clinton B Mathias
Clinton B Mathias的其他文献
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{{ truncateString('Clinton B Mathias', 18)}}的其他基金
Inhibitory effects of curcumin on Th2 sensitization and mast cell function in a m
姜黄素对小鼠Th2致敏和肥大细胞功能的抑制作用
- 批准号:
8767779 - 财政年份:2014
- 资助金额:
$ 40.28万 - 项目类别:
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