Lung IDO-1+ TNFR2+ cDC2 subset in control of lung mucosal tolerance: Mechanism and Application
肺IDO-1 TNFR2 cDC2亚群控制肺粘膜耐受:机制和应用
基本信息
- 批准号:10536690
- 负责人:
- 金额:$ 44.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:Adoptive Cell TransfersAffectAllergic DiseaseAlveolarAmino AcidsAsthmaCaringCause of DeathCellsChemicalsChimeric ProteinsChronic Obstructive Pulmonary DiseaseChronic lung diseaseCuesDendritic CellsDevelopmentDisease ProgressionEnzymesEpithelial CellsEpitheliumExtrinsic asthmaGoalsHealthcareHumanIFNAR1 geneImmune ToleranceImmune systemImpairmentInfectionInflammationInhalationInterferon alphaKnockout MiceKnowledgeLungLung diseasesLung immune responseMHC Class II GenesMediatingMedicineMetabolicMolecularMonoclonal AntibodiesMucous MembraneMusOrganPathogenicityPatientsPersonsPopulationProductionProto-Oncogene Proteins c-aktPulmonary InflammationPyroglyphidaeReceptors, Tumor Necrosis Factor, Type IIRegimenRegulatory T-LymphocyteReportingRepressionResearchRoleSTAT1 geneSTAT3 geneSignal TransductionSourceSteroid ResistanceTNFRSF1B geneTherapeuticTherapeutic InterventionTransforming Growth Factor betaTryptophan 2,3 Dioxygenasealveolar type II cellarginaseautocrinechronic inflammatory lung diseaseconditional knockouteffective therapyefficacy evaluationimmunogenicimprovedin vivoinflammatory lung diseaseinhibitorinnovationmicrobiotamouse modelneutrophilparacrinepneumocytepreventprogramsrelapse patientsresponsetargeted treatmenttherapeutic targettranslational potential
项目摘要
Abstract
The lung is a natural tolerogenic organ. Lung mucosal tolerance must be exquisitely controlled by the lung
immune system to avoid the development of chronic inflammatory lung diseases. Our knowledge of lung
tolerance is, however, inadequate. This is evident in asthma treatments. Current asthma therapies are limited to
blunting the progression of the disease. Patients relapse once the treatments are stopped because the
treatments do not repair the underlying, dysregulated lung mucosal tolerance. Lung dendritic cells (DCs)
orchestrate lung immune responses. We recently reported a lung epithelial cells IFNβ-TNFR2+ cDC2 (R2D2) -
Tregs axis in control of lung tolerance. We further showed that lung R2D2 cells are plastic, which makes them
an ideal target for therapeutic intervention. The essential role of lung Tregs in maintaining tolerance has been
firmly established. In this proposal, we focus on i) uncovering the molecular and cellular mechanisms of the lung
epithelial cells IFNβ-R2D2 control of lung mucosal tolerance; ii) developing an IFNβ-based regimen to restore
lung tolerance in chronic inflammatory lung diseases. We showed, in this proposal, that lung alveolar type II cells
(AT-II) are the IFNβ+ cells, and STING is essential for basal IFNβ production in the lung. In Aim1, we will
determine the in vivo mechanism by which lung AT-II cells sustain lung IFNβ level and maintain lung tolerance
at the steady-state. In Aim2, we will determine the tolerogenic IFNβ program in mouse and human lung R2D2
cells. In Aim3, we will develop an IFNβ-based regimen to enhance, restore lung tolerance, and prevent, treat
inflammatory lung diseases in mice. Chronic inflammatory lung diseases are the 4th leading cause of death in
the U.S. Understanding the fundamental mechanism for lung tolerance and develop a new innovative regimen
to restore lung mucosal tolerance in chronic lung diseases are highly significant.
抽象的
肺是天然的耐受器官,肺粘膜的耐受性必须由肺精确控制。
免疫系统以避免慢性炎症性肺部疾病的发展 我们对肺部的了解。
然而,目前的哮喘治疗仅限于耐受性不足。
一旦治疗停止,患者就会减缓疾病的进展,因为
治疗不能修复潜在的、失调的肺粘膜耐受性。
我们最近报道了肺上皮细胞 IFNβ-TNFR2+ cDC2 (R2D2) -
Tregs 轴控制肺耐受性 我们进一步表明,肺 R2D2 细胞具有可塑性,这使得它们具有可塑性。
肺调节性T细胞在维持耐受性方面的重要作用是治疗干预的理想目标。
在这项提案中,我们重点关注 i) 揭示肺的分子和细胞机制。
上皮细胞 IFNβ-R2D2 控制肺粘膜耐受性;ii) 开发基于 IFNβ 的方案来恢复
在这项提案中,我们证明了肺泡 II 型细胞对慢性炎症性肺部疾病的肺耐受性。
(AT-II) 是 IFNβ+ 细胞,STING 对于肺部基础 IFNβ 的产生至关重要。
确定肺 AT-II 细胞维持肺 IFNβ 水平并维持肺耐受的体内机制
在 Aim2 中,我们将确定小鼠和人肺 R2D2 中的耐受性 IFNβ 程序。
在 Aim3 中,我们将开发一种基于 IFNβ 的方案来增强、恢复肺耐受性,并预防、治疗。
慢性炎症性肺部疾病是小鼠的第四大死亡原因。
美国了解肺耐受的基本机制并开发新的创新疗法
恢复肺粘膜耐受力对于慢性肺部疾病具有高度意义。
项目成果
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{{ truncateString('LEI JIN', 18)}}的其他基金
Lung IDO-1+ TNFR2+ cDC2 subset in control of lung mucosal tolerance: Mechanism and Application
肺IDO-1 TNFR2 cDC2亚群控制肺粘膜耐受:机制和应用
- 批准号:
10322171 - 财政年份:2021
- 资助金额:
$ 44.15万 - 项目类别:
Impact of Human STING Variants on Pneumococcal Vaccine Effectiveness
人类 STING 变体对肺炎球菌疫苗有效性的影响
- 批准号:
9165880 - 财政年份:2016
- 资助金额:
$ 44.15万 - 项目类别:
Mechanisms of STING-Mediated Mucosal Vaccine Adjuvant Activity of Cyclic di-GMP
STING介导的环二-GMP粘膜疫苗佐剂活性机制
- 批准号:
8880430 - 财政年份:2014
- 资助金额:
$ 44.15万 - 项目类别:
Mechanisms of STING-Mediated Mucosal Vaccine Adjuvant Activity of Cyclic di-GMP
STING介导的环二-GMP粘膜疫苗佐剂活性机制
- 批准号:
8815747 - 财政年份:2014
- 资助金额:
$ 44.15万 - 项目类别:
Mechanisms of STING-Mediated Mucosal Vaccine Adjuvant Activity of Cyclic di-GMP
STING 介导的环二 GMP 粘膜疫苗佐剂活性机制
- 批准号:
9185213 - 财政年份:2014
- 资助金额:
$ 44.15万 - 项目类别:
Mechanisms of STING-Mediated Mucosal Vaccine Adjuvant Activity of Cyclic di-GMP
STING介导的环二-GMP粘膜疫苗佐剂活性机制
- 批准号:
8969663 - 财政年份:2014
- 资助金额:
$ 44.15万 - 项目类别:
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