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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：
10322171
负责人：
LEI JIN
金额：
$ 44.95万
依托单位：
UNIVERSITY OF FLORIDA
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：
https://reporter.nih.gov/project-details/10322171
关键词：
Adoptive Cell Transfers Affect Allergic Allergic Disease Alveolar Amino Acids Asthma Caring Cause of Death Cells Chemicals Chimeric Proteins Chronic Obstructive Pulmonary Disease Chronic lung disease Cues Dendritic Cells Development Disease Progression Enzymes Epithelial Epithelial Cells Extrinsic asthma Goals Healthcare Human IFNAR1 gene Immune Immune Tolerance Immune system Impairment Infection Inflammation Inhalation Interferon-alpha Knockout Mice Knowledge Lung Lung diseases Lung immune response MHC Class II Genes Mediating Medicine Metabolic Molecular Monoclonal Antibodies Mucous Membrane Mus Organ Pathogenicity Patients Persons Population Production Proto-Oncogene Proteins c-akt Pulmonary Inflammation Pyroglyphidae Regimen Regulatory T-Lymphocyte Reporting Research Role STAT1 gene STAT3 gene Signal Transduction Source Steroid Resistance TNFRSF1B gene Therapeutic Therapeutic Intervention Tryptophan 2,3 Dioxygenase alveolar type II cell arginase autocrine base chronic inflammatory lung disease conditional knockout effective therapy immunogenic improved in vivo inflammatory lung disease inhibitor innovation microbiota mouse model neutrophil paracrine pneumocyte prevent programs relapse patients response targeted treatment therapeutic target translational 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.

摘要