Understanding Dysregulated Crosstalk Between Regulatory T Cells and Lung Dendritic Cells in the Pathogenesis of Chronic Obstructive Pulmonary Disease

了解慢性阻塞性肺疾病发病机制中调节性 T 细胞和肺树突状细胞之间的失调串扰

• 批准号: 10460830
• 负责人: Dawit Mengistu
• 金额: $ 3.91万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-07-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10460830
• 关键词: Adoptive Transfer; Air; Automobile Driving; Blocking Antibodies; Breathing; Cause of Death; Cell physiology; Cells; Chronic Obstructive Pulmonary Disease; Clinical; Clinical Data; Clinical Trials; Coculture Techniques; Complement; Consent; Coughing; Cytokine Signaling; Dendritic Cells; Development; Disease; Disease Progression; Disease model; Environment; Equilibrium; Equipment; Excision; Feedback; Flow Cytometry; Genes; Goals; Healthcare Systems; Homeostasis; Host Defense; Human; Immune; Immune system; Immunology; Immunosuppression; Immunotherapy; Individual; Infiltration; Inflammatory; Inhalation; Knowledge; Laboratories; Lead; Leukocytes; Location; Lung; Lung diseases; Measures; Michigan; Microscopy; Modeling; Morbidity - disease rate; Mucous body substance; Mus; Natural Killer Cells; Operative Surgical Procedures; Oxidants; Pathogenesis; Patients; Phenotype; Play; Population; Production; Progressive Disease; Pulmonary Emphysema; Regulation; Regulatory T-Lymphocyte; Research; Role; Sampling; Smoke; Smoker; Structure of parenchyma of lung; T cell differentiation; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Training; Translational Research; Treg therapy; United States; University resources; airway obstruction; base; cell killing; cigarette smoke; cigarette smoke-induced COPD; cytokine; cytotoxicity; disease phenotype; effector T cell; exposure to cigarette smoke; human data; inflammatory milieu; member; microscopic imaging; mortality; mouse model; novel therapeutic intervention; polarized cell; pre-clinical; prevent; programs; pulmonary function; pulmonary function decline; response; therapy development; time use

Chronic obstructive pulmonary disease (COPD) is a highly prevalent lung disease and is the 4th leading cause of death in the world. COPD results from inhalation of oxidants, such as cigarette smoke, which causes inflammatory cell infiltration and lung destruction. COPD is a progressive disease leading to significant morbidity and mortality. There are no therapies to halt the decline in lung function. Our long-term goal is to understand the mechanisms underlying COPD pathogenesis so that we can develop an immunotherapy to stop disease progression. T regulatory cells (Tregs) decreased in the lungs of smokers with COPD compared to smokers without COPD. Lung dendritic cells (DCs), which are able to polarize T cells to become Tregs or T effector cells (Teff), are more mature in COPD, suggesting that they have a pro-inflammatory as opposed to a tolerogenic phenotype. We hypothesize that in COPD, the increased number of mature pro-inflammatory DCs are driving T cells towards Teff phenotype, whereas under normal conditions, tolerogenic DCs would be more likely to promote induction of Tregs. In return, Tregs can modulate DC phenotype and function, suggesting that subtle crosstalk feedback mechanisms are involved in the regulation of DC and Treg. However, no studies have looked at whether dysregulated crosstalk between Treg and DC populations contributes to COPD pathogenesis. Our specific aims are: 1) to demonstrate that COPD is associated with a shift from tolerogenic to pro-inflammatory DCs; 2) to show that pro-inflammatory DCs preferentially polarize T cells towards a Teff phenotype compared to tolerogenic DCs; and 3) to provide evidence that the transfer of Tregs will restore the number of tolerogenic DCs in the lung. This proposal will utilize an established murine cigarette-smoke based COPD model and also excess human lung tissue from consented patients undergoing clinically-indicated lung surgeries, both with and without COPD. This allows us to conduct translational research and take observations from human samples to the mouse model where we can answer more mechanistic questions. Despite the abundance of clinical trials related to Treg therapy, there are currently no similar trials looking at Tregs in patients with COPD. Successful completion of this proposal will fill critical gaps in knowledge and provide pre-clinical data in support of exploring Treg therapy for COPD patients. This proposal will take place with the combined resources of the University of Michigan and the VA Ann Arbor Healthcare System (the physical location of the laboratory). There are world-class facilities at both locations. The VA houses a murine smoke-exposure facility, Microscopy Core, and FACSAria sorter, and all equipment and space needed to conduct the research. Many members of the Immunology Graduate Program have labs at the VA, making for a robust scientific environment. The training plan developed to successfully complete this proposal includes advanced training in acquisition and analysis of fluorescent microscopy images, laboratory-specific training for the study of lung leukocytes, and training in human research protections and the analysis of human data.

慢性阻塞性肺疾病（COPD）是一种高度普遍的肺部疾病，是第四个主要原因 世界上的死亡。 COPD是由吸入氧化剂（例如香烟烟）引起的引起的 炎症细胞浸润和肺部破坏。 COPD是一种进行性疾病，导致重要 发病率和死亡率。没有疗法可以阻止肺功能下降。我们的长期目标是 了解COPD发病机理的基础机制，以便我们可以开发出一种免疫疗法 停止疾病进展。与COPD的吸烟者肺的T调节细胞（Tregs）相比降低 给没有COPD的吸烟者。肺树突状细胞（DC），能够使T细胞偏振以成为Treg或T 效应细胞（TEFF）在COPD中更加成熟，表明它们具有促炎症而不是 耐受性表型。我们假设在COPD中，成熟的促炎DC数量增加 正在将T细胞驱动到TEFF表型，而在正常条件下，耐受性DC会更 可能促进treg的诱导。作为回报，Tregs可以调节直流表型和功能，建议 这种微妙的串扰反馈机制与DC和Treg的调节有关。但是，没有研究 已经研究了Treg和DC种群之间的串扰失调是否有助于COPD 发病。我们的具体目的是：1）证明COPD与从耐受性到的转变有关 促炎DCS； 2）表明促炎DC优先将T细胞偏振teff 与耐受性DC相比表型； 3）提供证据表明Tregs的转移将恢复 肺中的耐受性DC的数量。该提案将利用既定的鼠香烟 COPD模型以及接受临床指示肺的同意患者的过量人类肺组织 有和没有COPD的手术。这使我们能够进行翻译研究并进行 从人类样品到小鼠模型的观察，我们可以回答更多的机械性问题。 尽管与Treg疗法有关的大量临床试验丰富，但目前尚无类似的试验 COPD患者的Treg。该提案的成功完成将填补知识的关键空白和 提供临床前数据，以支持探索COPD患者的Treg治疗。该提议将发生 借助密歇根大学和VA Ann Arbor Healthcare System的总资源（The 实验室的物理位置）。两个地点都有世界一流的设施。弗吉尼亚州装有鼠 烟雾暴露设施，显微镜核心和Facsaria分类器以及所有需要的设备和空间 进行研究。免疫学研究生课程的许多成员在弗吉尼亚州拥有实验室 强大的科学环境。制定的培训计划已成功完成该建议包括 荧光显微镜图像的采集和分析方面的高级培训，实验室特异性培训 肺白细胞的研究以及人类研究保护和人类数据分析的培训。