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）是一种高度流行的肺部疾病，是第四大病因 世界上的死亡。慢性阻塞性肺病是由于吸入氧化剂，如香烟烟雾， 炎性细胞浸润和肺破坏。慢性阻塞性肺病是一种进行性疾病，会导致严重的 发病率和死亡率。没有治疗方法可以阻止肺功能的下降。我们的长期目标是 了解COPD发病机制，以便我们能够开发免疫疗法， 阻止疾病发展。COPD吸烟者肺内调节性T细胞（TcR）减少， 没有COPD的吸烟者肺树突状细胞（DC），能够使T细胞活化成为T细胞或T淋巴细胞。 效应细胞（Teff）在COPD中更成熟，这表明它们具有促炎作用，而不是促炎作用。 致耐受表型我们假设在COPD中，成熟的促炎性DC数量的增加， 是驱动T细胞向Teff表型，而在正常条件下，致耐受性DC将更多 可能会促进THP的诱导。反过来，TdR可以调节DC的表型和功能，表明 微妙的串扰反馈机制参与了DC和Treg的调节。然而，没有研究 研究了Treg和DC群体之间失调的串扰是否会导致COPD 发病机制我们的具体目标是：1）证明COPD与从致耐受性转变为 促炎DC; 2）显示促炎DC优先将T细胞朝向Teff 表型;和3）提供证据表明TcB的转移将恢复TcB的表型。 肺中致耐受性DC的数量。该提案将利用一个建立的基于鼠烟雾的 COPD模型以及来自接受临床指征肺移植的知情同意患者的过量人肺组织 手术，无论是否患有COPD。这使我们能够进行转化研究， 从人类样本到小鼠模型的观察，我们可以回答更多的机械问题。 尽管有大量与Treg治疗相关的临床试验，但目前还没有类似的试验， COPD患者中的甲状腺激素。成功完成本建议书将填补知识方面的关键空白， 为探索COPD患者的Treg治疗提供临床前数据。这项提议将在 与密歇根大学和弗吉尼亚州安阿伯医疗保健系统（ 实验室的物理位置）。这两个地方都有世界一流的设施。退伍军人事务部养了一只老鼠 烟雾暴露设施、显微镜核心和FACSAria分选机，以及 进行研究。免疫学研究生项目的许多成员在VA拥有实验室， 强大的科学环境。为成功完成本建议书而制定的培训计划包括 荧光显微镜图像采集和分析的高级培训， 肺白细胞的研究，以及人体研究保护和人体数据分析方面的培训。