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) 是一种非常流行的肺部疾病，是第四大原因 世界上的死亡。慢性阻塞性肺病是由于吸入氧化剂（例如香烟烟雾）引起的，这会导致 炎症细胞浸润和肺部破坏。 COPD 是一种进行性疾病，可导致严重的 发病率和死亡率。没有任何疗法可以阻止肺功能的下降。我们的长期目标是 了解慢性阻塞性肺病发病机制，以便我们能够开发免疫疗法 阻止疾病进展。与慢性阻塞性肺病吸烟者相比，吸烟者肺部的 T 调节细胞 (Treg) 减少 没有慢性阻塞性肺病的吸烟者。肺树突状细胞 (DC)，能够极化 T 细胞成为 Tregs 或 T 效应细胞（Teff）在慢性阻塞性肺病（COPD）中更加成熟，表明它们具有促炎性而不是促炎性。 耐受表型。我们假设在 COPD 中，成熟促炎 DC 的数量增加 正在驱动 T 细胞走向 Teff 表型，而在正常条件下，耐受性 DC 会更倾向于 可能促进 Tregs 的诱导。作为回报，Tregs 可以调节 DC 表型和功能，这表明 DC和Treg的调节涉及微妙的串扰反馈机制。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。我们的具体目标是：1) 证明 COPD 与从耐受性向耐受性的转变相关。 促炎 DC； 2) 表明促炎 DC 优先将 T 细胞极化为 Teff 与耐受性 DC 相比的表型； 3）提供证据证明Tregs的转移将恢复 肺中耐受性 DC 的数量。该提案将利用已建立的基于小鼠香烟烟雾的 COPD 模型以及来自接受临床指示肺治疗的同意患者的多余人类肺组织 手术，无论是否患有慢性阻塞性肺病。这使我们能够进行转化研究并采取 从人类样本到小鼠模型的观察，我们可以回答更多的机制问题。 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着眼于 COPD 患者中的 Tregs。该提案的成功完成将填补知识和技术方面的关键空白 提供临床前数据支持探索 COPD 患者的 Treg 疗法。这项提案将进行 结合密歇根大学和 VA Ann Arbor 医疗系统（the VA Ann Arbor Healthcare System）的资源 实验室的物理位置）。两个地点都拥有世界一流的设施。 VA 饲养了一只小鼠 烟雾暴露设施、显微镜核心和 FACSAria 分选机，以及所需的所有设备和空间 进行研究。免疫学研究生项目的许多成员在退伍军人管理局都有实验室，这使得 健全的科学环境。为成功完成该提案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、实验室特定培训 肺白细胞的研究，以及人类研究保护和人类数据分析方面的培训。