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

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。 这个世界上的死亡。慢性阻塞性肺疾病是由于吸入氧化剂，如香烟烟雾，导致 炎性细胞浸润和肺破坏。慢性阻塞性肺疾病是一种进行性疾病，导致显著 发病率和死亡率。目前还没有治疗方法来阻止肺功能的下降。我们的长期目标是 了解COPD的发病机制，以便我们能够开发免疫疗法来治疗 阻止疾病的发展。吸烟者与COPD患者相比，肺内T调节细胞(Treg)减少 给没有慢性阻塞性肺病的吸烟者。肺树突状细胞(DC)，能够将T细胞极化为Tregs或T 效应细胞在COPD中更成熟，这表明它们具有促炎作用，而不是 耐受性表型。我们假设，在COPD中，成熟的促炎DC的数量增加 正在推动T细胞向TJeff表型转变，而在正常情况下，耐受性DC会更多 可能会促进Tregs的诱导。反过来，Treg可以调节DC的表型和功能，这表明 这种微妙的串扰反馈机制参与了DC和Treg的调节。然而，没有研究表明 我研究了Treg和DC人群之间的失调串扰是否会导致COPD 发病机制。我们的具体目标是：1)证明COPD与从耐受性到 促炎DC；2)显示促炎DC优先极化T细胞 表型与耐受树突状细胞的比较；以及3)提供证据表明转移Tregs将恢复 肺中可耐受的DC的数量。这项提议将利用已建立的老鼠香烟烟雾为基础 COPD模型和接受临床指征肺手术的同意患者的过量人体肺组织 手术，不管有没有慢性阻塞性肺病。这使我们能够进行翻译研究并采取 从人类样本观察到老鼠模型，在那里我们可以回答更多机械性的问题。 尽管有大量与Treg疗法相关的临床试验，但目前还没有类似的试验 慢性阻塞性肺疾病患者的T细胞亚群。成功完成这项提议将填补知识和技术方面的重大空白 提供临床前数据，支持探索慢性阻塞性肺疾病患者的Treg疗法。这项提议将会实施 与密歇根大学和VA Ann Arbor Healthcare System( 实验室的实际位置)。这两个地点都有世界级的设施。退伍军人事务部安置了一只小鼠 烟雾曝光设施、显微镜核心和FACSAria分类器，以及以下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 一个健全的科学环境。为成功完成本提案而制定的培训计划包括 获取和分析荧光显微镜图像的高级培训，实验室专用培训 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。

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.