Human Lung T cell subsets in Disease

疾病中的人肺 T 细胞亚群

• 批准号: 9169074
• 负责人: Anne I. Sperling
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-19 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9169074
• 关键词: Affect; Age; Alveolar; Blood; CD4 Positive T Lymphocytes; Cell surface; Chicago; Clinic; Clinical; Data; Diagnosis; Diffuse; Disease; Disease Progression; Employee Strikes; Epithelial Cells; Ethnic Origin; Fibroblasts; Fibrosis; Flow Cytometry; Funding Mechanisms; Gender; Gene Expression; Gifts and Donations; Goals; Gynecologic Oncology Group; Hamman-Rich syndrome; Human; Illinois; Immune response; Immune system; Interstitial Lung Diseases; KLRB1 gene; Knowledge; Location; Lung; Lung Transplantation; Lung diseases; Malignant Neoplasms; Measurement; Measures; Methods; Organ; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Production; Progressive Disease; Race; Respiratory physiology; Role; Sampling; Signal Pathway; Structure of parenchyma of lung; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Tissues; Transplantation; United States; Universities; Vital capacity; adaptive immunity; base; chemokine receptor; cohort; cytokine; insight; interstitial; lymph nodes; mortality; new therapeutic target; peripheral blood; pulmonary function; receptor expression; respiratory; response; therapeutic target; transcription factor

ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown cause that affects over 128,000 people in the United States. Median survival from diagnosis is 2-3 yrs, worse than many cancers. Irreversible fibrosis in IPF is classically thought to be the end result of abnormal signaling pathways involving alveolar epithelial cells and interstitial fibroblasts. While the role of the immune system in IPF pathogenesis remains controversial, a recent study has found that T cell specific gene expression predicts outcomes in IPF patients, thereby implicating an underlying change in T cells in patients with actively progressive disease. T cells can be divided into distinct functional subsets based on their cytokine production. As such, the changes in IPF T cell gene expression could reflect quantitative and/or qualitative changes in these subsets. Understanding the distinct subsets of T cells present in the lungs of IPF patients may explain why the variability of disease course exists as well as identify potential novel therapeutic targets. In this application, we present exciting preliminary data suggesting that striking alterations in CD4 T cell phenotypes exist within IPF lung tissue and lung draining lymph nodes (LLN) and that these alterations correlate with disease progression. We have compared CD4 T cells from explanted lung tissue and LLN from 9 subjects with IPF who underwent lung transplantation to T cells from 13 age and gender matched donor lungs and LLN that were not suitable for transplant (generous donation from Gift of Hope Regional Organ Bank of Illinois; GOH/ROBI). Using these samples, we have found that chemokine receptor expression on CD4 T cells from IPF patients differ dramatically from GOG/ROBI donor lungs. In the blood, chemokine receptors have been used to identify functionally distinct CD4 T cell subsets. Whether chemokine receptors designate specific CD4 T cell subsets in respiratory tissues is unknown and is a major objective of this application. Thus, our central hypothesis is that CD4 T cell subsets are functionally altered during IPF pathogenesis resulting in changes in their cytokine patterns within the blood, lung and LLN. The long-term goal of these studies is to elucidate the altered T cell immune response in patients with IPF, how this response changes over time, and whether it is associated with declining lung function. In this study, we propose the to elucidate if chemokine receptor expression determines functionally different CD4 subsets within the lungs and LLN in patients with IPF, and to determine how CD4 T cell subsets and T cell cytokines in the blood of a cohort of patients with IPF change over time. Completion of these studies will provide essential knowledge about the extent of these differences and the potential mechanisms by which these differences contribute to IPF pathology. Whether altered T cells are a response to fibrosis or contributing to fibrosis, understanding the location-based differences in cellular compositions, and changes in peripheral T cell cytokines over time, will provide insight into the role of key T cell subsets in IPF progression.

摘要 特发性肺纤维化（IPF）是一种原因不明的进行性和致死性肺部疾病， 美国有128，000人。诊断后的中位生存期为2-3年，比许多癌症更差。 IPF中不可逆的纤维化通常被认为是异常信号通路的最终结果， 肺泡上皮细胞和间质成纤维细胞。虽然免疫系统在IPF发病机制中的作用 尽管仍存在争议，但最近的一项研究发现，T细胞特异性基因表达可预测IPF的结局 患者，从而暗示了具有活跃进展性疾病的患者中T细胞的潜在变化。不 细胞可根据其细胞因子的产生而分为不同的功能亚群。因此， IPF T细胞基因表达可反映这些亚群的定量和/或定性变化。 了解IPF患者肺部存在的不同T细胞亚群可能可以解释这种变异性的原因 以及确定潜在的新的治疗靶点。在本申请中，我们提出 令人兴奋的初步数据表明，IPF肺内存在CD 4 T细胞表型的显著改变， 组织和肺引流淋巴结（LLN），这些变化与疾病进展相关。我们 比较了来自肺组织的CD 4 T细胞和来自9例接受肺移植的IPF受试者的LLN， 移植到来自13个年龄和性别匹配的供体肺和LLN的T细胞，这些供体肺和LLN不适合用于 移植（来自伊利诺伊州希望之礼地区器官银行的慷慨捐赠; GOH/ROBI）。使用这些 我们发现，IPF患者的CD 4 T细胞上的趋化因子受体表达与正常人不同， 从GOG/ROBI捐赠者的肺中显著地分离出来。在血液中，趋化因子受体已被用于识别 功能不同的CD 4 T细胞亚群。趋化因子受体是否指定特异性CD 4 T细胞亚群 在呼吸组织中是未知的，并且是本申请的主要目的。因此，我们的中心假设是 CD 4 T细胞亚群在IPF发病过程中发生功能性改变，导致其细胞因子发生变化， 血液肺和淋巴结内的模式这些研究的长期目标是阐明改变的T细胞 IPF患者的免疫应答，该应答如何随时间变化，以及是否与 肺功能下降在这项研究中，我们提出了阐明趋化因子受体表达是否决定 IPF患者肺和LLN内功能不同的CD 4亚群，并确定CD 4 T细胞亚群在肺和LLN中的分布， 一组IPF患者血液中的T细胞亚群和T细胞细胞因子随时间变化。完成 这些研究将提供关于这些差异的程度和潜在的 这些差异导致IPF病理学的机制。改变的T细胞是否是对 纤维化或促成纤维化，了解细胞组成中基于位置的差异，以及 外周T细胞细胞因子随时间的变化，将有助于深入了解关键T细胞亚群在IPF中的作用 进展