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.

抽象的 特发性肺纤维化（IPF）是一种不明原因的进展性致命肺部疾病，会影响 美国128,000人。诊断的中位生存期为2 - 3年，比许多癌症差。 在经典上，IPF中不可逆的纤维化是涉及异常信号通路的最终结果 牙槽上皮细胞和间质成纤维细胞。而免疫系统在IPF发病机理中的作用 仍然有争议，最近的一项研究发现，T细胞特异性基因表达可以预测IPF的结果 患者，暗示了主动性进行性疾病患者的T细胞的潜在变化。 t 细胞可以根据其细胞因子的产生分为不同的功能子集。因此，变化 IPF T细胞基因表达可以反映这些子集的定量和/或定性变化。 了解IPF患者肺中存在的T细胞的不同子集可能解释了为什么可变性 存在疾病病程，并确定潜在的新型治疗靶标。在此应用程序中，我们提出 令人兴奋的初步数据表明，IPF肺中存在CD4 T细胞表型的惊人变化 组织和肺排水淋巴结（LLN），这些改变与疾病进展相关。我们 已经比较了来自肺部的9名受试者的肺组织和LLN的CD4 T细胞 从13岁开始向T细胞的移植和性别匹配的供体肺和LLN不适合 移植（伊利诺伊州希望区域器官银行的慷慨捐赠； goh/robi）。使用这些 样本，我们发现来自IPF患者的CD4 T细胞上的趋化因子受体表达不同 GOG/ROBI供体肺部急剧。在血液中，趋化因子受体已被用来识别 功能上不同的CD4 T细胞子集。趋化因子受体是否指定特定的CD4 T细胞子集 在呼吸道组织中是未知的，是该应用的主要目标。因此，我们的中心假设是 在IPF发病机制中，CD4 T细胞子集在功能上发生了变化，导致其细胞因子的变化 血液中的模式，肺和LLN。这些研究的长期目标是阐明改变的T细胞 IPF患者的免疫反应，这种反应如何随时间变化以及是否与之相关 肺功能下降。在这项研究中，我们建议阐明趋化因子受体表达是否确定 IPF患者的肺部和LLN的功能不同的CD4子集，并确定CD4 T 随着时间的推移，IPF患者队列中的血液中细胞子群和T细胞因子的血液中。完成 这些研究将提供有关这些差异程度和潜力程度的基本知识 这些差异有助于IPF病理学的机制。改变T细胞是否是对 纤维化或有助于纤维化，了解细胞组成的基于位置的差异以及 随着时间的推移，周围T细胞细胞因子的变化将洞悉关键T细胞子集在IPF中的作用 进展。