T Cells in Beryllium Sensitization and Disease

铍致敏和疾病中的 T 细胞

• 批准号: 7659795
• 负责人: Andrew P. Fontenot
• 金额: $ 14.78万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-10 至 2009-08-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659795
• 关键词: Adrenal Cortex Hormones; Affect; Aftercare; Alveolitis; Beryllium; Biological Markers; Biopsy; Blood; CD4 Positive T Lymphocytes; Cells; Chemicals; Chest; Chronic berylliosis; Data; Development; Disease; Disease Progression; Fibrosis; Frequencies; Functional disorder; Goals; Granulomatous; Immune; Immune response; Individual; Industry; Inflammation; Interleukin-2; Lead; Lung; Lung Inflammation; Lung diseases; Mediating; Monitor; Natural History; Occupational; Patients; Play; Population; Proliferating; Public Health; Role; Salts; Severities; Severity of illness; Social Welfare; Specimen; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Time; Work; Workplace; base; beryllium sulfate; cohort; disorder risk; enzyme linked immunospot assay; high risk; human subject; improved; infliximab; lung development; lymphocyte proliferation; patient population; peripheral blood; physical property; public health relevance; pulmonary function; translational study

DESCRIPTION (provided by applicant): Chronic beryllium disease (CBD) is a granulomatous lung disorder caused by beryllium exposure in the workplace and is characterized by the accumulation of large numbers of beryllium-specific CD4+ T cells in the lung. Due to its unique chemical and physical properties, beryllium continues to be utilized in high-technology industries. Thus, CBD remains an important public health concern with more than 1,000,000 workers having been exposed to beryllium and at risk for disease development. Beryllium sensitization is detected by the ability of blood CD4+ T cells to proliferate in the presence of beryllium salts in culture. A subset of beryllium- sensitized (BeS) individuals progress to CBD at a rate of 6-8% per year, and the natural history of CBD is characterized by the development of lung fibrosis. What factors are involved in the progression from beryllium sensitization to disease and how various T cell subsets play a role in this progression remain important unanswered questions and form the basis of this application. We have recently shown that the frequency of beryllium-responsive CD4+ T cells in blood of CBD patients is significantly greater than that found in BeS subjects and directly correlates with markers of lung inflammation, suggesting that the number of beryllium- specific T cells in the circulating pool reflects the severity of the CD4+ T cell alveolitis. In addition, our preliminary data suggest that the quantity of naturally-occurring, Foxp3-expressing T regulatory (Treg) cells in the lung of CBD patients is diminished compared to the lung of BeS subjects. We hypothesize that progression from beryllium sensitization to CBD is due to the presence of deficient and/or dysfunctional naturally-occurring Treg cells in lung. As a direct consequence, an increased number of pathogenic beryllium-responsive CD4+ T cells accumulate in blood and lung, associated with an exaggerated T cell dependent immune response. The first specific aim will analyze the role of naturally- occurring, Foxp3-expressing Treg cells in disease progression. Specific aim 2 will determine whether the frequency of circulating beryllium-responsive CD4+ T cells serves as a biomarker of disease progression and severity while the final aim will evaluate the effects of the anti-TNF-a mAb, infliximab, on the frequency and function of beryllium-responsive CD4+ T cells and naturally-occurring regulatory CD4+ T cells in blood and BAL of CBD patients. Thus, the development of intermediate biomarkers capable of detecting disease progression in high-risk individuals and the ability of monitor these biomarkers after treatment initiation would represent a tremendous advance in the field of granulomatous lung disease as well as other CD4+ T cell-mediated disorders. PUBLIC HEALTH RELEVANCE: This translational study will utilize blood and lung specimens from human subjects with an occupational lung disorder for the development of potential biomarkers that predict disease progression and severity in high-risk subjects. This study will further our understanding of the beryllium-induced immune mechanisms that lead to disabling lung dysfunction, potentially leading to an improved welfare of this patient population.

描述（申请人提供）：慢性铍病（CBD）是一种由工作场所接触铍引起的肉芽肿性肺部疾病，其特征是肺部积聚大量铍特异性CD4+T细胞。由于其独特的化学和物理特性，铍继续被用于高科技行业。因此，CBD 仍然是一个重要的公共卫生问题，有超过 1,000,000 名工人接触过铍并面临患病风险。铍致敏作用是通过血液 CD4+ T 细胞在培养物中存在铍盐的情况下增殖的能力来检测的。一部分铍敏感 (BeS) 个体以每年 6-8% 的速度进展为 CBD，CBD 的自然病程以肺纤维化的发展为特征。从铍致敏到疾病的进展涉及哪些因素以及各种 T 细胞亚群如何在这一进展中发挥作用仍然是重要的未解答的问题，并构成了该应用的基础。我们最近发现，CBD 患者血液中铍反应性 CD4+ T 细胞的频率显着高于 BeS 受试者，并且与肺部炎症标志物直接相关，这表明循环中铍特异性 T 细胞的数量池反映了 CD4+ T 细胞肺泡炎的严重程度。此外，我们的初步数据表明，与 BeS 受试者的肺部相比，CBD 患者肺部天然存在的、表达 Foxp3 的 T 调节 (Treg) 细胞的数量有所减少。我们假设从铍致敏到 CBD 的进展是由于肺中存在缺陷和/或功能失调的天然 Treg 细胞。其直接后果是，血液和肺部中积累的致病性铍反应性 CD4+ T 细胞数量增加，与过度的 T 细胞依赖性免疫反应相关。第一个具体目标是分析天然存在的、表达 Foxp3 的 Treg 细胞在疾病进展中的作用。具体目标 2 将确定循环铍反应性 CD4+ T 细胞的频率是否可作为疾病进展和严重程度的生物标志物，而最终目标将评估抗 TNF-a 单克隆抗体英夫利昔单抗 (infliximab) 对铍反应性 CD4+ T 细胞频率和功能的影响。 CBD 患者血液和 BAL 中的铍响应性 CD4+ T 细胞和天然存在的调节性 CD4+ T 细胞。因此，开发能够检测高危个体疾病进展的中间生物标志物以及在治疗开始后监测这些生物标志物的能力将代表肉芽肿性肺病以及其他CD4+T细胞介导的疾病领域的巨大进步。公共卫生相关性：这项转化研究将利用患有职业性肺病的人类受试者的血液和肺部标本来开发潜在的生物标志物，以预测高危受试者的疾病进展和严重程度。这项研究将进一步加深我们对铍诱导的导致肺功能障碍的免疫机制的理解，从而有可能改善该患者群体的福利。