Project 3 - T Cells in Beryllium Sensitization and Disease

项目 3 - 铍致敏和疾病中的 T 细胞

• 批准号: 8382599
• 负责人: Andrew P. Fontenot
• 金额: $ 30.57万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8382599
• 关键词: Adrenal Cortex Hormones; Affect; Aftercare; Alveolitis; Antigens; Berylliosis; Beryllium; Biological Assay; Biological Markers; Biopsy; Blood; CD4 Positive T Lymphocytes; Chest; Chronic berylliosis; Cross-Sectional Studies; Data; Development; Disease; Disease Progression; Fibrosis; Frequencies; Functional disorder; Genetic; Goals; Granulomatous; IL2RA gene; Immune; Immune response; Immunosuppression; Individual; Industry; Inflammation; Instruction; Interferons; Interleukin-2; Lead; Lung; Lung Inflammation; Lung diseases; Mediating; Monitor; Natural History; Occupational; Patients; Play; Population; Proliferating; Public Health; Regulatory T-Lymphocyte; Role; Salts; Severities; Severity of illness; Social Welfare; Specimen; Staging; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Work; Workplace; base; beryllium sulfate; chemical property; cohort; disorder risk; enzyme linked immunospot assay; high risk; human subject; improved; infliximab; lung development; patient population; peripheral blood; physical property; pulmonary function; response; translational study

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 unique chemical and physical properties, beryllium continues to be utilized in hightechnology 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.

慢性铍病（CBD）是一种肉芽肿性肺病， 工作场所，其特征是大量铍特异性CD 4 * T细胞的积累， 肺由于独特的化学和物理性质，铍继续在高科技中使用 行业因此，CBD仍然是一个重要的公共卫生问题， 暴露于铍并有患病风险的工人。贝那普利致敏是 通过血液CD 4 * T细胞在培养物中铍盐存在下增殖的能力来检测。一 铍致敏（BeS）个体的一个子集以每年6-8%的速度进展到CBD，而自然的 CBD的历史以肺纤维化的发展为特征。哪些因素参与了 从铍致敏到疾病的进展以及各种T细胞亚群如何在其中发挥作用 进展仍然是重要的未回答的问题，并形成本申请的基础。我们最近 表明CBD患者血液中铍反应性CD 4 ^ T细胞的频率显著高于正常人。 高于BeS受试者，并与肺部炎症标志物直接相关，表明 循环池中铍特异性T细胞的数量反映了CD 4 * T细胞的严重程度， 肺泡炎此外，我们的初步数据表明，天然存在的Foxp 3表达的细胞数量， 与BeS受试者的肺相比，CBD患者的肺中的T调节性（Treg）细胞减少。我们 假设从铍致敏到CBD进展是由于存在缺乏 和/或肺中功能失调的天然存在的Treg细胞。作为一个直接的后果， 许多致病性铍反应性CD 4 ^ T细胞在血液和肺中积聚， T细胞依赖性免疫反应过度第一个具体目标将分析的作用 天然存在的Foxp 3表达Treg细胞在疾病进展中的作用。具体目标2将决定是否 循环铍反应性CD 4 + T细胞的频率可作为疾病进展的生物标志物 而最终目的是评价抗TNF-α单克隆抗体英夫利西单抗（infliximab） 血液中铍反应性CD 4 * T细胞和天然存在的调节性CD 4 * T细胞的功能 CBD患者的BAL。因此，能够检测疾病的中间生物标志物的开发 高风险个体的进展以及在治疗开始后监测这些生物标志物的能力将 代表了肉芽肿性肺病领域的巨大进步。