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.

慢性铍疾病（CBD）是由铍暴露引起的肉芽肿性肺部疾病 工作场所的特征是大量铍特异性CD4* T细胞积累 肺。由于独特的化学和物理特性，铍继续用于Hightechnology 行业。因此，CBD仍然是一个重要的公共卫生问题，超过100万 工人暴露于铍，面临疾病发展的风险。铍敏化是 在培养中存在铍盐的情况下，血液CD4* T细胞在存在的能力中检测到。一个 铍敏化（BES）个体的子集以每年6-8％的速度发展到CBD，自然 CBD史的特征是肺纤维化的发展。涉及哪些因素 从铍致敏到疾病的发展以及各种T细胞子集如何在此中发挥作用 进步仍然是重要的未解决问题，并构成了本应用的基础。我们最近有 表明CBD患者血液中铍反应性CD4^ T细胞的频率显着 大于在BES受试者中发现的，并且与肺部炎症标记直接相关，这表明 循环池中铍特异性T细胞的数量反映了CD4* T细胞的严重程度 肺泡炎。此外，我们的初步数据表明，自然出现，表达FoxP3的数量 与BES受试者的肺相比，CBD患者肺中的T调节性（Treg）细胞减少。我们 假设从铍致敏到CBD的发展是由于存在 和/或肺中自然功能障碍的自然treg细胞。直接结果，增加了 病原性铍反应性CD4^ T细胞积聚在血液和肺中，相关 具有夸张的T细胞依赖性免疫反应。第一个具体目的将分析 疾病进展中的天然表达Treg细胞天然表达Treg细胞。具体目标2将决定是否 循环铍响应CD4''T细胞的频率是疾病进展的生物标志物 和严重性的同时最终目标将评估抗TNF-A mAb（英夫利昔单抗）对频率的影响 铍反应性CD4* T细胞和血液中天然调节CD4* T细胞的功能 和CBD患者的BAL。因此，能够检测疾病的中间生物标志物的发展 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 在肉芽肿性肺部疾病领域代表了巨大的进步。