PATHOGENIC T CELLS IN CHRONIC BERYLLIUM DISEASE

慢性铍病中的致病性 T 细胞

• 批准号: 6390308
• 负责人: Brian L Kotzin
• 金额: $ 22.71万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-15 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390308
• 关键词: MHC class II antigen; T cell receptor; antigen presentation; berylliosis; cellular pathology; clinical research; diagnostic respiratory lavage; helper T lymphocyte; human subject; hybridomas; immunologic skin test; longitudinal human study; monoclonal antibody; receptor expression; tissue /cell culture

DESCRIPTION (Adapted from Investigator's abstract): Chronic beryllium disease (CBD) is a granulomatous disorder that develops in individuals previously exposed to beryllium usually in the workplace. The lung is the predominant organ involved and granulomatous inflammation is associated with the accumulation of CD4+ T-cells in tissue and broncholveolar lavage (BAL). Studies from the investigators laboratories have found alterations in T-cell receptor (TCR) expression in the BAL of CBD patients including expanded CD4+ T-cell populations that express particular TCR Vbeta regions. Sequencing TCR beta-chain (TCRB) and TCR alpha-chain (TCRA) junctional regions expressed in BAL CD4+ T-cells demonstrated clonal T-cell expansions, and clones from different CBD patients were found to express nearly identical TCRs. The investigators now hypothesize that these expanded CD4+ T-cell clones are responding to beryllium/peptide complexes in the lungs of patients and are important in the pathogenesis of disease. Studies are proposed to verify that these T-cell clones are selectively expanded in CBD patients and, therefore, are not present in the lungs of healthy controls and patients with other granulomatous lung disorders. They will also study BAL in CBD patients at subsequent times of disease progression for the continued presence of these T-cell clones. Using patch testing to BeS04 in these same patients, studies will examine whether similar TCR are used by CD4+ T-cells infiltrating into the skin. The TCR of in vivo clonal expansions will also be compared to TCR expressed by BAL and blood T-cells in CBD patients recognize antigen and are stimulated. CD4+ T-cell hybridomas expressing the TCR of particular clonal expansions in CBD patients will be used to analyze the response to BeS04 and determine whether responses are restricted by self class II major histocompatibility complex (MHC) antigens. Additional studies will examine whether antigenic processing is required for stimulation and will characterize the nature of the beryllium/peptide/MHC complex involved in stimulating beryllium-reactive T-cells.

描述（改编自研究者摘要）：慢性铍 CBD是一种肉芽肿性疾病， 通常在工作场所接触铍。 肺是 累及的主要器官和肉芽肿性炎症是 与组织中CD 4 + T细胞的积累有关， 支气管肺泡灌洗（BAL）。 研究者的研究 实验室已经发现T细胞受体（TCR）表达的改变 在CBD患者的BAL中，包括扩增的CD 4 + T细胞群 表达特定的TCR V β区域。 TCR β链测序 BAL中表达的TCR α链（TCRB）和TCR α链（TCRA）连接区 CD 4 + T细胞表现出克隆性T细胞扩增，并且来自 发现不同的CBD患者表达几乎相同的TCR。 的 研究人员现在假设这些扩增的CD 4 + T细胞克隆是 对患者肺中铍/肽复合物的反应， 在疾病的发病机制中很重要。 建议开展研究， 证实这些T细胞克隆在CBD患者中选择性扩增 因此不存在于健康对照的肺中， 其他肉芽肿性肺病患者。 他们还将研究 在随后的疾病进展时间， 这些T细胞克隆的持续存在。对BeS 04进行补丁测试 在这些相同的患者中，研究将检查是否相似的TCR 通过CD 4 + T细胞渗入皮肤。 体内TCR 克隆扩增也将与BAL表达的TCR进行比较， CBD患者的血液T细胞识别抗原并被刺激。 表达特定克隆的TCR的CD 4 + T细胞杂交瘤 CBD患者的扩展将用于分析对BeS 04的反应 并确定是否受自身II类专业的限制 组织相容性复合体（MHC）抗原。 其他研究将 检查刺激是否需要抗原加工， 将表征铍/肽/MHC复合物的性质 参与刺激铍反应性T细胞