Isocyanate Antigens and T-cells that Cause Asthma

引起哮喘的异氰酸酯抗原和 T 细胞

• 批准号: 6733612
• 负责人: ADAM WISNEWSKI
• 金额: $ 24.53万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6733612
• 关键词: T lymphocyte; antigens; asthma; atopy; biopsy; blood chemistry; cell population study; chemical conjugate; haptens; human subject; immunoregulation; inflammation; isocyanates; occupational disease /disorder; pathologic process; patient oriented research; respiratory disorder epidemiology; respiratory function; respiratory hypersensitivity

Diisocyanates are a group of highly reactive, widely used low molecular weight chemicals, and are the most commonly reported cause of occupational asthma in developed countries. Yet, the mechanisms by which diisocyanate-induced asthma and those at risk. It has been theorized that reactive diisocyanates act as low-molecular weight haptens that trigger human T-cell responses. However, considerable uncertainty exists regarding the natural "carrier" proteins for diisocyanate in vivo and the putative T-cells central to eliciting asthma- related airway inflammation following exposure. We hypothesize that diisocyanates bind to specific proteins in human airways including, albumin and keratin-18, and that these diisocyanate asthmatics and exposed non-asthmatic workers manifest distinct T-cell responses to diisocyanate-conjugated protein antigens that will aid in understanding the pathogenesis of diisocyanate asthma and identifying these subjects. To test these hypotheses we will: (AIM 1) Further characterize biologically relevant diisocyanate-protein complexes that result following the exposure of normal human airway tissues and proteins, (AIM 2). Evaluate diisocyanate antigenicity at the T-cell based on in vitro responses t specific diisocyanate-protein conjugates, and (AIM 3) Determine the roles of different T cell subsets (i.e. CD4+, CD8+, alpha/beta, gamma/beta) in the pathogenetic immune response to diisocyanate-conjugated proteins, through in vitro studies with T cells derived from airway biopsies and peripheral blood of diisocyanate asthmatic and exposed control subjects. These studies build upon our previous work that has identified novel diisocyanate-protein conjugates that occur in vivo and has generated antigen-specific T-cell lines from human airway endobronchial biopsy samples. The experiments will utilize peripheral blood; bronchial lavage and airway biopsy samples from a well-defined population of diisocyanate asthmatic and control subjects enrolled in ongoing studies at the Yale School of Medicine. Together the results should provide significant insights into the pathogenesis of diisocyanate asthma.

二异氰酸酯是一组高活性，广泛使用的低分子量化学品，是发达国家职业性哮喘最常见的报告原因。然而，二异氰酸酯诱发哮喘的机制和那些有风险的。从理论上讲，反应性二异氰酸酯作为低分子量半抗原触发人类t细胞反应。然而，对于体内二异氰酸酯的天然“载体”蛋白和暴露后引发哮喘相关气道炎症的假定t细胞，存在相当大的不确定性。我们假设二异氰酸酯与人类气道中的特定蛋白质结合，包括白蛋白和角蛋白-18，并且这些二异氰酸酯哮喘患者和暴露的非哮喘工人对二异氰酸酯偶联蛋白抗原表现出不同的t细胞反应，这将有助于理解二异氰酸酯哮喘的发病机制并识别这些受试者。为了验证这些假设，我们将：（AIM 1）进一步表征暴露于正常人类气道组织和蛋白质后产生的生物学相关的二异氰酸酯-蛋白质复合物（AIM 2）。基于对特异性二异氰酸酯蛋白偶联物的体外反应评估t细胞的二异氰酸酯抗原性，以及（AIM 3）确定不同t细胞亚群（即CD4+， CD8+, α / β, γ / β）在对二异氰酸酯偶联蛋白的致病免疫反应中的作用，通过体外研究来自气道活检和二异氰酸酯哮喘和暴露对照受试者的外周血的t细胞。这些研究建立在我们之前的工作基础上，我们已经确定了新的二异氰酸酯-蛋白偶联物，这些偶联物发生在体内，并从人气道支气管活检样本中产生抗原特异性t细胞系。实验将利用外周血；支气管灌洗和气道活检样本来自明确定义的二异氰酸酯哮喘患者和耶鲁医学院正在进行的研究的对照受试者。总之，这些结果应该为二异氰酸酯哮喘的发病机制提供重要的见解。