A NOVEL MOUSE MODEL OF ISOCYANATE - INDUCED ASTHMA

异氰酸酯诱发哮喘的新型小鼠模型

• 批准号: 6185202
• 负责人: KIM BOTTOMLY
• 金额: $ 36.79万
• 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: 1999-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6185202
• 关键词: CD8 molecule; T lymphocyte; asthma; disease /disorder model; haptens; hypersensitivity; immunogenetics; inhalation drug administration; isocyanates; laboratory mouse; model design /development; occupational hazard; pathologic process; skin

Isocyanates are a leading cause of occupation-related asthma. The pathophysiology of this condition, however, remains poorly understood, in part due to a lack of appropriate animal models. One critical question that is currently unanswered is what role different sites of exposure (i.e. lung versus skin) may play in subsequent development of reactive airway symptoms. In addition, it is unclear what particular antigenic form of an isocyanate is serving as the primary immunogen. Answers to these questions would have enormous impact on development of appropriate measures to protect workers. Our laboratory has established and is studying immune mechanisms to a mouse model of antigen-induced allergic asthma. Recently, we have extended this model to include sensitization through the skin, using a newly developed method of epicutaneous exposure to soluble protein under an occlusive skin patch. The systemic responses induced differ significantly from contact hypersensitivity responses induced by skin painting with haptens in that they involve preferential activation of Th2 cells. Inhaled antigen challenge of epicutaneously immunized mice in our system resulted in lung inflammatory responses with characteristics of human asthma, including airway eosinophilia and increased mucus production. In this study, we propose the development and analysis of a murine model of isocyanate-induced asthma. Specifically, hexamethylene diisocyanate (HDI)-specific immune responses will be established in mice by epicutaneous or inhalational exposure to HDI. The nature of these immune responses will be characterized and compared to responses induced by protein antigens. Underlying the proposal is the hypothesis that unlike what has been observed in a model of ovalbumin induced airway responses, different subsets of T cell (Th1 or CD8) contribute to the pathophysiology observed. This will be tested in 3 specific aims: 1) To determine what type of exposure leads to optimal HDI sensitization; 2) To determine the priming conditions that lead to HDI-induced lung inflammatory responses and airway hyperresponsiveness; and 3) To define the effector cells and molecules mediating lung responses. Establishment of this mouse model will provide a means for future investigation of: 1) the pathophysiology of isocyanate asthma; 2) the relative immunogenicity of different classes or antigenic forms of isocyanates; and 3) the role of different sites of exposure in sensitization. This information will provide valuable insight into the pertinent risk factors for developing isocyanate asthma and will help guide development of appropriate strategies for protection in the workplace.

异氰酸酯是职业相关哮喘的主要原因。然而，这种情况的病理生理学仍然知之甚少，部分原因是缺乏合适的动物模型。目前尚未解答的一个关键问题是不同的暴露部位（即肺部与皮肤）在反应性气道症状的后续发展中可能发挥什么作用。 此外，还不清楚异氰酸酯的哪种特定抗原形式充当主要免疫原。 这些问题的答案将对制定保护工人的适当措施产生巨大影响。 我们实验室已经建立并正在研究抗原诱导过敏性哮喘小鼠模型的免疫机制。 最近，我们使用一种新开发的方法，在封闭的皮肤贴片下使表皮暴露于可溶性蛋白质，从而扩展了该模型，包括通过皮肤的致敏。 诱导的全身反应与用半抗原皮肤涂抹诱导的接触超敏反应显着不同，因为它们涉及 Th2 细胞的优先激活。 在我们的系统中，对经皮免疫的小鼠进行吸入抗原攻击，导致具有人类哮喘特征的肺部炎症反应，包括气道嗜酸性粒细胞增多和粘液产生增加。 在这项研究中，我们建议开发和分析异氰酸酯诱发哮喘的小鼠模型。 具体来说，六亚甲基二异氰酸酯（HDI）特异性免疫反应将通过小鼠的皮下或吸入暴露于 HDI 来建立。 这些免疫反应的性质将被表征并与蛋白质抗原诱导的反应进行比较。 该提议的基础是这样的假设：与卵清蛋白诱导气道反应模型中观察到的情况不同，不同的 T 细胞亚群（Th1 或 CD8）对观察到的病理生理学有贡献。 这将在 3 个具体目标中进行测试：1）确定哪种类型的暴露会导致最佳 HDI 敏化； 2）确定导致HDI诱导的肺部炎症反应和气道高反应性的启动条件； 3) 定义介导肺反应的效应细胞和分子。 该小鼠模型的建立将为未来研究以下方面提供手段：1）异氰酸酯哮喘的病理生理学； 2) 不同类别或抗原形式的异氰酸酯的相对免疫原性； 3）不同暴露部位在致敏中的作用。 这些信息将为了解异氰酸酯哮喘的相关危险因素提供有价值的见解，并将有助于指导制定适当的工作场所保护策略。