Eosinophil Activities in Murine Models of Lung Disease

描述（由申请人提供）：肺部嗜酸性粒细胞增多伴随哮喘的病理已经被认为是一个相关的特征，甚至在早期的研究中就已经认识到这一疾病。无数的调查已经证实并详细说明了这种关系，表明嗜酸性粒细胞的存在预示着疾病的严重程度，即使在轻微的病例中也会发生。嗜酸性粒细胞的募集也发生在过敏原介导的呼吸道炎症动物模型中；尤其是老鼠，已经被广泛研究过。尽管有大量的临床研究和可用的小鼠模型将肺嗜酸性粒细胞增多与肺功能障碍联系起来，但对嗜酸性粒细胞效应功能的了解甚少，事实上，这些白细胞的作用（如果有的话）仍然存在疑问。我们培育出了一种基因上没有嗜酸性粒细胞的新型小鼠。这种消融是通过一种自杀基因（即白喉毒素a链）的特异性表达来完成的，这种表达只在转基因小鼠的嗜酸性粒细胞谱系的细胞中进行。嗜酸性粒细胞消融是绝对的和特异性的，因为没有观察到对其他造血来源细胞的影响。该建议利用我们独特的无嗜酸性粒细胞小鼠系，以及我们开发的其他新的嗜酸性粒细胞特异性试剂/方法，在两种并行的方法中测试嗜酸性粒细胞在过敏性气道疾病中具有致病作用的假设（即，急性和慢性过敏原挑战方案以及与其他已建立的转基因/基因敲除模型系统的遗传杂交）。这些目标将通过完成以下具体目标来实现：(1)明确确定嗜酸性粒细胞效应功能对急性过敏原致敏/气溶胶攻击模型中引起的肺部病变的贡献；(2)利用过敏原介导的慢性炎症模型确定嗜酸性粒细胞在肺重塑中的作用；(3)明确嗜酸性粒细胞依赖机制导致过敏原激发后晚期支气管收缩；(4)确定嗜酸性粒细胞对先前表征的肺表达IL-5转基因小鼠肺部病理的贡献。

DESCRIPTION (provided by applicant): The pulmonary eosinophilia accompanying the pathologies of asthma has been a correlative feature recognized even in the earliest studies investigating this disease. Innumerable investigations have confirmed and detailed this relationship, demonstrating that the presence of eosinophils is predictive of disease severity and occurs even in mild cases. The recruitment of eosinophils also occurs in animal models of allergen-mediated respiratory inflammation; the mouse, in particular, has been extensively studied. Despite the abundance of clinical studies and the availability of mouse models that correlate pulmonary eosinophilia with lung dysfunction, eosinophil effector functions are poorly understood and, indeed, questions remain as to the role(s), if any, of these leukocytes. We have created a novel line of mice genetically devoid of eosinophils. This ablation is accomplished through the specific expression of a suicide gene (i.e., Diphtheria Toxin A chain) exclusively in eosinophil-lineage committed cells of transgenic mice. The eosinophil ablation is absolute and specific as no effects are observed on other hematopoietically derived cells. This proposal utilizes our unique eosinophil-less line of mice, as well as other novel eosinophil-specific reagents/methodologies that we have developed, in two concurrent approaches testing the hypothesis that eosinophils have a causative role(s) in allergic airways disease (i.e., acute and chronic allergen-challenge protocols and genetic crosses with other established transgenic/gene knockout model systems). These objectives will be achieved by the completion of the following Specific Aims: (1) To determine unequivocally the contribution(s) of eosinophil effector functions to the pulmonary pathologies arising in an acute allergen sensitization/aerosol challenge model; (2) To define the role(s) of eosinophils in lung remodeling using a chronic model of allergen-mediated inflammation; (3) To define eosinophil-dependent mechanism(s) leading to late phase bronchoconstriction following allergen provocation; (4) To determine the contribution(s) of eosinophils to the previously characterized pulmonary pathologies of lung-expressing IL-5 transgenic mice.