Eosinophil Activities in Murine Models of Lung Disease

描述(由申请人提供)：最近对哮喘患者的研究清楚地表明，根据临床环境中表现出的症状和炎症特征，人群具有多样性。因此，除了通常通过皮质类固醇激素控制的嗜酸性呼吸道炎症的过敏性患者外，研究发现越来越多的患者更难治疗，包括类固醇难治性患者。 重症患者同时表现为嗜酸性和中性粒细胞炎症性疾病变种。免疫反应的这种更大的多样性在一定程度上是由肺反应的过敏原特异性T细胞可塑性所介导的。值得注意的是，我们在小鼠身上同时进行的研究表明，嗜酸性粒细胞在免疫调节所必需的途径和肺部发生的炎症事件的特征中的作用被低估了。这项工作始于我们使用嗜酸性粒细胞缺陷小鼠(PHIL)进行的早期研究，然而，我们最近使用新创建的可诱导嗜酸性粒细胞缺陷小鼠(IPHIL)的研究使我们认为，过敏原攻击时的嗜酸性粒细胞活动与驱动T细胞亚型的多样性有关 肺部炎症(即嗜酸性粒细胞、中性粒细胞或混合变异型)。拟议的研究利用了这些初步数据，以及我们创建的“下一代”小鼠模型(EoCRE)，允许嗜酸性粒细胞特异性基因敲除和靶向基因过度表达。我们将通过(I)直接影响中性粒细胞在肺内的募集/聚集和(Ii)调节过敏原特异性T细胞亚型的选择，在有嗜酸性粒细胞的情况下极化Th2的反应，在没有嗜酸性粒细胞的情况下调节Th17/Th1，来检验嗜酸性粒细胞活动对ALL呼吸道炎症特征的贡献。从长远来看，我们的目标是确定可能解释患者疾病表型多样性的潜在机制，以及围绕当前治疗方法的混淆问题，如皮质类固醇和Mepolizumab的使用。这项建议的目的将通过完成下列特定目标来检验我们的中心假说：(1)证明嗜酸性粒细胞通过表达由12/15-脂氧合酶活性衍生的抗炎脂来直接抑制变应原诱导的气道中性粒细胞水平；(2)确定嗜酸性粒细胞衍生的IL-4和转化生长因子�表达作为调节T细胞亚型导致Th2占优势的T细胞亚型与中性粒细胞混合Th2/Th17/Th1免疫反应的机制的意义；(3)确定类固醇难治性中性粒细胞亚群过敏性呼吸道炎症是由皮质激素介导的嗜酸性粒细胞使能效应引起的，还是作为靶向嗜酸性粒细胞和Th2细胞的联合结果。

DESCRIPTION (provided by applicant): Recent studies of asthma patients clearly demonstrate a diverse population based on symptoms and the character of inflammation displayed in clinical settings. Thus, in addition to allergic patients with eosinophilic airway inflammation that are generally controlled through corticosteroids, studies have identified growing populations of patients that are much more difficult to treat, including steroid refractory severe patients displaying both eosinophilic and neutrophilic inflammatory disease variants. This greater diversity of immune responses is mediated, in part, by allergen-specific T cell plasticity of pulmonary responses. Significantly, our concurrent studies in the mouse have suggested that eosinophils have under- appreciated roles in pathways necessary for immune regulation and the character of the inflammatory events occurring in the lung. This work originated with our early studies using eosinophil-deficient mice (PHIL), however, our more recent studies using a newly created inducible eosinophil-deficient mouse (iPHIL) have led us to suggest that eosinophil activities at the time of allergen challenge are linked to the diversity of T cell subtypes driving pulmonary inflammation (i.e., eosinophilic, neutrophilic, or mixed variants). The proposed studies capitalize on these preliminary data as well as our creation of a "next generation" mouse model (eoCRE) allowing eosinophil-specific gene knockouts and targeted gene overexpression. We will test the central hypothesis that eosinophil activities contribute to the character of alleric respiratory inflammation by (i) direct effects on neutrophil recruitment/accumulation in the lung and by (ii) modulating allergen-specific T cell subtype selection, polarizing responses to Th2 in the presence of eosinophils and Th17/Th1 in their absence. In the long term, our goal is to identify potential mechanisms that may explain the diversity of disease phenotypes in patients and confounding issues surrounding current therapies such as the use of corticosteroids and Mepolizumab". The objectives of this proposal will test our central hypothesis by the completion of the following Specific Aims: (1) To demonstrate that eosinophils directly suppress the level of allergen-induced airway neutrophils through the expression of anti-inflammatory lipids derived from 12/15- lipoxygenase activities; (2) To define the significance of eosinophil-derived IL-4 and TGF� expression as mechanisms modulating T cell subtypes leading to Th2 dominant vs. neutrophilic mixed Th2/Th17/Th1 immune responses; (3) To determine if steroid refractory neutrophilic subsets of allergic respiratory inflammation arise from eosinophil-ablating effects mediated by corticosteroids or as a combined consequence of targeting eosinophil and Th2 T cells.