Eosinophil Activities in Murine Models of Lung Disease

小鼠肺病模型中的嗜酸性粒细胞活性

• 批准号: 8691458
• 负责人: JAMES Joseph LEE
• 金额: $ 41.5万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8691458
• 关键词: Abbreviations; Adoptive Transfer; Adrenal Cortex Hormones; Alleles; Allergens; Allergic; Anti-Inflammatory Agents; Anti-inflammatory; Appearance; Arachidonate 15-Lipoxygenase; Asthma; Automobile Driving; CD59 Antigen; Cells; Clinic; Clinical; Clinical Research; Cohort Studies; Complex; Cues; Data; Development; Diphtheria Toxin; Disease; Event; Gene Targeting; Genes; Goals; Heterogeneity; Housing; Immune; Immune response; Inflammation; Inflammatory; Inflammatory Response; Interleukin-4; Investigation; Leukocytes; Link; Lipids; Lung; Lung diseases; Mediating; Modeling; Mouse Strains; Mus; Neutrophil Infiltration; Ovalbumin; Pathway interactions; Patients; Phenotype; Pneumonia; Population Heterogeneity; Process; Protocols documentation; Pyroglyphidae; Reagent; Refractory; Regulation; Reporting; Respiratory physiology; Role; Route; Steroids; Subgroup; Symptoms; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Time; Transgenic Mice; Variant; Virus Diseases; Work; airway inflammation; commensal microbes; diphtheria toxin receptor; disease phenotype; eosinophil; expectation; improved; knockout gene; lipid mediator; mepolizumab; mouse development; mouse model; neutrophil; next generation; overexpression; patient population; population based; public health relevance; receptor; repaired; respiratory; response

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.

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，患者群体存在多样性。因此，除了通常通过皮质类固醇控制的嗜酸粒细胞性气道炎症过敏患者外，研究还发现越来越多的患者更难以治疗，包括类固醇难治性患者 表现出嗜酸性粒细胞和中性粒细胞炎症性疾病变异的重症患者。这种免疫反应的多样性在一定程度上是由肺部反应的过敏原特异性 T 细胞可塑性介导的。值得注意的是，我们对小鼠的同时研究表明，嗜酸性粒细胞在免疫调节所需途径和肺部发生的炎症事件特征中的作用未被充分认识。这项工作起源于我们使用嗜酸性粒细胞缺陷型小鼠 (PHIL) 进行的早期研究，然而，我们最近使用新创建的可诱导型嗜酸性粒细胞缺陷型小鼠 (iPHIL) 进行的研究使我们发现，过敏原激发时的嗜酸性粒细胞活性与驱动 T 细胞亚型的多样性有关。 肺部炎症（即嗜酸性粒细胞、中性粒细胞或混合型炎症）。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。我们将测试以下中心假设：嗜酸性粒细胞活性通过（i）直接影响肺部中性粒细胞的募集/积累，以及（ii）调节过敏原特异性T细胞亚型选择，在嗜酸性粒细胞存在时对Th2的反应极化，在嗜酸性粒细胞不存在时对Th17/Th1的反应极化。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，以及围绕当前疗法（例如使用皮质类固醇和美泊利单抗）的混杂问题。该提案的目标将通过完成以下具体目标来检验我们的中心假设：（1）证明嗜酸性粒细胞通过 源自12/15-脂氧合酶活性的抗炎脂质的表达； (2) 定义嗜酸性粒细胞衍生的 IL-4 和 TGFβ 表达作为调节 T 细胞亚型导致 Th2 主导型与中性粒细胞混合型 Th2/Th17/Th1 免疫反应的机制的重要性； (3) 确定类固醇难治性中性粒细胞亚群是否 过敏性呼吸道炎症是由皮质类固醇介导的嗜酸性粒细胞消融作用引起的，或者是靶向嗜酸性粒细胞和 Th2 T 细胞的综合结果。