Differentiation of Th2 cytokine-producing innate cells

产生 Th2 细胞因子的先天细胞的分化

• 批准号: 7385057
• 负责人: HUA HUANG
• 金额: $ 32.65万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385057
• 关键词: Acetylation; Acute; Allergens; Allergic; Applications Grants; Asthma; Basophils; Biological Assay; Blood Circulation; Bone Marrow; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Count; Country; DNA; Data; Detection; Development; Disease; Effector Cell; Epigenetic Process; Fluorescence; GATA1 gene; Genes; Goals; Helper-Inducer T-Lymphocyte; Horns; Hypersensitivity; IL4 gene; Immune; Immunity; In Vitro; Incidence; Infection; Inflammation; Interleukin-13; Interleukin-4; Interleukin-5; Interleukin-9; Interleukins; Knockout Mice; Lead; Location; Lung; Measures; Messenger RNA; Methods; Methylation; Molecular; Mus; Natural Immunity; Numbers; Parasitic infection; Play; Pollution; Proteins; Proto-Oncogene Protein c-kit; Regulation; Regulatory Element; Reporter; Research Personnel; Role; STAT6 gene; Severities; Small Interfering RNA; Staging; Stem cells; System; Testing; Th2 Cells; Tissues; airway inflammation; allergic airway inflammation; base; cytokine; eosinophil; in vivo; insight; knock-down; mRNA Expression; mast cell; mortality; novel; programs; reconstitution; research study; response

DESCRIPTION (provided by applicant): Airway inflammation induced by various allergens, pollution, and infections is a major underlying cause of asthma, a disease with alarming increases in incidence and mortality in the western countries in the past two decades. We seek to understand the cellular and molecular basis for exacerbation of asthma. Our immediate goal is to investigate the mechanisms by which CD4+ T helper cells (Th) regulate differentiation of innate Th2-type effector cells. Both CD4+ Th 2 cells and Th2-type innate effector cells have been shown to play critical roles in causing allergic airway inflammation by producing interleukin (IL)-4, IL-5, IL-9, IL-13 and IL-25. However, the mechanisms by which CD4+ Th2 cells regulate innate Th2-type effector cells are unknown. We studied these mechanisms by using IL-4 reporter mice. We found that IL-4 plays an important role in the differentiation of Th2 cytokine-producing innate cells both in vivo and in vitro. Based on our preliminary findings, we hypothesize that IL-4 primes bone marrow progenitor cells into Th2-type innate effector cells via a GATAS-dependent mechanism, while IL-5 does so via TAT5/GATA1-dependent mechanisms. We propose three specific aims to test our hypothesis. in Aim 1, we will determine whether CD4+Th2 effector cells coordinate with innate cells to generate Th2-type immunity through secretion of IL-4 and IL-5. In Aim 2, we will determine whether IL-4 directs bone marrow progenitor cells to differentiate into innate Th2-type effector cells via a GATA3-dependent mechanism; and In Aim 3, we will determine whether IL-5 directs bone marrow progenitor cells to differentiate into Th2-type innate effector cells via a STAT5/GATA1-dependent mechanism. These studies will identify novel aspects of interaction between adaptive immunity and innate cells. For diseases such as allergic inflammation, asthma, parasitic infection, and other immune dysregulations, our findings could lead to more effective treatments.

描述（由申请人提供）：由各种过敏原、污染和感染诱导的气道炎症是哮喘的主要潜在原因，哮喘是一种在过去二十年中在西方国家发病率和死亡率惊人增加的疾病。我们试图了解哮喘恶化的细胞和分子基础。我们的近期目标是研究CD 4 + T辅助细胞（Th）调节先天性Th 2型效应细胞分化的机制。CD 4 + Th 2细胞和Th 2型先天性效应细胞通过产生白细胞介素（IL）-4、IL-5、IL-9、IL-13和IL-25在引起过敏性气道炎症中起关键作用。然而，CD 4 + Th 2细胞调节先天性Th 2型效应细胞的机制尚不清楚。我们使用IL-4报告小鼠研究了这些机制。我们发现，IL-4在体内和体外的Th 2细胞的分化中起着重要的作用。基于我们的初步研究结果，我们假设IL-4通过GATAS依赖性机制将骨髓祖细胞诱导为Th 2型先天性效应细胞，而IL-5通过TAT 5/GATA 1依赖性机制这样做。我们提出了三个具体目标来检验我们的假设。在目的1中，我们将确定CD 4 + Th 2效应细胞是否通过分泌IL-4和IL-5与先天性细胞协调产生Th 2型免疫。在目标2中，我们将确定IL-4是否通过GATA 3依赖性机制指导骨髓祖细胞分化为先天性Th 2型效应细胞;在目标3中，我们将确定IL-5是否通过STAT 5/GATA 1依赖性机制指导骨髓祖细胞分化为先天性Th 2型效应细胞。这些研究将确定适应性免疫和先天细胞之间相互作用的新方面。对于过敏性炎症，哮喘，寄生虫感染和其他免疫失调等疾病，我们的发现可能会导致更有效的治疗方法。