The role of cyclooxygenase in the adaptive immune response and tolerance

环氧合酶在适应性免疫反应和耐受中的作用

• 批准号: 7797252
• 负责人: Ray Stokes Peebles
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797252
• 关键词: Acetaminophen; Adult; Affect; Allergens; Allergic; Allergic Disease; Allergic inflammation; Allergic rhinitis; Animal Model; Anti-Allergic Agents; Atopic Dermatitis; CD4 Positive T Lymphocytes; Cell Count; Cell Differentiation process; Cell Maturation; Cell physiology; Chronic Disease; Coxibs; Cyclooxygenase Inhibitors; Dendritic Cells; Development; Disease; Early treatment; Epidemic; Epidemiologic Studies; Essential Fatty Acids; Extrinsic asthma; Food Hypersensitivity; Generations; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Greater sac of peritoneum; Health; Human; Hypersensitivity; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunization; Inflammation; Interleukin-4; Ligands; Lung; Lymph; Memory; Metabolic Pathway; Military Personnel; Modality; Modeling; Molecular; Morbidity - disease rate; Mus; Ovalbumin; Pathway interactions; Pharmaceutical Preparations; Population; Prevalence; Prevention; Production; Prostaglandin-Endoperoxide Synthase; Public Health; Regulatory T-Lymphocyte; Research; Risk; Risk Factors; Role; STAT6 gene; Signal Transduction; Site; T cell differentiation; T cell response; T memory cell; T-Cell Activation; Th2 Cells; Tissues; United States; Veterans; adaptive immunity; allergic response; base; cyclooxygenase 1; cyclooxygenase 2; effective intervention; fatty acid metabolism; improved; jagged1 protein; memory CD4 T lymphocyte; mouse model; notch protein; prevent; public health relevance; receptor; response

DESCRIPTION (provided by applicant): ABSTRACT Allergic diseases are some of the most common and most costly illnesses in the United States and the prevalence of allergy has doubled in the last four decades. Mounting evidence from recent epidemiological studies reveals an association between frequent use of the cyclooxygenase (COX) inhibiting drug acetaminophen and increased risk of developing allergic diseases, suggesting a possible role of COX inhibition in causing the allergy epidemic. This possibility is supported by our studies using a mouse model of ovalbumin (OVA)-induced allergic inflammation that reveal COX inhibition augments the allergen-induced inflammation, a Th2 immune response. However, the mechanism by which COX inhibition increases Th2 immunity is not clear. Our preliminary results indicate that COX inhibition during allergic sensitization is sufficient to enhance Th2 immune priming and memory, and that COX inhibition abolishes OVA-specific immune tolerance, suggesting an active role of the COX pathway in the development of Th2 immune responses. Furthermore, COX inhibition strongly augments allergic Th2 responses in a STAT6-independent fashion, suggesting that a non-classical and STAT6-independent Th2 differentiation pathway is strongly activated by COX inhibition. The overall HYPOTHESIS to be evaluated is that COX inhibition augments allergic responses by enhancing dendritic cell immune stimulatory function, increasing memory T cell generation, and suppressing regulatory T cells (Tregs). The SPECIFIC AIMS are: (1) Determine the effect of COX inhibition during allergic sensitization on dendritic cell maturation, differentiation and function. (2) Determine the mechanism by which COX inhibition during allergic sensitization augments STAT6-independent Th2 responses, increases the generation of memory CD4 T cells, and abolishes allergen-specific immunologic tolerance. By defining the cellular and molecular mechanisms for COX inhibition-augmented allergic responses, these studies will advance our understanding of the impact of the COX metabolic pathway on the genesis of adaptive immunity and STAT6- independent Th2 responses, while providing potential targets for early interventions against the development of allergic diseases. PUBLIC HEALTH RELEVANCE: Project Narrative Allergic diseases are a major burden to public health in the United States, and the prevalence has doubled in the past three decades. This is of particular relevance to Veterans of the US Military in whom the prevalence of allergic rhinitis is approximately 30% and allergic asthma is approximately 6%. Thus, allergic diseases are an important cause of morbidity among Veterans. The proposed research will advance our understanding of the genesis of allergic disorders and identify potential targets for the development of anti-allergic modalities capable of treating and preventing allergic diseases, thus improving the health of our Veterans.

描述（由申请人提供）： 抽象过敏性疾病是美国一些最常见，最昂贵的疾病，在过去的四十年中，过敏疾病的流行率翻了一番。来自最近流行病学研究的越来越多的证据表明，频繁使用环氧酶（COX）抑制药物对乙酰氨基酚的频繁使用与增加过敏性疾病的风险增加，这表明COX抑制在导致过敏流行中起作用。我们的研究使用了椭圆蛋白（OVA）诱导的过敏性炎症的小鼠模型来支持这种可能性，这表明COX抑制增加了过敏原诱导的炎症，Th2免疫反应。但是，COX抑制增加Th2免疫力的机制尚不清楚。我们的初步结果表明，在过敏敏化期间的COX抑制足以增强Th2免疫启动和记忆，并且COX抑制作用消除了OVA特异性的免疫耐受性，这表明COX途径在Th2免疫反应发展中的积极作用。此外，Cox抑制以独立于Stat6的方式强烈增强过敏性TH2反应，这表明非古典和STAT6独立的TH2分化途径被COX抑制强烈激活。要评估的总体假设是COX抑制通过增强树突状细胞免疫刺激功能，增加记忆T细胞的产生和抑制调节性T细胞（TREG）。具体目的是：（1）确定过敏敏化期间Cox抑制作用对树突状细胞成熟，分化和功能的影响。 （2）确定过敏敏化期间COX抑制的机制增加了STAT6独立的TH2反应，增加了记忆CD4 T细胞的产生，并消除了过敏原特异性免疫耐受性。通过定义针对COX抑制作用的过敏反应的细胞和分子机制，这些研究将提高我们对COX代谢途径对适应性免疫和STAT6-独立TH2反应起源的影响的理解，同时为早期干预措施提供针对过敏性疾病发展的潜在靶标。 公共卫生相关性： 项目叙事过敏性疾病是美国公共卫生的重大负担，在过去的三十年中，患病率增加了一倍。这与美军的退伍军人特别相关，美国军方的过敏性鼻炎的患病率约为30％，过敏性哮喘约为6％。因此，过敏性疾病是退伍军人发病率的重要原因。拟议的研究将促进我们对过敏性疾病的起源的理解，并确定能够治疗和预防过敏性疾病的抗过敏方式发展的潜在靶标，从而改善退伍军人的健康。