Role of gender in TH17-mediated inflammation in severe asthma

性别在 TH17 介导的严重哮喘炎症中的作用

• 批准号: 8989154
• 负责人: Dawn C Newcomb
• 金额: $ 24.66万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-22 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8989154
• 关键词: Adult; Affect; Asthma; Bronchoalveolar Lavage Fluid; CD4 Positive T Lymphocytes; Caring; Cell Differentiation process; Cell Separation; Cells; Cellular biology; Child; Clinical Trials; Data; Estradiol; Estrogens; Female; Flow Cytometry; Future; Gender; Gender Role; Gonadal Steroid Hormones; Harvest; Health; Health Care Costs; Healthcare; Immune; Inbred BALB C Mice; Infiltration; Inflammation; Inflammatory; Interleukin-13; Interleukin-17; Interleukin-4; Journals; Liquid substance; Lung; Mediating; Memory; Metaplasia; MicroRNAs; Monoclonal Antibodies; Morbidity - disease rate; Mucous body substance; Mus; Ovalbumin; Ovarian hormone; Pathogenesis; Patients; Phenotype; Pilot Projects; Placebos; Prevalence; Production; Progesterone; Protein Secretion; Puberty; Publications; Regulation; Research; Role; Signal Transduction; Surface; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Th2 Cells; Therapeutic; Woman; airway inflammation; base; boys; cost; cytokine; design; girls; in vivo; inhibitor/antagonist; interleukin-23; male; memory CD4 T lymphocyte; men; mortality; mouse model; personalized medicine; protein expression; receptor; response; trend

 DESCRIPTION (provided by applicant): Severe asthma is a significant health care concern with patients having poorer asthma control, frequent asthma attacks, and increased heath care costs compared to milder asthma phenotypes. Boys have an increased prevalence of severe asthma compared to girls. This increased prevalence of severe asthma switches from boys to women around puberty, suggesting a role for sex hormones. However, it remains unknown how gender and ovarian hormones affect severe asthma pathogenesis. IL-17A, a cytokine secreted by CD4+ T cells and γō T cells, is increased in the bronchoalveolar lavage fluid of patients with severe asthma compared to milder asthma phenotypes. IL-17A is also associated with increased airway inflammation, airway responsiveness (AR), and mucus production. Our preliminary data show increased IL-17A protein expression in Th17 differentiated cells from women compared to men. We also show 17β-estradiol (E2) and progesterone (P4) administration in ovariectomized female mice increased Th17 differentiated cell expression of IL-17A. We hypothesize that female gender, via ovarian hormones, increases Th17 cell differentiation and IL-17A secretion from Th17 cells and γō T cells. We further hypothesize that in vivo 17β-E2 and P4 administration increases Th17-mediated airway inflammation, AR, and mucus production in mice. In Aim 1, we will differentiate Th17 cells from healthy women and men and determine the role of gender in Let-7f regulation of IL-23 receptor (R) and IL-17A protein expression on Th17 differentiating cells. In Aim 2, memory T cells will be isolated to determine if women with severe asthma have increased IL-17A secreting memory CD4+ T cells compared to men with severe asthma. In Aim 3, we will delineate the mechanisms by which in vivo administration of 17β-E2 and P4 increases IL-17A-mediated airway inflammation in mice. Our results will be the first to determine the role of gender and ovarian hormones on IL-17A-mediated airway inflammation in severe asthma. Our findings may also be helpful in designing future clinical trials by determining if women and men with severe asthma have differential IL-17A production and responses to therapeutics in clinical trials for moderate to severe asthma.

 描述(申请人提供)：重度哮喘是一个重要的医疗保健问题，与较轻的哮喘表型相比，患者的哮喘控制较差，哮喘发作频繁，医疗费用较高。与女孩相比，男孩严重哮喘的患病率更高。严重哮喘的患病率在青春期前后从男孩转移到女性，这表明性激素起到了作用。然而，性别和卵巢激素如何影响严重哮喘的发病机制仍不清楚。IL-17A是一种由γō+T细胞和CD4+T细胞分泌的细胞因子，在慢性阻塞性肺疾病患者的支气管肺泡灌洗液中升高。 重度哮喘与轻度哮喘表型比较。IL-17A还与呼吸道炎症、气道反应性(AR)和粘液产生增加有关。我们的初步数据显示，与男性相比，女性Th17分化细胞中IL-17A蛋白的表达增加。我们还发现17β-雌二醇(E_2)和孕酮(P_4)对去卵巢雌性小鼠Th17分化细胞IL-17A的表达有促进作用。我们假设女性通过卵巢激素促进Th17细胞分化和Th17细胞和γōT细胞分泌IL-17A。我们进一步假设，在体内，17β-E2和P4给药增加了Th17介导的小鼠呼吸道炎症、AR和粘液产生。在目标1中，我们将从健康女性和男性中分离出Th17细胞，并确定性别在let-7f调节Th17分化细胞上IL-23受体(R)和IL-17A蛋白表达中的作用。在目标2中，将分离记忆T细胞，以确定与严重哮喘男性相比，严重哮喘女性是否增加了分泌IL-17A的记忆CD4+T细胞。在目标3中，我们将描述体内给予17β-E2和P4增加IL-17A介导的小鼠呼吸道炎症的机制。我们的结果将首次确定性别和卵巢激素在重症哮喘患者IL-17A介导的呼吸道炎症中的作用。我们的发现也可能有助于设计未来的临床试验，通过确定在中到重度哮喘的临床试验中，女性和男性重度哮喘患者是否有不同的IL-17A产生和对治疗的反应。