Role of Helicobacter Pylori in the Pathogenesis of Childhood Asthma

幽门螺杆菌在儿童哮喘发病机制中的作用

• 批准号: 8524060
• 负责人: Lisa A Miller
• 金额: $ 38.95万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-16 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8524060
• 关键词: Address; Aerosols; Affect; Africa; Age; Allergens; Allergic Disease; Allergic inflammation; Antibiotics; Asthma; Attenuated; Biological; California; Case-Control Studies; Cells; Child; Childhood Asthma; Chronic; Chronic Gastritis; Communicable Diseases; Complex; Developed Countries; Developing Countries; Development; Disease; Environmental Risk Factor; Epidemiology; Exposure to; Extrinsic asthma; Family Sizes; Frequencies; Gastritis; Gastrointestinal tract structure; Gender; Helicobacter; Helicobacter Infections; Helicobacter pylori; Histopathology; Human; Hygiene; Immune; Immune response; Immunophenotyping; Immunosuppressive Agents; Incidence; Individual; Infant; Infection; Inflammation; Life; Link; Lung; Lymphocyte; Macaca; Macaca mulatta; Mammals; Mediating; Modeling; Monkeys; Obesity; Ozone; Pathogenesis; Pathogenicity Island; Peptic Ulcer; Phenotype; Population; Prevalence; Prevention; Primates; Public Health; Publishing; Pyroglyphidae; Regulatory T-Lymphocyte; Research; Research Personnel; Role; Stomach; T-Lymphocyte; Testing; Time; Toxin; airborne allergen; airway inflammation; base; candidate identification; clinically relevant; cytokine; early childhood; early life exposure; lymph nodes; malignant stomach neoplasm; mucosal site; novel; nutrition; peripheral blood; prevent; pulmonary function; research study; response; treatment strategy

DESCRIPTION (provided by applicant): Helicobacter pylori commonly infects the human stomach, where it causes inflammation (gastritis) in all individuals and peptic ulcer disease or gastric cancer in some. The prevalence of H. pylori in children in developed countries is less than 10%, while it is nearly universal in most developing countries. As the prevalence of H. pylori has declined, several diseases have dramatically increased, one of which is childhood asthma. Recent retrospective and case control studies suggest that infection with H. pylori, particularly strains bearing the proinflammatory cag pathogenicity island, is inversely associated with asthma. H. pylori induction of a regulatory T cell (Treg) response in children is a biologically plausible mechanism that may explain this association. The primary objective of this proposal is to determine if early life exposure to H. pylori can prevent the development of childhood asthma. Our overall hypothesis is that H. pylori promotes a Treg-biased immune response in children that can suppress synthesis of pulmonary and systemic cytokines that promote allergic inflammation, thereby protecting the airways from development of reactivity in early life. This hypothesis is based on our preliminary findings in rhesus macaques that Treg cells in maturing airways are attenuated by house dust mite aerosol exposure, and the published observation that H. pylori promotes development of gastric mucosal Treg cells in children. Thus, we propose that enhancement of Treg cell populations by H. pylori infection may prevent the inhibitory effects of aeroallergen on this immunosuppressive lymphocyte. The rhesus macaque models of H. pylori and asthma developed at the California National Primate Research Center (CNPRC) provide a unique opportunity to study the hypothesis that H. pylori protects against childhood asthma, which we will test with the following specific aims: (1) Determine if experimental H. pylori infection can prevent the asthma phenotype in the infant rhesus macaque model of childhood asthma. (2) Examine the effects of H. pylori infection on systemic, gastric, and pulmonary immune correlates of the childhood asthma phenotype. Completion of these Specific Aims will provide important experimental support for epidemiologic findings, and may be directly extrapolated towards identification of candidate compounds for the prevention of childhood asthma and other co-morbid conditions.

描述（由申请人提供）：幽门螺杆菌通常感染人类胃，在所有个体中引起炎症（胃炎），在一些个体中引起消化性溃疡疾病或胃癌。H.在发达国家，儿童幽门螺杆菌感染率不到10%，而在大多数发展中国家几乎是普遍存在的。H.幽门螺杆菌的数量下降了，几种疾病却急剧增加，其中之一就是儿童哮喘。最近的回顾性和病例对照研究表明，感染H。幽门螺杆菌，特别是携带促炎性CAG致病岛的菌株，与哮喘呈负相关。H.幽门螺杆菌诱导儿童调节性T细胞（Treg）反应是一种生物学上合理的机制，可以解释这种关联。这项建议的主要目的是确定是否早期生活暴露于H。幽门螺杆菌可以预防儿童哮喘的发展。我们的总体假设是H.幽门螺杆菌促进了儿童Treg偏向的免疫应答，其可以抑制促进过敏性炎症的肺和全身细胞因子的合成，从而保护气道在早期生活中不发生反应性。这一假设是基于我们在恒河猴中的初步发现，即成熟气道中的Treg细胞被屋尘螨气溶胶暴露所减弱，以及已发表的观察结果，即H。pylori促进儿童胃粘膜Treg细胞的发育因此，我们认为H. pylori感染可能阻止了空气变应原对这种免疫抑制性淋巴细胞的抑制作用。以H. pylori和哮喘的研究提供了一个独特的机会来研究H. pylori可以预防儿童哮喘，我们将通过以下具体目标进行测试：（1）确定实验性H. pylori感染可预防幼年恒河猴哮喘模型中的哮喘表型。(2)检查H的影响。幽门螺杆菌感染对儿童哮喘表型的全身、胃和肺免疫相关性的影响这些特定目标的完成将为流行病学研究结果提供重要的实验支持，并可直接外推到用于预防儿童哮喘和其他共病状况的候选化合物的鉴定。