Regulation of T cell responses to allergens and environmental microbes

T 细胞对过敏原和环境微生物反应的调节

• 批准号: 10092896
• 负责人: Beatriz Leon Ruiz
• 金额: $ 44.55万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-10 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10092896
• 关键词: Adult; Adult asthma; Affect; Age; Allergens; Allergic; Allergic inflammation; Asthma; Breast Feeding; Cell Differentiation process; Cells; Child; Childhood; Childhood Asthma; Chronic; Chronic lung disease; Clinical Data; Data; Dendritic Cells; Developed Countries; Development; Diet; Disease; Dose; Dust; Economic Burden; Endotoxins; Environment; Environmental Exposure; Exposure to; Extrinsic asthma; Farming environment; Formulation; Genes; Genetic; Genetic Transcription; Helper-Inducer T-Lymphocyte; Human Milk; Hygiene; Hypersensitivity; ITGAM gene; Impairment; Incidence; Infant; Inflammation; Inflammatory Response; Interferon Type II; Interleukin-12; Interleukin-18; Interleukin-6; Lactation; Licensing; Life; Life Style; Mediating; Mediator of activation protein; Microbe; Morbidity - disease rate; Mus; Outcome; Pathogenesis; Play; Predisposition; Prevalence; Prevention; Prevention approach; Process; Production; Public Health; Publishing; Relapse; Risk; Risk Factors; Role; Severities; Signal Transduction; Source; Symptoms; T cell regulation; T cell response; T-Lymphocyte; TNF gene; Testing; Th2 Cells; Up-Regulation; Work; airborne allergen; allergic airway inflammation; allergic response; asthma prevention; base; chronic inflammatory lung disease; cost; cytokine; early childhood; experience; experimental study; high risk; infancy; interest; microbial; microorganism; milk supply; monocyte; mortality; prevent; programs; response; rural area; urban area

Summary. Asthma is a chronic lung disease that inflames/narrows the airways. Chronic allergic inflammation is primarily mediated by the aberrant activation/expansion of T-helper 2 (Th2) cells to airborne allergens. Interestingly, most people with Th2 asthma experience their first symptoms at a young age, suggesting that outcomes in adult asthma are determined in early childhood. In recent decades, incidence, morbidity, and mortality of pediatric allergic asthma and associated cost have been increasing worldwide, specifically among industrialized countries; and not due to the genetic background, but mainly because of the effect of environmental and lifestyle risk factors. The "hygiene hypothesis" proposes that the decreased exposure to dust containing high levels of bacterial endotoxin (LPS) and other microorganism-derived compounds at a very early age is one of the main drivers of the increasing incidence of asthma. However, no precise mechanism for this unique requirement for a high-LPS environment during infancy had been delineated. We have published that exposure to allergen induced allergen-specific Th2 cell responses; but exposure to allergen containing relatively low-doses of LPS prevented the initial priming of Th2 cells and development of subsequent Th2 cell- mediated inflammatory response in the airways of adult but not infant mice. These data show that adult and infant mice respond to LPS with different thresholds and, thus, relatively higher-doses of LPS are required to prevent Th2 cell responses and allergic inflammation in infant mice. Mechanistically, we found that unlike adult counterparts, infant conventional dendritic cells (cDCs) had impaired ability to suppress allergic-Th2 responses upon low-dose endotoxin sensitization. Importantly, our new data suggest that for the effective suppression of allergic Th2 cell activity, both the functional activation of cDCs, and the responsiveness of activated T cells are contingent on the coordinated actions of several cytokines (i.e., TNFα, IL-12, IL-18, IFNγ, and IL-6). Further, our data suggest that the first cells that sense LPS and produce cytokines to license the function of the cDCs are monocyte-derived dendritic cells (moDCs). Finally, our data show that the mother's milk-based diet conditions the differentiation and function of moDCs, which ultimately leads to a shift toward Th2 cell bias during infancy. Thus, we hypothesize that in response to low-dose LPS/allergen sensitization, moDCs initiate a cascade of cytokines, which ultimately mediate the suppression of Th2-driven allergic inflammation in adults. In infants, otherwise, this path is suppressed by the influence of the natural diet; rendering them more susceptible to allergy disease. In this proposal, we will test how specific cytokines modulate T helper cell program to allergens and how the infant diet and microbial exposure differentially affects this process. We believe the experiments in this proposal will significantly contribute to our understanding of how diet-environment interactions contribute to the development of allergic sensitization in children and ultimately will reveal new information about potential targets for prevention of asthma/allergies in children.

摘要：哮喘是一种慢性肺部疾病，会导致气道发炎/狭窄。 主要由辅助 T 细胞 2 (Th2) 细胞对空气中过敏原的异常激活/扩张介导。 这意味着，大多数 Th2 哮喘患者在年轻时就会出现首次症状，这表明 近几十年来，成人哮喘的发病率、发病率和发病率在儿童早期就已确定。 全世界儿童过敏性哮喘的死亡率和相关费用一直在增加，特别是在儿童中 工业化国家；并不是由于遗传背景，而主要是因为 “卫生假说”提出，减少接触环境和生活方式的风险因素。 含有高浓度细菌内毒素 (LPS) 和其他微生物衍生化合物的粉尘 早年是哮喘发病率增加的主要驱动因素之一，但尚无确切的机制。 我们已经描述了婴儿期高 LPS 环境的独特要求。 暴露于过敏原会诱导过敏原特异性 Th2 细胞反应，但暴露于含有过敏原的环境中； 相对低剂量的 LPS 阻止了 Th2 细胞的初始启动和后续 Th2 细胞的发育 这些数据表明，在成年小鼠和幼年小鼠的呼吸道中介导炎症反应。 幼年小鼠对 LPS 的反应阈值不同，因此需要相对较高剂量的 LPS 从机制上讲，我们发现与成年小鼠不同。 婴儿传统树突状细胞 (cDC) 抑制过敏 Th2 反应的能力受损 重要的是，我们的新数据表明，低剂量内毒素致敏可以有效抑制。 过敏性 Th2 细胞活性、cDC 的功能激活和活化 T 细胞的反应性 取决于多种细胞因子（即 TNFα、IL-12、IL-18、IFNγ 和 IL-6）的协调作用。 我们的数据表明，第一批感知 LPS 并产生细胞因子以许可 cDC 功能的细胞 是单核细胞衍生的树突状细胞（moDC） 最后，我们的数据表明，以母乳为基础的饮食。 调节 moDC 的分化和功能，最终导致 Th2 细胞偏好的转变 因此，我们希望 moDC 能够响应低剂量的 LPS/过敏原致敏反应。 细胞因子级联，最终介导抑制成人 Th2 驱动的过敏性炎症。 婴儿，否则，这条路径会受到自然饮食的影响而受到抑制； 在本提案中，我们将测试特定细胞因子如何调节 T 辅助细胞程序以实现过敏性疾病。 过敏原以及婴儿饮食和微生物暴露如何不同地影响这一过程。 该提案中的实验将极大地有助于我们理解饮食与环境之间的关系 相互作用有助于儿童过敏的发生，并最终揭示新的 有关预防儿童哮喘/过敏的潜在目标的信息。