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.

概括。哮喘是一种慢性肺部疾病，炎症/缩小气道。慢性过敏性注射 主要是由T-Helper 2（Th2）细胞的异常激活/扩展到空气传播的介导的。 有趣的是，大多数患有TH2哮喘的人在很小的时候就会出现第一次症状，这表明 成人哮喘的结果是在幼儿期确定的。近几十年来，事件，发病率和 小儿过敏性哮喘和相关成本的死亡率在全球范围内一直在增加，特别是 工业化国家；而不是由于遗传背景，而是主要是由于 环境和生活方式风险因素。 “卫生假设”提出的提议减少了暴露于 含有高水平的细菌内毒素（LPS）和其他微生物衍生的化合物的粉尘 幼年是哮喘发病率增加的主要驱动因素之一。但是，没有针对的精确机制 划定了对婴儿期高LPS环境的独特要求。我们已经出版了 对过敏原诱导过敏原特异性Th2细胞反应的暴露；但是暴露于含有过敏原的 相关的低剂量LPS​​阻止了Th2细胞的初始启动，并开发了随后的Th2细胞 - 成人但没有婴儿小鼠的气道中介导的炎症反应。这些数据表明成人和 婴儿小鼠对不同阈值的LP响应，因此需要相对较高的LPS才能 预防婴儿小鼠的Th2细胞反应和过敏感染。从机械上讲，我们发现与成人不同 对应物，婴儿常规树突状细胞（CDC）抑制过敏性TH2反应的能力受损 低剂量内毒素敏感性。重要的是，我们的新数据表明，有效抑制 过敏性Th2细胞活性，CDC的功能激活以及活化T细胞的反应性是 取决于几种细胞因子的协调作用（即TNFα，IL-12，IL-18，IFNγ和IL-6）。更远， 我们的数据表明，第一个感知LP并产生细胞因子来许可CDC功能的细胞 是单核细胞衍生的树突状细胞（MODC）。最后，我们的数据表明母亲的牛奶饮食 调节MODC的分化和功能，最终导致向Th2细胞偏置转移 在婴儿期。这是我们假设，对于低剂量LPS​​/过敏原敏感性，MODC启动A 一系列细胞因子，最终介导了成人Th2驱动的过敏性注射的抑制。 否则，婴儿被自然饮食的影响抑制了这条路。使他们更容易受到影响 过敏疾病。在此提案中，我们将测试特定细胞因子如何调节T辅助细胞程序 过敏原以及婴儿饮食和微生物暴露对这一过程的影响不同。我们相信 该提案中的实验将极大地有助于我们对饮食环境的理解 互动有助于儿童过敏性传感化的发展，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。