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: 9011504
• 负责人: Beatriz Leon Ruiz
• 金额: $ 36.75万
• 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 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9011504
• 关键词: Adult; Adult asthma; Affect; Age; Agreement; Allergens; Allergic; Antigen Presentation; Antigens; Asthma; B-Lymphocytes; Breathing; CD4 Positive T Lymphocytes; Cell Communication; Cells; Child; Childhood; Chronic; Chronic Disease; Clinical; Data; Dendritic Cells; Development; Disease; Effector Cell; Endotoxins; Exposure to; Extrinsic asthma; Generations; Genetic Transcription; Goals; Health; Helper-Inducer T-Lymphocyte; Home environment; Immune response; Infant; Inflammation; Life; Lung; Maintenance; Mediating; Memory; Microbe; Modality; Modeling; Morbidity - disease rate; Mus; Nature; Neonatal; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Play; Predisposition; Prevalence; Process; Public Health; Regulation; Relapse; Reporting; Role; Severities; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Symptoms; T cell response; T memory cell; T-Lymphocyte; Testing; Th2 Cells; Therapeutic; Therapeutic Intervention; Time; Toll-like receptors; Work; age related; airway inflammation; base; cost; cytokine; early childhood; environmental allergen; environmental endotoxin; experience; imprint; in vivo; infancy; infant animal; inflammatory lung disease; lymph nodes; microbial; mortality; neonate; prevent; research study; response; targeted treatment; therapeutic target

 DESCRIPTION (provided by applicant): The worldwide prevalence, morbidity and mortality of allergic asthma and associated cost are increasing. Moreover, asthma is the most common chronic disease reported in children, limiting the activities of many of then. In addition, allergi sensitization in childhood is a major predictor of chronic-relapsing asthma in adulthood. The pathophysiological features of chronic inflammation in allergic asthma are primarily the result of the aberrant activation and expansion of pathogenic T-helper 2 (TH2) immune responses to common environmental allergens. Thus, therapeutics that target the development, maintenance or function of allergen- specific TH2 cells could be used to treat asthma-associated pathology. Unfortunately, there are significant gaps in our understanding of mechanisms that initiate and regulate TH2 responses to inhaled allergens, which complicates the identification of therapeutic modalities that specifically block TH2 responses. Our preliminary data suggest that TH2 type-T follicular helper (TFH)-like cells represent TH2 memory precursors that persist long-term and convert into TH2 cell effector upon allergen recall responses. Moreover, our data suggest that the requirements to induce TH2 type-TFH-like/memory precursors vary with the age of the allergen sensitization and the levels of exposure to endotoxin. Finally, our data suggest that the age-related variances are, at least in part, mediated by differences in dendritic cell (DC) intrinsc response to toll-like receptor (TLR)-mediated activation. Thus, we hypothesize that allergen sensitization induce DC-mediated priming of TH2-type TFH cells that full develop and survive as allergen-specific TH2-type memory cells for extended periods of time after interaction with B cells within the follicle. After allergen re-exposure, allergen-specific TH2-type TFH/memory cells differentiate into short-term effector-TH2 cells and home into the lung to cause pathology. Importantly, we hypothesize that the process of allergen sensitization is more efficient in childhood due to the fact that DCs differently respond to environmental endotoxin levels and induce enhanced priming of HDM-specific pre-TH2- type TFH cells and/or TH2-type TFH cells display an enhanced survival/maintenance in childhood. In this proposal we will test this model and evaluate how allergen-bearing DCs initiate TFH cell commitment and imprint a TH2-cytokine profile in adults and infants and how microbial exposure differentially affects this process. We will study the factors required for the long-term maintenance of allergen-specific TH2 type-TFH- like/memory cells and explore the plasticity of TH2-type TFH-like cell compartment. Finally, we will evaluate the potential clinical benefits of TFH-cell antagonist to deplete HDM-specific memory TFH cells and treat allergen- specific TH2 responses. We believe that our work will contribute to our understanding of how allergen TH2-type cell responses are initiated and maintained and ultimately reveal new information about potential targets for therapeutic intervention in patients with asthma.

 描述（由申请人提供）：全世界过敏性哮喘的患病率、发病率和死亡率以及相关费用正在增加。此外，哮喘是儿童中最常见的慢性疾病，限制了许多儿童的活动。此外，儿童时期的过敏致敏是成年后慢性复发性哮喘的主要预测因素。过敏性哮喘慢性炎症的病理生理学特征主要是致病性 T 辅助细胞 2 (TH2) 对常见环境过敏原的免疫反应异常激活和扩展的结果。因此，针对过敏原特异性TH2细胞的发育、维持或功能的治疗可用于治疗哮喘相关病理。不幸的是，我们对启动和调节 TH2 对吸入过敏原反应的机制的理解存在重大差距，这使得特异性阻断 TH2 反应的治疗方式的识别变得复杂。我们的初步数据表明，TH2 型 T 滤泡辅助细胞 (TFH) 样细胞代表长期存在的 TH2 记忆前体细胞，并在过敏原回忆反应后转化为 TH2 细胞效应细胞。此外，我们的数据表明，诱导TH2型-TFH样/记忆前体的要求随着过敏原致敏年龄和内毒素暴露水平的不同而变化。最后，我们的数据表明，与年龄相关的差异至少部分是由树突状细胞（DC）对 Toll 样受体（TLR）介导的激活的固有反应的差异介导的。因此，我们假设过敏原致敏诱导 DC 介导的 TH2 型 TFH 细胞启动，这些细胞在与毛囊内的 B 细胞相互作用后，作为过敏原特异性 TH2 型记忆细胞充分发育并存活较长时间。再次接触过敏原后，过敏原特异性 TH2 型 TFH/记忆细胞分化为短期效应 TH2 细胞，并进入肺部引起病理。重要的是，我们假设过敏原致敏过程在儿童期更为有效，因为 DC 对环境内毒素水平的反应不同，并诱导 HDM 特异性前 TH2 型 TFH 细胞和/或 TH2 型 TFH 细胞的增强启动，从而在儿童期表现出增强的存活/维持。在本提案中，我们将测试该模型并评估携带过敏原的 DC 如何启动 TFH 细胞定型并在成人和婴儿中印记 TH2 细胞因子谱，以及微生物暴露如何对这一过程产生不同的影响。我们将研究过敏原特异性TH2型TFH样/记忆细胞长期维持所需的因素，并探索TH2型TFH样细胞区室的可塑性。最后，我们将评估 TFH 细胞拮抗剂消除 HDM 特异性记忆 TFH 细胞和治疗过敏原特异性 TH2 反应的潜在临床益处。我们相信，我们的工作将有助于我们了解过敏原 TH2 型细胞反应如何启动和维持，并最终揭示有关哮喘患者治疗干预潜在目标的新信息。