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（由适用提供）：世界的流行，发病率和过敏性哮喘和相关成本的死亡率正在增加。此外，哮喘是儿童中最常见的慢性疾病，限制了当时的许多活动。此外，儿童时期的敏感性是成年后慢性哮喘的主要预测指标。过敏性哮喘中慢性感染的病理生理特征是病原性T-助手2（TH2）免疫反应对常见环境过敏原的异常激活和扩展的结果。那是针对过敏原Th2细胞发育，维持或功能的治疗，可用于治疗哮喘相关的病理。不幸的是，我们对启动和调节对掺入过敏原反应的机制的理解存在很大的差距，这使鉴定治疗方式的鉴定复杂化，这些方法专门阻止了TH2反应。我们的初步数据表明，Th2 Type-T卵泡辅助器（TFH）样细胞代表TH2记忆前体，这些记忆前体长期持续并在过敏原回忆反应上转化为Th2细胞效应子。此外，我们的数据表明，诱导Th2 Type-TFH的/记忆前体的要求随过敏原感觉的年龄和内毒素暴露水平而变化。最后，我们的数据表明，与年龄相关的方差至少部分是由树突状细胞（DC）Intrinsc对Toll样接收器（TLR）介导的激活的差异的差异介导的。这是我们假设，过敏原感应化诱导了Th2型TFH细胞的DC介导的启动，这些启动是完全发育并作为过敏原特异性的Th2型记忆细胞在与B细胞相互作用后的长时间内的长时间生存。过敏原重新暴露后，过敏原特异性Th2型TFH/记忆细胞分化为短期效应TH2细胞，并将其归为肺部以引起病理。重要的是，我们假设过敏原敏感性的过程在儿童时期更有效，因为DC对环境内毒素水平有所不同，并诱导HDM特异性Th2- Th2-型TFH细胞和/或Th2-Type TFH细胞的启动增强。在此提案中，我们将测试该模型，并评估过敏原的DC启动TFH细胞承诺和烙印成人和婴儿中Th2-循环的特征，以及微生物暴露对这一过程的影响如何不同。我们将研究长期维持过敏原特异性Th2 Type-TFH样细胞室所需的因素。最后，我们将评估TFH细胞拮抗剂的潜在临床益处，以复制HDM特异性记忆TFH细胞并处理过敏原Th2反应。我们认为，我们的工作将有助于我们对如何启动和维护过敏原Th2型细胞反应的理解，并最终揭示有关哮喘患者治疗干预措施的潜在靶标的新信息。