Regulation of T cell responses to allergens and environmental microbes

 描述(申请人提供)：过敏性哮喘及其相关费用的全球流行率、发病率和死亡率正在增加。此外，哮喘是儿童报告的最常见的慢性病，限制了许多儿童的活动。此外，儿童时期的过敏原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特征主要是致病T辅助细胞2(TH2)对常见环境变应原免疫反应异常激活和扩张的结果。因此，以过敏原特异性TH2细胞的发育、维持或功能为目标的疗法可用于治疗哮喘相关的病理。不幸的是，我们对启动和调节TH2对吸入性变应原反应的机制的理解存在重大差距，这使得识别专门阻断TH2反应的治疗方式变得复杂。我们的初步数据表明，TH2型-T滤泡助手(TFH)样细胞代表TH2记忆前体，长期存在，并在过敏原回忆反应时转换为TH2细胞效应器。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的年龄和暴露于内毒素的水平而不同。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)介导的激活的内在反应的差异所介导的。因此，我们假设过敏原敏化诱导DC介导的TH2型TFH细胞启动，在与滤泡内的B细胞相互作用后，TH2型TFH细胞完全发育并作为过敏原特异性TH2型记忆细胞存活很长一段时间。在过敏原再次暴露后，变应原特异性TH2型TFH/记忆细胞分化为短期效应TH2细胞，并进入肺内导致病理。重要的是，我们假设变应原致敏过程在儿童时期更有效，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细胞在儿童时期表现出增强的生存/维持能力。在这项提案中，我们将测试这一模型，并评估携带过敏原的DC如何在成人和婴儿中启动TFH细胞承诺和印记TH2-细胞因子谱，以及微生物暴露如何不同地影响这一过程。我们将研究TH2型TFH样/记忆细胞长期维持所需的因素，并探索TH2型TFH样细胞室的可塑性。最后，我们将评估TFH细胞拮抗剂耗尽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理解过敏原TH2型细胞反应是如何启动和维持的，并最终揭示有关哮喘患者治疗干预的潜在靶点的新信息。

 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.