Innate Immunity In Allergic and Non-Allergic Responses

描述(由申请人提供)：最近哮喘发病率的增加迫使在过敏反应中检查不同的、可修改的途径。我们认为Toll样受体2(TLR2)可能是修饰过敏反应的关键靶点。我们专注于TLR2(一种常见肺部暴露的受体，包括革兰氏阳性和阴性细菌)在调节过敏反应中的作用。来自我们初步数据的实验证据表明，TLR2通路在一个特征良好的小鼠模型中改变了过敏反应。TLR2配体肽聚糖(Ppg)或PamSCys刺激TLR2信号可降低过敏反应，而TLR2缺乏的小鼠过敏反应增加。这些数据支持我们的主要假设，即TLR2信号通路在抑制过敏反应中发挥关键作用。为了剖析TLR2介导的过敏反应抑制，我们将重点放在T细胞上，这是一种我们以前已经证明在调节过敏反应中至关重要的细胞类型。与其他天然分子相比，TLR2介导的过敏反应抑制不会导致Th1反应的增加。这一数据使我们假设其他T细胞亚群参与其中，包括调节性T细胞(Treg)，即已知表达TLR2的T细胞。Treg细胞可以抑制T细胞的激活，并能分泌IL-10，这是一种强有力的免疫抑制细胞因子。我们的初步数据显示，给致敏小鼠注射ppg变应原可以增加IL-10水平，同时减少过敏反应。Treg细胞中的TLR2信号可能在抑制过敏反应中提供了一条潜在的重要途径。在目标1中，我们将从时间、细胞因子和TLR2配体ppg的影响方面研究TLR2信号转导的关键途径。在目标2中，我们将研究TLR2对变态反应性炎症的调节是否通过包括Tregs在内的T细胞依赖的相互作用来介导。在目标3和4中，我们重点关注TLR2信号对Tregs标志物和过敏性炎症的影响。基本策略是研究关键分子TLR2在调节过敏免疫反应中的作用。

DESCRIPTION (provided by applicant): The recent increase in asthma incidence compels examination of distinct, modifiable pathways in allergic responses. We propose that Toll-like receptor 2 (TLR2) may be a critical target for modification in allergic responses. We focus on the role of TLR2 (a receptor for common pulmonary exposures including gram positive and negative bacteria) in the modulation of allergic responses. Experimental evidence from our preliminary data demonstrates that TLR2 pathways modify allergic responses in a well-characterized murine model. Stimulation of TLR2 signaling by the TLR2 ligand peptidoglycan (Ppg) or PamSCys decreases allergic responses and mice deficient in TLR2 have increased allergic responses. This data supports our major postulate that TLR2 signaling pathways play a crucial role in the suppression of allergic responses. To dissect TLR2 mediated suppression of allergic responses, we focus on T cells, a cell type we have previously shown to be critical in regulating allergic responses. In contrast to other innate molecules, the TLR2 mediated suppression of allergic responses does not result in increased Thl responses. This data leads us to hypothesize involvement of other T cell subsets, including regulatory (Treg), T cells known to express TLR2. Treg cells can inhibit T cell activation and are known to secrete IL-10, a potent immunosuppressive cytokine. Our preliminary data demonstrates that administration of Ppg allergen to sensitized mice increases IL- 10 levels while decreasing allergic responses. TLR2 signaling in Treg cells may provide a potentially important pathway in the suppression of allergic responses. In Aim 1, we will examine critical pathways for TLR2 signaling in terms of timing, cytokines and effects of the TLR2 ligand, Ppg. In Aim 2, we will investigate whether TLR2 modulation of allergic inflammation is mediated by T cell dependent interactions including Tregs. In Aims 3 and 4, we focus on the effect of TLR2 signals on markers of Tregs, and allergic inflammation. The fundamental strategy is to examine the contribution of the key molecule TLR2 in the modulation of allergic immune responses.