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检查过敏反应中不同的、可改变的途径。我们认为Toll样受体2（TLR 2）可能是过敏反应中修饰的关键靶点。我们专注于TLR 2（一种常见肺部暴露的受体，包括革兰氏阳性和阴性细菌）在过敏反应调节中的作用。来自我们的初步数据的实验证据表明，TLR 2途径在良好表征的小鼠模型中修饰过敏反应。TLR 2配体肽聚糖（Ppg）或PamSCys对TLR 2信号传导的刺激降低过敏反应，并且TLR 2缺陷的小鼠具有增加的过敏反应。这些数据支持我们的主要假设，即TLR 2信号通路在抑制过敏反应中起着至关重要的作用。为了剖析TLR 2介导的过敏反应的抑制，我们专注于T细胞，我们以前已经证明，在调节过敏反应的关键细胞类型。与其他先天性分子相比，TLR 2介导的过敏反应抑制不会导致Thl反应增加。这些数据使我们假设其他T细胞亚群的参与，包括已知表达TLR 2的调节性（Treg）T细胞。 Treg细胞可以抑制T细胞活化，并且已知分泌IL-10，一种有效的免疫抑制细胞因子。我们的初步数据表明，Ppg过敏原致敏小鼠的管理增加IL- 10水平，同时减少过敏反应。Treg细胞中的TLR 2信号传导可能在抑制过敏反应中提供潜在的重要途径。在目标1中，我们将研究TLR 2信号转导的关键途径，包括时间、细胞因子和TLR 2配体Ppg的作用。在目标2中，我们将研究TLR 2对变应性炎症的调节是否由包括T细胞的T细胞依赖性相互作用介导。在目的3和4中，我们关注TLR 2信号对TGFAP和过敏性炎症的标志物的影响。基本策略是检查关键分子TLR 2在过敏性免疫应答调节中的贡献。

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.