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对过敏反应中不同的、可改变的途径进行检查。我们认为toll样受体2 （TLR2）可能是过敏反应修饰的关键靶点。我们关注TLR2（一种常见肺部暴露的受体，包括革兰氏阳性和阴性细菌）在过敏反应调节中的作用。从我们的初步数据的实验证据表明，TLR2途径改变过敏反应在一个良好的小鼠模型。TLR2配体肽聚糖（Ppg）或PamSCys刺激TLR2信号传导可降低过敏反应，TLR2缺陷小鼠的过敏反应增加。这些数据支持了我们的主要假设，即TLR2信号通路在抑制过敏反应中起着至关重要的作用。为了解剖TLR2介导的过敏反应抑制，我们将重点放在T细胞上，这是一种我们之前已经证明在调节过敏反应中至关重要的细胞类型。与其他先天分子相比，TLR2介导的过敏反应抑制不会导致Thl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，包括已知表达TLR2的调节性T细胞（Treg）。Treg细胞可以抑制T细胞的激活，并分泌IL-10，一种有效的免疫抑制细胞因子。我们的初步数据表明，给致敏小鼠注射Ppg过敏原可增加IL- 10水平，同时降低过敏反应。Treg细胞中的TLR2信号可能是抑制过敏反应的一个潜在的重要途径。在Aim 1中，我们将从时间、细胞因子和TLR2配体Ppg的作用方面研究TLR2信号传导的关键途径。在Aim 2中，我们将研究TLR2对过敏性炎症的调节是否由T细胞依赖的相互作用介导，包括Tregs。在Aims 3和4中，我们重点研究了TLR2信号对Tregs标记物和过敏性炎症的影响。基本策略是检查关键分子TLR2在过敏性免疫反应调节中的作用。

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.