Dendrituc Cell-Mediated Immunity in AD

特应性皮炎（AD）是一种双相性炎症性皮肤病，其特征是以初始阶段为主， Th 2细胞因子的作用，然后转移到第二个更慢性的Th 1湿疹期。研究表明 树突状细胞（DC）在AD的发病机制中起重要作用。DC被认为是最有效的抗原 呈递细胞（ARC）凭借其将先天性免疫应答与适应性免疫应答桥接的能力， 反应DC在CD 4 T细胞启动时的状态可以决定免疫的类型，T细胞或T细胞， 辅助细胞1（Th 1）或Th 2。最近，我们已经证明，依赖于产生IL-10的能力，DC Th 1或Th 2免疫反应。IL-10是一种由多种细胞产生的多效性细胞因子 类型，抑制抗原特异性活化和T细胞增殖，并最终导致T细胞的终止。 炎症反应。因此，IL-10的调节可以显著改变免疫应答。IL-4，a Th2 诱导细胞因子，抑制DC IL-10表达并随后诱导IL-12。因此，暴露于IL-4的DC 分泌更多的IL-12并促进Th 1而不是Th 2分化。这些数据表明了一个复杂的 细胞因子调节网络，并表明相同的细胞因子具有调节免疫的独特功能。 通过ARC回应。我们推测DC产生IL-10的能力有助于发病机制 通过引导Th免疫应答来治疗AD。在AD早期，DC被变应原通过Toll样受体激活 (TLR)并产生炎症和抗炎细胞因子，通过分泌 高IL-10，结果低IL-12。随着疾病的发展，局部环境中IL-4的含量 升高，因此DC将产生较少的IL-10，导致Th 1应答。我们将测试这个 通过关注DC功能和DC介导的发病机制的调节， 使用动物模型和人类患者的AD。我们的长期目标是更好地了解 DC介导的AD发病机制，这将有助于我们在未来设计改进的治疗工具。到 为了达到这个目标，我们提出了三个具体目标。在目标1中，我们将研究TLR介导的 DC的活化，假设DC上的TLR对于当过敏原被激活时活化DC是关键的。 遇到和随后的炎症。目的二是利用转基因小鼠研究DC介导的免疫功能 它将国家的组成性主动形式（StatGVT）表达为AD模式系统。我们假设 DC功能在这些小鼠中改变，因为StatGVT小鼠具有升高水平的Th 2细胞因子，包括 IL-4。最后一个目的是通过检测AD患者皮肤冲洗液来研究DC功能 病变和从患者收集的血液样品。利用动物模型， AD样症状以及AD患者，我们将获得有价值的信息，这将为我们提供更好的 了解AD和其他过敏性疾病中DC介导的免疫。

Atopic dermatitis (AD) is a biphasic inflammatory skin disease characterized by an initial phase predominated by Th2 cytokines which then shifts to a second, more chronic Th1 eczematous phase. Studies have shown that dendritic cells (DC) are important for the pathogenesis of AD. DC are considered the most potent antigen presenting cells (ARC) by virtue of their ability to bridge an innate immune response to an adaptive immune response. The status of DC at the time of priming CD4 T cells can determine the type of immunity, either T helper 1 (Th1) or Th2. Recently, we have demonstrated that, depending on the ability to produce IL-10, DC can direct either Th1 or Th2 immune responses. IL-10, a pleiotropic cytokine produced by many different cell types, inhibits antigen-specific activation and proliferation of T cells and ultimately leads to the termination of inflammatory responses. Thus, regulation of IL-10 can dramatically alter immune responses. IL-4, a Th2 inducing cytokine, inhibits DC IL-10 expression and subsequently induces IL-12. Thus, DC exposed to IL-4 secrete more IL-12 and promote Th1 instead of Th2 differentiation. These data demonstrate a complex cytokine regulatory network and indicate that the same cytokine has a distinct function modulating the immune response via ARC. We hypothesize that the ability of DC to produce IL-10 contributes to the pathogenesis of AD by directing the Th immune response. In early AD, DC are activated by allergen via toll-like receptors (TLR) and produce both inflammatory and anti-inflammatory cytokines directing Th2 development by secreting high IL-10 and as a result, low IL-12. As the disease progresses, the amount of IL-4 in the local environment is elevated and as a consequence DC will produce less IL-10 leading to a Th1 response. We will test this hypothesis in the current application by focusing on DC function and regulation of DC-mediated pathogenesis of AD using both animal models and human patients. Our long-term goal is to have a better understanding of AD pathogenesis mediated by DC, which will help us to design improved therapeutic tools in the future. To achieve this goal, we propose three specific aims. In Aim 1, we will investigate the role of TLR-mediated activation of DC with the hypothesis that TLR on DC are critical to activate DC when an allergen is encountered and for subsequent inflammation. Aim 2 will study DC-mediated immunity using transgenic mice that express a constitutively active form of State (StatGVT) as an AD model system. We hypothesize that DC functions are altered in these mice because StatGVT mice have elevated levels of Th2 cytokines including IL-4. The last Aim is devoted to studying DC function from AD patients by testing the wash fluid from the skin lesion and blood samples collected from patients. Using both an animal model that develops spontaneous AD-like symptoms as well as AD patients, we will obtain valuable information that will provide us a better understanding of DC-mediated immunity in AD and other allergic diseases.