Dendrituc Cell-Mediated Immunity in AD

特应性皮炎(AD)是一种以初期为主的双相炎症性皮肤病 通过Th2细胞因子，然后转移到第二个更慢性的Th1湿疹阶段。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 提呈细胞(ARC)，因为它们具有连接先天免疫反应和适应性免疫反应的能力 回应。树突状细胞在启动CD4T细胞时的状态可以决定免疫的类型，T 帮助者1(Th1)或Th2。最近，我们已经证明，依赖于产生IL-10的能力，DC 可以引导Th1或Th2免疫反应。IL-10，多种细胞产生的多效性细胞因子 抑制抗原特异性T细胞的激活和增殖，并最终导致 炎症反应。因此，调节IL-10可以显著改变免疫反应。IL-4，Th2 诱导细胞因子，抑制DC IL-10的表达，继而诱导IL-12。因此，暴露于IL-4的DC 分泌更多IL-12，促进Th1而不是Th2分化。这些数据证明了一个复杂的 细胞因子调节网络，表明相同的细胞因子具有不同的免疫调节功能 通过ARC进行响应。我们推测DC产生IL-10的能力与其发病机制有关。 通过引导Th免疫反应来预防AD。在AD早期，DC通过Toll样受体被变应原激活 (TLR)，并产生炎症和抗炎细胞因子，通过分泌 高IL-10，结果是低IL-12。随着疾病的发展，局部环境中IL-4的数量 因此DC会产生较少的IL-10，从而导致Th1应答。我们将对此进行测试 假说在目前的应用中侧重于DC的功能及其对DC介导的发病机制的调控 使用动物模型和人类患者对AD进行研究。我们的长期目标是更好地了解 树突状细胞介导的AD发病机制，这将有助于我们未来设计改进的治疗工具。至 为了实现这一目标，我们提出了三个具体目标。在目标1中，我们将研究TLR介导的作用 DC的激活，假设DC上的TLR在变态反应原激活DC时是关键的 对于遇到的和随后的炎症。AIM 2将利用转基因小鼠研究DC介导的免疫 它将构成活动形式的国家(StatGVT)表示为AD模型系统。我们假设 这些小鼠的DC功能发生了变化，因为StatGVT小鼠的Th2细胞因子水平升高，包括 IL-4。最后一个目的是通过测试皮肤上的洗涤液来研究AD患者的DC功能 从病人身上采集的病变和血液样本。使用一种自发发展的动物模型 AD类症状以及AD患者，我们将获得有价值的信息，这些信息将为我们提供更好的 对DC免疫在AD等变态反应性疾病中的认识。

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.