THE ROLE OF IL-17 PRODUCING T LYMPHOCYTES IN ALLERGIC CONTACT DERMATITIS

描述(申请人提供)：过敏性接触性皮炎(ACD)是一种T细胞介导的皮肤炎症性疾病，由皮肤表面暴露于反应性变应原引起。对有毒常春藤的反应物漆酚的炎症反应就是这样一个例子。CD4Th1、CD8Tc1细胞和CD8CTL是本病的效应细胞。干扰素-γ是由Th1和Tc1细胞产生的一种典型的炎性细胞因子，被认为是ACD炎症反应的介质。然而，有证据表明，干扰素-γ可能不参与ACD。我们最近的研究表明，过敏原特异性T细胞产生IL-17，一种促炎细胞因子。最近的文献表明，产生IL-17的T细胞在自身免疫性疾病和炎症性疾病中发挥关键作用，而这些疾病以前被认为是由Th1细胞介导的。IL-17和IL-17产生的T细胞在ACD中的作用尚不清楚。我们的初步数据表明，特定抗体中和IL-17可抑制过敏原致敏动物的ACD发病。此外，在IL-17受体缺陷小鼠中，激活的野生型T细胞对ACD的转移受到抑制。我们假设IL-17是炎症反应的关键介质，产生IL-17的T细胞是ACD的主要效应细胞。为了检验这一假说，本文提出了两个具体目标。目的1确定过敏原诱导的IL-17产生T细胞在ACD中的作用。IL-17在ACD诱导中的作用将在IL-17受体缺陷的小鼠身上得到证实。将解剖IL-17、干扰素-γ产生细胞和CTL的表型和功能。此外，我们还将鉴定产生CD_4和CD_8的IL-17 T细胞，并确定哪个亚群代表主要效应细胞。目的2将研究IL-15和IL-23在诱导和调节产生IL-17的过敏原特异性T细胞中的作用。细胞因子对产生IL-17的T细胞的调节作用将在ACD的发展过程中得到进一步验证。这一建议的结果将为鉴定新的效应性T细胞和ACD的新机制提供重要信息。这将为进一步全面研究IL-17和IL-17产生的T细胞在ACD中作用的细胞和分子机制提供基础。过敏原特异性效应T细胞的特征和调节效应细胞的机制的阐明将为制定针对疾病中过敏原特异性免疫细胞的治疗策略提供关键信息。白细胞介素17是一种可溶性蛋白，主要由活化的T淋巴细胞产生，在炎症性疾病中发挥重要作用。目前的项目旨在研究白细胞介素17如何在变态反应性接触性皮炎中介导炎症反应，并确定哪些因素调节产生白细胞介素17的T淋巴细胞的活性。这一结果可能为炎症性疾病的新治疗策略提供信息。

DESCRIPTION (provided by applicant): Allergic contact dermatitis (ACD) is a T cell mediated cutaneous inflammatory disease caused by epicutaneous exposure to reactive allergens. The inflammatory reaction to urushiol, the reactive agent of poison ivy, is one such example. CD4+ Th1, CD8+ Tc1 cells and CD8+ CTL have been demonstrated to be effector cells for the disease. IFN-gamma, a prototypic inflammatory cytokine produced by Th1 and Tc1 cells, has been considered to be the mediator for inflammatory reactions in ACD. However, there is evidence indicating that IFN-gamma may not be involved in ACD. Our recent studies demonstrate that allergen specific T cells produce IL-17, a pro-inflammatory cytokine. IL-17 producing T cells have been demonstrated in recent literature to play critical roles in autoimmune and inflammatory diseases, which had previously been considered to be mediated by Th1 cells. The function of IL-17 and IL-17 producing T cells in ACD has not yet been investigated. Our preliminary data indicate that neutralization of IL-17 by a specific antibody suppresses the onset of ACD in animals that are sensitized by allergens. Moreover, transfer of ACD by primed wild type T cells is suppressed in IL-17 receptor deficient mice. We hypothesize that IL-17 is a critical mediator for inflammatory reactions and IL-17 producing T cells are primary effector cells in ACD. Two specific aims are proposed to examine this hypothesis. Aim 1 will determine the role of allergen primed IL-17 producing T cells in ACD. The effect of IL-17 on the elicitation of ACD will be proven in mice that are deficient in IL-17 receptor. The phenotype and function of IL-17, IFN-gamma producing cells and CTL will be dissected. In addition, we will characterize CD4+ and CD8+ IL-17 producing T cells and determine which subset represents primary effector cells. Aim 2 will examine the role of IL-15 and IL-23 in the induction and regulation of allergen specific IL-17 producing T cells. The cytokine mediated effect on IL-17 producing T cells will be further verified in the development of ACD. The outcome of this proposal will generate important information for identification of novel effector T cells and new mechanisms for ACD. This will provide basis for further comprehensive studies on cellular and molecular mechanisms for the role of IL-17 and IL-17 producing T cells in ACD. Characterization of allergen specific effector T cells and illumination of the mechanism for the regulation of the effector cells will provide pivotal information for the development of therapeutic strategies specifically aimed at the allergen specific immune cells in the disease. Interleukine-17 is a soluble protein that is primarily produced by activated T lymphocytes and plays important roles in inflammatory diseases. The current project intends to examine how interleukine-17 mediates inflammatory reactions in allergic contact dermatitis and determine what factors modulate the activity of T lymphocytes that produce interleukine-17. The outcome may provide information for new therapeutic strategies for inflammatory diseases.