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

描述（由申请人提供）：变应性接触性皮炎（ACD）是一种T细胞介导的皮肤炎症性疾病，由表皮暴露于反应性过敏原引起。漆酚的炎症反应，毒葛的反应剂，就是这样一个例子。CD 4 + Th 1、CD 8 + Tc 1细胞和CD 8 + CTL是本病的效应细胞。IFN-γ是由Th 1和Tc 1细胞产生的原型炎性细胞因子，已被认为是ACD中炎性反应的介质。然而，有证据表明IFN-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。在最近的文献中已经证明产生IL-17的T细胞在自身免疫性和炎性疾病中发挥关键作用，这些疾病以前被认为是由Th 1细胞介导的。IL-17和产生IL-17的T细胞在ACD中的功能尚未研究。我们的初步数据表明，由特异性抗体中和IL-17可抑制过敏原致敏动物的ACD发作。此外，在IL-17受体缺陷型小鼠中，经致敏的野生型T细胞的ACD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中的主要效应细胞。提出了两个具体目标来检验这一假设。目的1探讨过敏原致敏的IL-17产生性T细胞在ACD中的作用。将在IL-17受体缺陷的小鼠中证明IL-17对ACD诱发的作用。对IL-17、IFN-γ产生细胞和CTL的表型和功能进行了分析。此外，我们将表征产生CD 4+和CD 8 + IL-17的T细胞，并确定哪个亚群代表初级效应细胞。目的2研究IL-15和IL-23在诱导和调节过敏原特异性产生IL-17的T细胞中的作用。细胞因子介导的对产生IL-17的T细胞的作用将在ACD的发展中进一步验证。该提案的结果将为识别新型效应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和产生IL-17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细胞的表征和效应细胞调节机制的阐明将为开发专门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是一种可溶性蛋白质，主要由活化的T淋巴细胞产生，在炎症性疾病中起重要作用。当前项目旨在研究白细胞介素-17如何介导过敏性接触性皮炎的炎症反应，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。该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.