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

IL-17 产生 T 淋巴细胞在过敏性接触性皮炎中的作用

• 批准号: 7256827
• 负责人: Hui Xu
• 金额: $ 21.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256827
• 关键词: Allergens; Allergic; Allergic Contact Dermatitis; Animals; Antibodies; Autoimmune Process; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Adhesion Molecules; Cells; Contact Dermatitis; Cutaneous; Cytotoxic T-Lymphocytes; Data; Development; Disease; Effector Cell; Exposure to; Haptens; Human; Immune; Infiltration; Inflammatory; Interferon Type II; Interferons; Interleukin-12; Interleukin-15; Interleukin-17; Leukocytes; Lighting; Literature; Lymphocyte; Mediating; Mediator of activation protein; Molecular; Morbidity - disease rate; Mus; Natural Killer Cells; Outcome; Patients; Phenotype; Play; Production; Proteins; Reaction; Regulation; Reporting; Rhus radicans; Role; T-Lymphocyte; Th1 Cells; Therapeutic; Time; Transcriptional Activation; Up-Regulation; base; chemokine; cytokine; experience; improved; interleukin-23; novel; novel therapeutics; receptor; response; urushiol

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.

描述（由申请人提供）：过敏性接触性皮炎（ACD）是一种由表皮暴露于反应性过敏原引起的T细胞介导的皮肤炎症性疾病。对漆酚的炎症反应就是这样一个例子，漆酚是毒葛的反应剂。CD4+ Th1， CD8+ Tc1细胞和CD8+ CTL已被证明是该疾病的效应细胞。ifn - γ是一种由Th1和Tc1细胞产生的典型炎症细胞因子，被认为是ACD炎症反应的介质。然而，有证据表明ifn - γ可能与ACD无关。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，通过特异性抗体中和IL-17可以抑制被过敏原致敏的动物发生ACD。此外，在IL-17受体缺陷小鼠中，启动野生型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。为了检验这一假设，提出了两个具体的目的。目的1将确定过敏原引发的产生IL-17的T细胞在ACD中的作用。IL-17对ACD的诱导作用将在IL-17受体缺乏的小鼠中得到证实。我们将解剖IL-17、ifn - γ产生细胞和CTL的表型和功能。此外，我们将表征CD4+和CD8+产生IL-17的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在诱导和调节过敏原特异性IL-17产生T细胞中的作用。细胞因子对产生IL-17的T细胞的介导作用将在ACD的发展过程中得到进一步验证。这一结果将为鉴定新的效应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中的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控机制的阐明将为制定针对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，在炎症性疾病中起重要作用。目前的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。