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. ? ? ?
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| He, Donggou; Li, Hui; Yusuf, Nabiha et al. (2012) IL-17 mediated inflammation promotes tumor growth and progression in the skin. PLoS One 7:e32126 |
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