Atopic dermatitis (AD) and asthma are common allergic inflammatory diseases that affect the airways and the skin. Although much information has been gained on the mechanism of allergic asthma, little is known about allergen-induced dermatitis, in part because of the lack of an animal model. We recently developed a mouse model of allergic dermatitis using repeated epicutaneous (EC) sensitization with ovalbumin (OVA). This model is unique because it elicits a predominantly Th2 response and generates skin lesions characterized by infiltration of CD4+ T cells and eosinophils and by expression of mRNA for the Th2 cytokines IL-4 and IL-5, and, to a lesser extent, for IFN-gamma. EC sensitized mice exhibit bronchial hyper-responsiveness to inhalation of a single dose of OVA. Thus, our model has histologic, immunologic and clinical features of human AD. EC sensitization requires tape stripping which results in skin injury. We found that tape stripping induces rapid expression of mRNA for IL-10, cyclooxygenase-2 (COX-2) and for the Th2 selective chemokine TARC in the skin. Moreover, IL-10 deficient mice have a severe reduction in IL-4 and IL-5 mRNA expression and decreased eosinophil influx in sensitized skin. We propose to apply state of the art knowledge and techniques to our unique model of allergen induced skin inflammation to gain better insight into the pathogenesis of AD. We plan to address three important questions: 1. What is the role of T cell subsets and Thl and Th2 cytokines in skin infiltration by CD4+ cells and eosinophils? We will characterize in detail the T cells that infiltrate the skin and we will assess the role of T cell subsets and T cell cytokines in our model, using genetically manipulated mice, B.M. chimeras and adoptive transfer experiments. 2. What is the mechanism(s) by which EC sensitization skews the response of Th-cells to Th2? We will examine the role of skin injury, IL-10, prostaglandin E2 and histamine in skewing the Th-cell response towards Th2 and investigate. In addition, dendritic cells from lymph nodes that drain EC sensitized skin of wild type and genetically manipulated mice will be examined for their capacity to skew the Th response. 3. What is the role of chemokines in the recruitment of Th2 cells to the skin? We will examine chemokine and chemokine receptor expression in injured and inflamed skin and assess their role in our model using neutralizing antibodies and chemokine receptor deficient mice. We will determine whether Th2 cells induced by immunization at other anatomical sites are recruited to the skin. Finally, we will examine the effects of inducible expression of chemokines in keratinocytes on Th2 cell recruitment to skin. The proposed studies should provide a better understanding of AD and help devise novel therapies for this disease.
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