AD affects up to 15% of children and is characterized by allergic skin inflammation and skin remodeling. In many children, the onset of AD is the first step in the atopic march that leads to allergic rhinitis and asthma. To begin to address mechanisms implicated in the pathogenesis of AD we have developed a mouse model of allergic skin inflammation using repeated epicutaneous (EC) sensitization of shaved tape stripped skin with the protein antigen ovalbumin (OVA). This model shares important immunological, histological and clinical features with human AD, and the mechanical injury inflicted by stripping the skin mimics the mechanical injury induced by scratching in AD. Our overall hypothesis is that mechanical injury caused either by scratching of dry skin in patients with AD or by stripping the skin of the mouse triggers mechanisms in antigen presenting dendritic cells (DCs) that favor the development of effector Th2 cells, that home to skin and cause skin inflammation, eosinophil infiltration and tissue remodeling. We have shown that tape stripping results in the upregulation of IL-10 and IL-6 mRNA expression in the skin and that IL-10 promotes Th2 development following EC sensitization. We also showed that the Th2 cytokines IL-4 and IL-13, eosinophils and leukotrienes are essential for collagen deposition in the skin in our model. We propose to test the effect of mechanical skin injury on the polarity of antigen-presenting skin DCs by examining their ability to induce a Th2 response in T cells. We will examine the roles of keratinocyte-derived, DC-derived IL-10, IL-6 and thymic stromal lymphopoietin in determining DC polarity after skin injury. We will then test the hypothesis that CD4+CD25+ regulatory T cells (T-reg cells) inhibit the development of effector cells following EC sensitization. We will examine the numbers and function of T regulatory (T-reg) cells in the skin and draining LN of EC sensitized mice, determine whether depletion of T-reg cells exacerbates allergic skin inflammation and test whether interventions aimed at increasing T-reg cell activity inhibit allergic skin inflammation. Finally, we will determine the major mechanisms that lead to skin remodeling in allergic skin inflammation. We will examine the role of eosinophils in the generation of cysteinyl leukotrienes and TGF-p in allergic skin inflammation and define the role of these two mediators in collagen deposition in the inflamed skin. The results of the proposed experiments will aid in our understanding of the pathogenesis of AD in humans and should lead to novel therapies for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR047417-09
Application #
7858322
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Cibotti, Ricardo
Project Start
2001-03-20
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
9
Fiscal Year
2010
Total Cost
$352,522
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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