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 #
5R01AR047417-08
Application #
7628492
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
2009-06-01
Budget End
2010-05-31
Support Year
8
Fiscal Year
2009
Total Cost
$356,083
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Leisten, Sabine; Oyoshi, Michiko K; Galand, Claire et al. (2013) Development of skin lesions in filaggrin-deficient mice is dependent on adaptive immunity. J Allergy Clin Immunol 131:1247-50, 1250.e1
Bartnikas, Lisa M; Gurish, Michael F; Burton, Oliver T et al. (2013) Epicutaneous sensitization results in IgE-dependent intestinal mast cell expansion and food-induced anaphylaxis. J Allergy Clin Immunol 131:451-60.e1-6
Oyoshi, Michiko K; He, Rui; Li, Yitang et al. (2012) Leukotriene B4-driven neutrophil recruitment to the skin is essential for allergic skin inflammation. Immunity 37:747-58
Oyoshi, Michiko K; He, Rui; Kanaoka, Yoshihide et al. (2012) Eosinophil-derived leukotriene C4 signals via type 2 cysteinyl leukotriene receptor to promote skin fibrosis in a mouse model of atopic dermatitis. Proc Natl Acad Sci U S A 109:4992-7
Chou, Janet; Hanna-Wakim, Rima; Tirosh, Irit et al. (2012) A novel homozygous mutation in recombination activating gene 2 in 2 relatives with different clinical phenotypes: Omenn syndrome and hyper-IgM syndrome. J Allergy Clin Immunol 130:1414-6
Oyoshi, Michiko K; Elkhal, Abdallah; Scott, Jordan E et al. (2011) Epicutaneous challenge of orally immunized mice redirects antigen-specific gut-homing T cells to the skin. J Clin Invest 121:2210-20
He, Rui; Oyoshi, Michiko K; Wang, James Y T et al. (2010) The prostaglandin D? receptor CRTH2 is important for allergic skin inflammation after epicutaneous antigen challenge. J Allergy Clin Immunol 126:784-90
He, Rui; Geha, Raif S (2010) Thymic stromal lymphopoietin. Ann N Y Acad Sci 1183:13-24
McDonald, Douglas R; Massaad, Michel J; Johnston, Alicia et al. (2010) Successful engraftment of donor marrow after allogeneic hematopoietic cell transplantation in autosomal-recessive hyper-IgE syndrome caused by dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol 126:1304-5.e3
Oyoshi, Michiko K; Larson, Ryan P; Ziegler, Steven F et al. (2010) Mechanical injury polarizes skin dendritic cells to elicit a T(H)2 response by inducing cutaneous thymic stromal lymphopoietin expression. J Allergy Clin Immunol 126:976-84, 984.e1-5

Showing the most recent 10 out of 25 publications