Atopic dermatitis and allergic contact hypersensitivity are common inflammatory diseases of the skin for which disease mechanisms are largely unknown. Both involve the thickening of the epidermis and the infiltration of the dermis by inflammatory leukocytes. The immunopathology seen in individuals with these conditions is consistent with Th2-type inflammatory response in the skin, with marked increases in IL-4, IL-5, and IL-13 levels, while allergic contact hypersensitivity can provoke either Th1 or Th2 responses, depending on the stimulus. While the factors that initiate the inflammatory cascade seen in these individuals are not known, a variety of studies in both humans and mice implicate the cytokine TSLP (thymic stromal lymphopoietin) in the disease process. For example, we have shown that mice lacking the TSLP receptor due to a targeted mutation are incapable of mounting a contact hypersensitive response to Th2-inducing haptens. Interestingly, these same mice have enhanced responses to Th1-mediating haptens, suggesting that TSLP is capable of regulating both Th1 and Th1 responses. The experiments described in this proposal will provide insight into the role of TSLP in regulating contact hypersensitivity. An analysis of the role of TSLP in these disease models will provide important information on disease initiation and progression, and help to identify potential therapeutic targets for eventual treatment.

Public Health Relevance

Inflammatory diseases of the skin, including atopic dermatitis and allergic contact hypersensitivity, afflict greater than 10% of the population, with the majority developing disease as children. In spite of the prevalence of these diseases, the mechanisms that underlie their development and progression remain obscure. We have found that the cytokine TSLP (thymic stromal lymphopoietin) is an essential mediator for these diseases. The experiments described in this proposal are designed to gain further understanding of the role of TSLP in initiating and regulating skin inflammatory responses. Although allergic inflammatory diseases afflict a substantial fraction of the population, little is known as to the pathways that lead to its onset. Recently, the epithelial-produced cytokine thymic stromal lymphopoietin (TSLP) has been shown to be markedly upregulated in allergic conditions. TSLP is a potent activator of dendritic cells (DCs), and CD4+ T cells primed by TSLP-treated DCs take on a pro-allergic, Th2 phenotype. Biopsies from patients with acute and chronic AD have shown that lesional keratinocytes express high levels of TSLP, with little or no expression detected in uninvolved or normal skin. Together, these data suggest that TSLP plays a key role in the pathogenesis of Th2-mediated allergic inflammatory diseases. Consistent with these human data, we have generated data in mouse models showing that TSLP is both necessary and sufficient for allergic airway inflammation, and can drive Th2-type inflammation in the skin. In addition, mice that lack TSLP responses fail to mount Th2-type contact hypersensitive responses. The experiments described in this proposal will provide important new insights into the mechanism that underlies the role of TSLP in contact hypersensitive responses, and extend these studies to general models of inflammation to ask what the role of TSLP is in controlling the balance between Th1- and Th2-mediated inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056113-05
Application #
8309443
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Cibotti, Ricardo
Project Start
2008-09-20
Project End
2014-02-28
Budget Start
2012-09-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$382,631
Indirect Cost
$173,543
Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
076647908
City
Seattle
State
WA
Country
United States
Zip Code
98101
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Larson, Ryan P; Comeau, Michael R; Ziegler, Steven F (2013) Cutting edge: allergen-specific CD4 T cells respond indirectly to thymic stromal lymphopoietin to promote allergic responses in the skin. J Immunol 190:4474-7
Ziegler, Steven F (2013) Reply: To PMID 22981788. J Allergy Clin Immunol 131:926-7
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Bell, Bryan D; Kitajima, Masayuki; Larson, Ryan P et al. (2013) The transcription factor STAT5 is critical in dendritic cells for the development of TH2 but not TH1 responses. Nat Immunol 14:364-71

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