Atopic dermatitis (AD) is a biphasic inflammatory skin disease characterized by an initial phase predominated by Th2 cytokines which then shifts to a second, more chronic Th1 eczematous phase. Studies have shown that dendritic cells (DC) are important for the pathogenesis of AD. DC are considered the most potent antigen presenting cells (ARC) by virtue of their ability to bridge an innate immune response to an adaptive immune response. The status of DC at the time of priming CD4 T cells can determine the type of immunity, either T helper 1 (Th1) or Th2. Recently, we have demonstrated that, depending on the ability to produce IL-10, DC can direct either Th1 or Th2 immune responses. IL-10, a pleiotropic cytokine produced by many different cell types, inhibits antigen-specific activation and proliferation of T cells and ultimately leads to the termination of inflammatory responses. Thus, regulation of IL-10 can dramatically alter immune responses. IL-4, a Th2 inducing cytokine, inhibits DC IL-10 expression and subsequently induces IL-12. Thus, DC exposed to IL-4 secrete more IL-12 and promote Th1 instead of Th2 differentiation. These data demonstrate a complex cytokine regulatory network and indicate that the same cytokine has a distinct function modulating the immune response via ARC. We hypothesize that the ability of DC to produce IL-10 contributes to the pathogenesis of AD by directing the Th immune response. In early AD, DC are activated by allergen via toll-like receptors (TLR) and produce both inflammatory and anti-inflammatory cytokines directing Th2 development by secreting high IL-10 and as a result, low IL-12. As the disease progresses, the amount of IL-4 in the local environment is elevated and as a consequence DC will produce less IL-10 leading to a Th1 response. We will test this hypothesis in the current application by focusing on DC function and regulation of DC-mediated pathogenesis of AD using both animal models and human patients. Our long-term goal is to have a better understanding of AD pathogenesis mediated by DC, which will help us to design improved therapeutic tools in the future. To achieve this goal, we propose three specific aims.
In Aim 1, we will investigate the role of TLR-mediated activation of DC with the hypothesis that TLR on DC are critical to activate DC when an allergen is encountered and for subsequent inflammation.
Aim 2 will study DC-mediated immunity using transgenic mice that express a constitutively active form of State (StatGVT) as an AD model system. We hypothesize that DC functions are altered in these mice because StatGVT mice have elevated levels of Th2 cytokines including IL-4. The last Aim is devoted to studying DC function from AD patients by testing the wash fluid from the skin lesion and blood samples collected from patients. Using both an animal model that develops spontaneous AD-like symptoms as well as AD patients, we will obtain valuable information that will provide us a better understanding of DC-mediated immunity in AD and other allergic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI070448-04
Application #
7862620
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
4
Fiscal Year
2009
Total Cost
$264,539
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Type
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Chang, Daniel; Yao, Weiguo; Tiller, Christina J et al. (2015) Exhaled nitric oxide during infancy as a risk factor for asthma and airway hyperreactivity. Eur Respir J 45:98-106
Sarria, Edgar E; Mattiello, Rita; Yao, Weiguo et al. (2014) Atopy, cytokine production, and airway reactivity as predictors of pre-school asthma and airway responsiveness. Pediatr Pulmonol 49:132-9
Turner, Matthew J; Dasilva-Arnold, Sonia C; Yi, Qiaofang et al. (2013) Topical application of a vitamin D analogue exacerbates atopic dermatitis and induces the atopic dermatitis-like phenotype in Stat6VT mice. Pediatr Dermatol 30:574-8
Walline, Crystal C; Sehra, Sarita; Fisher, Amanda J et al. (2013) Allergic airway disease in mice alters T and B cell responses during an acute respiratory poxvirus infection. PLoS One 8:e62222
Spandau, Dan F; Lewis, Davina A; Somani, Ally-Khan et al. (2012) Fractionated laser resurfacing corrects the inappropriate UVB response in geriatric skin. J Invest Dermatol 132:1591-6
Travers, Jeffrey B; Kozman, Amal; Yao, Yongxue et al. (2012) Treatment outcomes of secondarily impetiginized pediatric atopic dermatitis lesions and the role of oral antibiotics. Pediatr Dermatol 29:289-96
Sawant, Deepali V; Sehra, Sarita; Nguyen, Evelyn T et al. (2012) Bcl6 controls the Th2 inflammatory activity of regulatory T cells by repressing Gata3 function. J Immunol 189:4759-69
DaSilva, Sonia C; Sahu, Ravi P; Konger, Raymond L et al. (2012) Increased skin barrier disruption by sodium lauryl sulfate in mice expressing a constitutively active STAT6 in T cells. Arch Dermatol Res 304:65-71
Byrne, A M; Goleva, E; Chouiali, F et al. (2012) Induction of GITRL expression in human keratinocytes by Th2 cytokines and TNF-?: implications for atopic dermatitis. Clin Exp Allergy 42:550-9
Stritesky, Gretta L; Muthukrishnan, Rajarajeswari; Sehra, Sarita et al. (2011) The transcription factor STAT3 is required for T helper 2 cell development. Immunity 34:39-49

Showing the most recent 10 out of 37 publications