A major goal of the this AADCRC program is to define the role of the epithelial cell barrier in the pathogenesis of asthma and allergic disease and develop new preventative strategies. In that context, this project aims to investigate means by which to block progression from atopic dermatitis to asthma (often referred to as the atopic march). Patients with a history of severe atopic dermatitis (AD) exhibit a 8-to-10-fold greater incidence of developing asthma. Our recent observations demonstrated that in mice, epidermal-derived thymic stromal lymphopoietin (TSLP) was secreted by AD skin. Moreover, circulating levels of TSLP were sufficient to sensitize the lung airways to inhaled allergens in animals lacking any AD-like pathology, preexisting inflammation, or previous exposure to the allergen. In a pilot study in infants we uncovered a correlation between serum TSLP and aeroallergens. Based on these observations in mice and humans, we hypothesize the following mechanism for the atopic march. (1) Epidermal defect/injury during early childhood is sensed by an unknown mechanism that initiates production of TSLP in keratinocytes;(2) keratinocytes secrete TSLP into the serum. (3) Subsequently, circulating TSLP facilitates Th2 immune responses by dendritic cells and T-cells towards innocuous allergens (inhaled or introduced epicutaneously);and (4) this exaggerated adaptive Th2 response results in hypersensitivity to aeroallergens and consequent allergic asthma. We further hypothesize that interrupting some of these events in a model organism will lead to strategies for blocking the development of allergic disease and asthma in humans. To achieve this goal, we propose the to (I) examine how epidermal differentiation/barrier formation defects (intrinsic factors) as well as allergen or pathogens (extrinsic factor(s)) drive TSLP overexpression;(II) with the help of Cores B and C ask how TSLP secretion is regulated by human skin and lung cells in vitro and in patients. Next, (III) we will ask if we can blunt the effects of TSLP in the serum with small molecule adjuvants capable of manipulating the immune responses and (IV) analyze the contribution of the skin microbiome to the maintenance of skin barrier, TSLP expression, and airway hyper sensitivity. Finally, (V) we will confirm TSLP as a risk factor for asthma in a birth cohort (URECA) and, in collaboration with project1, compare its role in an RSV bronchiolitis in early life cohort (RBEL). Achievement of these aims will open up novel therapeutic approach to prevent asthma development in AD patients.

Public Health Relevance

A preexisting skin condition in children is a strong risk factor for asthma in adulthood. This proposal aims directly at the mechanism linking hose allergic conditions issue by defining the elements controlling expression, secretion and function of TSLP, a secreted cytokine we show can explain the atopic march. At minimum, we expect to provide strategies that will help prevent atopic march in at-risk AD patients. In the best case scenario, we may uncover novel pathways to therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI070489-07
Application #
8378539
Study Section
Special Emphasis Panel (ZAI1-PA-I)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
7
Fiscal Year
2012
Total Cost
$250,225
Indirect Cost
$85,603
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Liu, Yongjian; Gunsten, Sean P; Sultan, Deborah H et al. (2017) PET-based Imaging of Chemokine Receptor 2 in Experimental and Disease-related Lung Inflammation. Radiology 283:758-768
Chatterjee, Srirupa; Luthra, Priya; Esaulova, Ekaterina et al. (2017) Structural basis for human respiratory syncytial virus NS1-mediated modulation of host responses. Nat Microbiol 2:17101
Shilts, Meghan H; Rosas-Salazar, Christian; Tovchigrechko, Andrey et al. (2016) Minimally Invasive Sampling Method Identifies Differences in Taxonomic Richness of Nasal Microbiomes in Young Infants Associated with Mode of Delivery. Microb Ecol 71:233-42
Zhou, Weisong; Zhang, Jian; Goleniewska, Kasia et al. (2016) Prostaglandin I2 Suppresses Proinflammatory Chemokine Expression, CD4 T Cell Activation, and STAT6-Independent Allergic Lung Inflammation. J Immunol 197:1577-86
Bloodworth, Melissa H; Newcomb, Dawn C; Dulek, Daniel E et al. (2016) STAT6 Signaling Attenuates Interleukin-17-Producing ?? T Cells during Acute Klebsiella pneumoniae Infection. Infect Immun 84:1548-55
Xu, Amy Z; Tripathi, Shivani V; Kau, Andrew L et al. (2016) Immune dysregulation underlies a subset of patients with chronic idiopathic pruritus. J Am Acad Dermatol 74:1017-20
Zhou, Weisong; Toki, Shinji; Zhang, Jian et al. (2016) Prostaglandin I2 Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses. Am J Respir Crit Care Med 193:31-42
Banathy, Alex; Cheung-Flynn, Joyce; Goleniewska, Kasia et al. (2016) Heat Shock-Related Protein 20 Peptide Decreases Human Airway Constriction Downstream of ?2-Adrenergic Receptor. Am J Respir Cell Mol Biol 55:225-33
Dickinson, John D; Alevy, Yael; Malvin, Nicole P et al. (2016) IL13 activates autophagy to regulate secretion in airway epithelial cells. Autophagy 12:397-409
Kitcharoensakkul, Maleewan; Bacharier, Leonard B; Yin-Declue, Huiqing et al. (2016) Temporal biological variability in dendritic cells and regulatory T cells in peripheral blood of healthy adults. J Immunol Methods 431:63-5

Showing the most recent 10 out of 77 publications