Allergic diseases are some of the most common and most costly illnesses in the United States and the prevalence of allergy has doubled in the last four decades. Mounting evidence from recent epidemiological studies reveals an association between frequent use of the cyclooxygenase (COX) inhibiting drug acetaminophen and increased risk of developing allergic diseases, suggesting a possible role of COX inhibition in causing the allergy epidemic. This possibility is supported by our studies using a mouse model of ovalbumin (OVA)-induced allergic inflammation that reveal COX inhibition augments the allergen-induced inflammation, a Th2 immune response. However, the mechanism by which COX inhibition increases Th2 immunity is not clear. Our preliminary results indicate that COX inhibition during allergic sensitization is sufficient to enhance Th2 immune priming and memory, and that COX inhibition abolishes OVA-specific immune tolerance, suggesting an active role of the COX pathway in the development of Th2 immune responses. Furthermore, COX inhibition strongly augments allergic Th2 responses in a STAT6-independent fashion, suggesting that a non-classical and STAT6-independent Th2 differentiation pathway is strongly activated by COX inhibition. The overall HYPOTHESIS to be evaluated is that COX inhibition augments allergic responses by enhancing dendritic cell immune stimulatory function, increasing memory T cell generation, and suppressing regulatory T cells (Tregs).
The SPECIFIC AIMS are: (1) Determine the effect of COX inhibition during allergic sensitization on dendritic cell maturation, differentiation and function. (2) Determine the mechanism by which COX inhibition during allergic sensitization augments STAT6-independent Th2 responses, increases the generation of memory CD4 T cells, and abolishes allergen-specific immunologic tolerance. By defining the cellular and molecular mechanisms for COX inhibition-augmented allergic responses, these studies will advance our understanding of the impact of the COX metabolic pathway on the genesis of adaptive immunity and STAT6- independent Th2 responses, while providing potential targets for early interventions against the development of allergic diseases.

Public Health Relevance

Allergic diseases are a major burden to public health in the United States, and the prevalence has doubled in the past three decades. This is of particular relevance to Veterans of the US Military in whom the prevalence of allergic rhinitis is approximately 30% and allergic asthma is approximately 6%. Thus, allergic diseases are an important cause of morbidity among Veterans. The proposed research will advance our understanding of the genesis of allergic disorders and identify potential targets for the development of anti-allergic modalities capable of treating and preventing allergic diseases, thus improving the health of our Veterans.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000624-04
Application #
8397539
Study Section
Immunology A (IMMA)
Project Start
2009-10-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
156385783
City
Nashville
State
TN
Country
United States
Zip Code
37212
Toki, Shinji; Zhou, Weisong; Goleniewska, Kasia et al. (2018) Endogenous PGI2 signaling through IP inhibits neutrophilic lung inflammation in LPS-induced acute lung injury mice model. Prostaglandins Other Lipid Mediat 136:33-43
Bloodworth, Melissa H; Rusznak, Mark; Bastarache, Lisa et al. (2018) Association of ST2 polymorphisms with atopy, asthma, and leukemia. J Allergy Clin Immunol 142:991-993.e3
Brunwasser, Steven M; Gebretsadik, Tebeb; Gold, Diane R et al. (2018) A new model of wheezing severity in young children using the validated ISAAC wheezing module: A latent variable approach with validation in independent cohorts. PLoS One 13:e0194739
Celada, Lindsay J; Kropski, Jonathan A; Herazo-Maya, Jose D et al. (2018) PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-?1 production. Sci Transl Med 10:
Turi, Kedir N; Shankar, Jyoti; Anderson, Larry J et al. (2018) Infant Viral Respiratory Infection Nasal Immune-Response Patterns and Their Association with Subsequent Childhood Recurrent Wheeze. Am J Respir Crit Care Med 198:1064-1073
Stone Jr, Cosby A; McEvoy, Cindy T; Aschner, Judy L et al. (2018) Update on Vitamin E and Its Potential Role in Preventing or Treating Bronchopulmonary Dysplasia. Neonatology 113:366-378
Tashkin, Donald P; Peebles Jr, R Stokes (2018) Controversies in Allergy: Is Asthma Chronic Obstructive Pulmonary Disease Overlap a Distinct Syndrome That Changes Treatment and Patient Outcomes? J Allergy Clin Immunol Pract :
Stone Jr, Cosby A; Hemler, Jonathan A; Commins, Scott P et al. (2018) Reply. J Allergy Clin Immunol 141:1957-1958
Rosas-Salazar, Christian; Shilts, Meghan H; Tovchigrechko, Andrey et al. (2018) Nasopharyngeal Lactobacillus is associated with a reduced risk of childhood wheezing illnesses following acute respiratory syncytial virus infection in infancy. J Allergy Clin Immunol 142:1447-1456.e9
Bloodworth, Melissa H; Rusznak, Mark; Pfister, Connor C et al. (2018) Glucagon-like peptide 1 receptor signaling attenuates respiratory syncytial virus-induced type 2 responses and immunopathology. J Allergy Clin Immunol 142:683-687.e12

Showing the most recent 10 out of 42 publications