COX Regulation of Allergic Sensitization and Immune Memory Generation

Vanderbilt University, Nashville TN

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Abstract

PROJECT SUMMARY Allergic diseases are one 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 showing that COX inhibition with COX inhibitors increased allergic inflammation and airway hyperresponsiveness. However, the mechanism by which COX inhibition augments allergic responses is not clear. Our preliminary results in this application indicate that COX inhibition during allergic sensitization is sufficient to enhance Th2 immune priming and memory and that COX inhibition breaks the OVA-specific immune tolerance, suggesting an active role of the COX pathway in the development of allergy, a Th2 cell-mediated immune disorder. 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 increasing dendritic cell immune stimulatory function and the generation of immune memory T cells and by inhibiting the formation of immune suppressive prostaglandins PGE2 and PGI2. 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 and increases the generation of memory CD4 T cells. (3) Determine the role of the receptor signaling of PGE2 and PGI2 in the pro-allergic effect of COX inhibition. By defining the cellular and molecular mechanisms for COX inhibition-augmented allergic responses, this study will advance our understanding of the impact of the COX metabolic pathway on allergic sensitization, memory generation and STAT6-independent Th2 responses and provide potential targets for early interventions against the development of allergic diseases.