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International Immunology Advance Access originally published online on December 9, 2008
International Immunology 2009 21(1):81-93; doi:10.1093/intimm/dxn127
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

A small molecule CRTH2 antagonist inhibits FITC-induced allergic cutaneous inflammation

Stefen A. Boehme1, Karin Franz-Bacon1, Edward P. Chen1, Roman Sásik2,3, L. James Sprague2, Tai Wei Ly1, Gary Hardiman2,4 and Kevin B. Bacon1

1 Actimis Pharmaceuticals, Inc., 10835 Road to the Cure, Suite 200, San Diego, CA 92121, USA
2 Biomedical Genomics Microarray Facility, School of Medicine, University of California, San Diego, La Jolla, CA, USA
3 Moore's Cancer Center, University of California, La Jolla, CA, USA
4 Department of Medicine, University of California, La Jolla, CA, USA

Correspondence to: S. A. Boehme; E-mail: sboehme{at}actimis.com

A FITC-induced allergic contact hypersensitivity model was used to investigate the role that the prostaglandin D2 receptor–chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) plays in modulating cutaneous inflammation. Our results show that inhibition of CRTH2, achieved via administration of a potent, small molecule antagonist, Compound A (Cmpd A), effectively blocked edema formation and greatly reduced the inflammatory infiltrate and skin pathology observed in drug vehicle-treated animals. Gene expression analysis revealed that Cmpd A administration down-regulated the transcription of a wide range of pro-inflammatory mediators. This correlated with decreases in cytokine and chemokine protein levels, notably IL-4, IL-1β, tumor necrosis factor-{alpha}, transforming growth factor-β, GRO-{alpha}, MIP-2 and thymic stromal lymphopoietin (TSLP) in FITC-challenged ears. The administration of an anti-TSLP-neutralizing antibody was only partially effective in lowering the FITC-induced inflammatory infiltrate and cytokine production compared with the CRTH2 antagonist. Taken together, these data suggest that blockade of CRTH2 inhibits multiple pathways leading to cutaneous inflammation in this model. This suggests that CRTH2 antagonism may be a viable route for therapeutic intervention in allergic skin diseases, such as atopic dermatitis.

Keywords: allergy, CRTH2, inflammation, prostaglandin D2, skin

Transmitting editor: K. Inaba

Received 1 July 2008, accepted 6 November 2008.


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