Targeting CCR3

Abstract

Allergic responses are a result of an undesirable response to an otherwise innocuous antigen or allergen and are characterized by an increase in the number of eosinophils, Th2 lymphocytes, basophils and mast cells within the inflammed tissue. The specific recruitment of these leukocytes to the site of inflammation is principally mediated by a chemokine receptor known as CCR3, which signals in response to the eotaxin family of chemokines. Since the incidence of allergic diseases such as asthma and atopic dermatitis are approaching epidemic proportions in the Western World, much effort has been focused upon the specific targeting of CCR3 as a potential therapeutic avenue. This chapter reviews our understanding of the biology underpinning this ligand-receptor axis and discusses recent developments in antagonizing the interactions of CCR3 with its ligands. CCR3 and the Eotaxin Family of ChemokinesThe discovery of CCR3 and its chemokine ligands followed intensive efforts by several groups. The principal working hypothesis was that the selective recruitment of eosinophils oberved during the late response to allergen in sensitized individuals was mediated by endogenous selective eosinophil chemoattractant(s) and complimentary cell surface receptors on the eosinophil. The first CCR3 ligand to be discovered was named eotaxin and was identified following the fractionation of bronchoalveolar lavage fluid from allergen-sensitized guinea pigs [1]. Protein sequencing suggested that it was a member of the recently discovered CC family of chemokines including RANTES/CCL5, a chemokine which had previously been shown to be chemotactic for eosinophils but was