CCR3 blockade as a new therapy for asthma.
Among the inflammatory cells infiltrating the lungs of asthmatic patients, eosinophils and Th2 cells are thought to play a central role in the pathogenesis of this disease. Several studies have implicated that chemokines are prime candidates for being responsible for the selective recruitment of the leukocyte subsets found in atopic diseases. Regulated upon activation, normal T-cell-expressed and secreted (RANTES), monocyte chemoattractant protein-3 (MCP-3), MCP-4 and the eotaxins, for example, have been shown in vitro to potently induce eosinophil chemotaxis as well as initiate several other pro-inflammatory activities such as integrin activation, lipid mediator biosynthesis and degranulation. Ligand binding and chemotaxis experiments with these chemokines demonstrated that a G-protein coupled-receptor (GPCR) cloned from eosinophils, termed CCR3, was responsible for producing a chemokine selectivity profile identical to that of eosinophils. In addition, blocking CCR3 on eosinophils, with a monoclonal antibody, completely abolished eosinophil responses to these chemokines. Together these studies strongly suggest a central role for this receptor in eosinophil trafficking. CCR3 has also been found on in vitro derived Th2 cells and on T-cells co-localising with eosinophils in diseased tissue, thus revealing a possible pathogenic mechanism for T-cell recruitment into the airways. Therefore, blockade of CCR3 represents a highly attractive and innovative strategy for asthma therapy.
Bertrand
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Inflammatory Diseases Unit, Roche Bioscience, Palo Alto, CA 94304, USA. claude.bertrand@wl.com
Ponath
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D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal; D001249:Asthma / Q000188:drug therapy*; D054413:Chemokine CCL11; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil; D016207:Cytokines; D006801:Humans; D007249:Inflammation; D008024:Ligands; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*
D018927:Anti-Asthmatic Agents; D000911:Antibodies, Monoclonal; C515456:CCL11 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil; D016207:Cytokines; D008024:Ligands; D054397:Receptors, CCR3; D019707:Receptors, Chemokine