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CC-chemokine receptor 3 (CCR3)-stimulating chemokines are likely to have important in vivo roles in the regulation of eosinophil, basophil, and potentially helper T cell type 2 and mast cell recruitment. We have developed techniques to investigate the actions of eotaxin and other chemokines on multiple leukocyte populations in whole blood, without cell purification steps that might alter leukocyte responsiveness. We have shown that the potency of eotaxin in whole blood is limited by Duffy antigen binding, which may modulate the actions of this chemokine in vivo. We have also investigated the efficacy and potency of a new panel of small molecule antagonists of CCR3 on responses of eosinophils, neutrophils, basophils, and monocytes to chemokines, using whole blood assays of shape change, chemokine receptor internalization, and CD11b upregulation. These small molecule antagonists cause selective and potent inhibition of CCR3 on eosinophils and basophils, are bioavailable in blood, and are prototypic antagonists potentially of benefit in the treatment of human allergic disease. Such whole blood methods may also be employed in the investigation of other small molecule chemokine receptor antagonists.

The health burden of asthma is increasing globally at an alarming rate, providing a strong impetus for the development of new therapeutics. Currently available inhaled bronchodilators and anti-inflammatory drugs are effective in most asthmatics, but this palliative therapy requires long-term daily administration. Despite considerable efforts by the pharmaceutical industry, it has been difficult to develop novel therapeutic agents; the leukotriene antagonists and synthesis inhibitors being the only new class of asthma treatments to have been licensed in the last 30 years. It is clearly important to understand more about the underlying mechanisms of asthma and about how current drugs work before rational improvements in therapy can be expected. There are numerous therapies in clinical development that combat the inflammation found in asthma, specifically targeting eosinophils, IgE, adhesion molecules, cytokines and chemokines, inflammatory mediators and cell signalling. In particular, there is the obvious need for new therapy for severe asthma that is poorly controlled by high doses of corticosteroids, as well as agents to counter acute emergency asthma. A long-term goal is to develop disease-modifying immunotherapy, that could be introduced in childhood to alter the natural history of asthma. Thanks to the extensive efforts of the pharmaceutical industry, in the near future we can expect the introduction of a range of novel therapies for asthma.

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