Chemokine Receptor 2 Blockade Prevents Asthma in a Cynomolgus Monkey Model

Abstract

The pathophysiology of asthma is characterized by accumulation and activation of several cell types in the lung, which correlates with coordinated production of specific cytokines and chemokines. To study the effect of selective CCR2 chemokine receptor blockade on leukocyte recruitment to the lung and on bronchial function, we used a nonhuman primate model of allergic airway disease that closely resembles human asthma. Allergic cynomolgus monkeys were treated with the antagonist anti-CCR2 (CCR2-05) monoclonal antibody and then challenged with Ascaris suum antigen; the effect of antibody treatment on macrophage and eosinophil infiltration was determined. Pulmonary function was calculated by measurement of lung resistance and dynamic compliance. Local inflammatory responses were analyzed after intradermal challenge with A. suum antigen. CCL2 up-regulation in bronchoalveolar lavage (BAL) was analyzed by enzyme-linked immunosorbent assay, and in vitro CCR2-05 antagonistic activity was tested in monkey peripheral blood mononuclear cells using chemotaxis and calcium mobilization assays. The results show that neutralization of CCR2 reduces antigen-induced bronchial hyper-responsiveness and attenuates macrophage and eosinophil accumulation in the BAL of asthmatic monkeys. The results confirm that selective blockade of a single chemokine receptor involved in early stages of asthma can condition later disease stages and suggest the utility of anti-CCR2-neutralizing monoclonal antibodies in the treatment of asthma in man.