The chemokine CXCR2 antagonist (AZD5069) preserves neutrophil-mediated host immunity in non-human primates

摘要

Controlled trafficking of neutrophils is an important component of the host innate immunity.~(~(1)) Neutrophils express a number of chemokine receptors, CXCR2 among them, which, following activation by its cognate chemokines CXCL1 and CXCL8, become mobilized and preferentially home to inflamed tissues.~(~(2),~(3)) Dysregulated CXCR2 signaling that results in unresolving airway neutrophilia may contribute to the immunopathology of several chronic obstructive respiratory diseases, including bronchiectasis,~(~(4)) cystic fibrosis,~(~(5)) COPD~(~(6)) and severe asthma.~(~(7))AZD5069 is a selective small-molecule antagonist of the human CXCR2 chemokine receptors, with greater than 100-fold selectivity over CXCR1 receptors.~(~(8)) In preclinical models, airway neutrophil recruitment in response to inflammatory challenge is abrogated by selective targeting of CXCR2 using AZD5069.~(~(8)) Clinically, oral administration of AZD5069 (80 mg, twice a day [b.i.d]) significantly reduced sputum neutrophilia by 69% in patients with bronchiectasis,~(~(4)) whilst showing no impairment of optimal neutrophil immune responses.~(~(9)) Given the potential for CXCR2 antagonists like AZD5069 as novel neutrophil-directed immunotherapies, further understanding the controlled regulation of neutrophil trafficking and their innate immune functions are of considerable clinical relevance. We have, therefore, examined the effects of chronic treatment with the chemokine receptor CXCR2 antagonist (AZD5069) on two key effector mechanisms of neutrophil-mediated host immunity in cynomolgus monkeys, namely phagocytosis and oxidative burst activities.