Targeting the human beta(c) receptor inhibits inflammatory myeloid cells and lung injury caused by acute cigarette smoke exposure

Background and objective: Chronic obstructive pulmonary disease (COPD) is a devastating disease commonly caused by cigarette smoke (CS) exposure that drives tissue injury by persistently recruiting myeloid cells into the lungs. A significant portion of COPD patients also present with overlapping asthma pathology including eosinophilic inflammation. The beta(c) cytokine family includes granulocyte monocyte-colony-stimulating factor, IL-5 and IL-3 that signal through their common receptor subunit beta(c) to promote the expansion and survival of multiple myeloid cells including monocytes/macrophages, neutrophils and eosinophils. Methods: We have used our unique human beta(c) receptor transgenic (h beta(c)Tg) mouse strain that expresses human beta(c) instead of mouse beta(c) and beta(IL3) in an acute CS exposure model. Lung tissue injury was assessed by histology and measurement of albumin and lactate dehydrogenase levels in the bronchoalveolar lavage (BAL) fluid. Transgenic mice were treated with an antibody (CSL311) that inhibits human beta(c) signalling. Results: h beta(c)Tg mice responded to acute CS exposure by expanding blood myeloid cell numbers and recruiting monocyte-derived macrophages (cluster of differentiation 11b(+) [CD11b(+)] interstitial and exudative macrophages [IM and ExM]), neutrophils and eosinophils into the lungs. This inflammatory response was associated with lung tissue injury and oedema. Importantly, CSL311 treatment in CS-exposed mice markedly reduced myeloid cell numbers in the blood and BAL compartment. Furthermore, CSL311 significantly reduced lung CD11b(+) IM and ExM, neutrophils and eosinophils, and this decline was associated with a significant reduction in matrix metalloproteinase-12 (MMP-12) and IL-17A expression, tissue injury and oedema. Conclusion: This study identifies CSL311 as a therapeutic antibody that potently inhibits immunopathology and lung injury caused by acute CS exposure.