Blocking the human common beta subunit of the GM-CSF, IL-5 and IL-3 receptors markedly reduces hyperinflammation in ARDS models

Hao Wang,Timothy R Hercus,K H Yip,Steven Bozinovski,Catherine M Owczarek,Angel F Lopez,Christian Aloe,Nick Wilson,Ross Vlahos,Damon J Tumes

doi:10.1038/s41419-022-04589-z

Abstract

Acute respiratory distress syndrome (ARDS) is triggered by various aetiological factors such as trauma, sepsis and respiratory viruses including SARS-CoV-2 and influenza A virus. Immune profiling of severe COVID-19 patients has identified a complex pattern of cytokines including granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-5, which are significant mediators of viral-induced hyperinflammation. This strong response has prompted the development of therapies that block GM-CSF and other cytokines individually to limit inflammation related pathology. The common cytokine binding site of the human common beta (βc) receptor signals for three inflammatory cytokines: GM-CSF, IL-5 and IL-3. In this study, βc was targeted with the monoclonal antibody (mAb) CSL311 in engineered mice devoid of mouse βc and βIL-3 and expressing human βc (hβcTg mice). Direct pulmonary administration of lipopolysaccharide (LPS) caused ARDS-like lung injury, and CSL311 markedly reduced lung inflammation and oedema, resulting in improved oxygen saturation levels in hβcTg mice. In a separate model, influenza (HKx31) lung infection caused viral pneumonia associated with a large influx of myeloid cells into the lungs of hβcTg mice. The therapeutic application of CSL311 potently decreased accumulation of monocytes/macrophages, neutrophils, and eosinophils without altering lung viral loads. Furthermore, CSL311 treatment did not limit the viral-induced expansion of NK and NKT cells, or the tissue expression of type I/II/III interferons needed for efficient viral clearance. Simultaneously blocking GM-CSF, IL-5 and IL-3 signalling with CSL311 may represent an improved and clinically applicable strategy to reducing hyperinflammation in the ARDS setting.

Highlights

Acute respiratory distress syndrome (ARDS) is a hyperinflammatory disorder associated with an influx of activated myeloid cells into the pulmonary parenchyma and arteries that can contribute to fatal immunopathology
LPS challenge resulted in a significant increase in systemic inflammation involving expansion of circulating neutrophil and monocytes, which peaked at 24-hours in hβc Tg mice treated with the higher dose (10μg) of LPS (Fig. 1A, B)
Bronchoalveolar lavage (BAL) neutrophil numbers tracked with blood neutrophil numbers, where peak numbers were detected in mice treated with high dose LPS at 24-hours, whereas BAL macrophages were only significantly increased at the later 72-hour timepoint (Fig. 1C, D)

Summary

Introduction

Acute respiratory distress syndrome (ARDS) is a hyperinflammatory disorder associated with an influx of activated myeloid cells into the pulmonary parenchyma and arteries that can contribute to fatal immunopathology. T cells at the inflammatory site produce several cytokines including granulocyte macrophagecolony stimulating factor (GM-CSF), which is strikingly elevated in fatal cases of COVID-19 [1] and capable of triggering a hyperinflammatory storm [2, 3]. Excessive NET infiltrate in the lung and vasculature is thought to contribute to pathophysiology and mucosal cell death in severe COVID-19 patients [7,8,9]. Mavrilimumab and Lenzilumab are monoclonal antibodies targeting the α-chain of GM-CSF receptor (GM-CSFR) and GM-CSF respectively. Both have a favourable safety profile and are showing promising therapeutic benefit in small COVD-19 clinical trials [10, 11], which support the advancement to larger clinical studies to clarify the significance of GM-CSF-dependent immunopathogenesis. The role of type-2 immunity and IL-3 requires further investigation in severe

Methods

Results

Conclusion