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

  • Cell Death Dis. 2022 Feb 10;13(2):137. doi: 10.1038/s41419-022-04589-z.
Hao Wang  1 ,  Damon J Tumes  2 ,  Timothy R Hercus  2 ,  K H Yip  2 ,  Christian Aloe  1 ,  Ross Vlahos  1 ,  Angel F Lopez  2 ,  Nick Wilson  3 ,  Catherine M Owczarek  3 ,  Steven Bozinovski  4
Affiliations
  • 1. School of Health & Biomedical Sciences, RMIT University, Bundoora, VIC, Australia.
  • 2. Centre for Cancer Biology, SA Pathology and UniSA, Adelaide, Australia.
  • 3. CSL Limited, Parkville, VIC, Australia.
  • 4. School of Health & Biomedical Sciences, RMIT University, Bundoora, VIC, Australia. [email protected].
PMID: 35145069 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.

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