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
; 13(2): 137, 2022 02 10.
Article
in English
| MEDLINE | ID: covidwho-1683990
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 (ßc) receptor signals for three inflammatory cytokines GM-CSF, IL-5 and IL-3. In this study, ßc was targeted with the monoclonal antibody (mAb) CSL311 in engineered mice devoid of mouse ßc and ßIL-3 and expressing human ßc (hßcTg 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 hßcTg mice. In a separate model, influenza (HKx31) lung infection caused viral pneumonia associated with a large influx of myeloid cells into the lungs of hßcTg 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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Respiratory Distress Syndrome
/
Cytokine Receptor Common beta Subunit
Type of study:
Etiology study
/
Prognostic study
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
English
Journal:
Cell Death Dis
Year:
2022
Document Type:
Article
Affiliation country:
S41419-022-04589-z
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