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

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.

Targeting the human βc receptor inhibits inflammatory myeloid cells and lung injury caused by acute cigarette smoke exposure

“…We have previously investigated CSL311 in an acute model of influenza infection, where this treatment did not compromise expansion of NK/NKT cells and the clearance of influenza. 47 Furthermore, chronic antagonism of the GM-CSFR does not alter surfactant catabolism in mice, which is consistent with safety data from clinical trials where AMs maintain homeostatic competency. 48 A potential advantage of CSL311 over biologics that target the single GM-CSF/GM-CSFR axis (mavrilimumab or lenzilumab) is that it will also inhibit GM-CSF, IL-3 and IL-5 signalling.…”

“…Future studies are warranted to investigate whether homeostatic AM functions, such as pathogen eradication and surfactant catabolism, are maintained in CS‐exposed mice treated with CSL311. We have previously investigated CSL311 in an acute model of influenza infection, where this treatment did not compromise expansion of NK/NKT cells and the clearance of influenza 47 . Furthermore, chronic antagonism of the GM‐CSFR does not alter surfactant catabolism in mice, which is consistent with safety data from clinical trials where AMs maintain homeostatic competency 48 …”

Gut microbes of the cecum versus the colon drive more severe lethality and multi-organ damage

“…IL-5 expression level is often associated with lung inflammation [36], and in the present study, we found plasma IL-5 raised in the Cecum-FIP mice that manifested more severe pneumonia and pathological changes. IL-6 is a sensitive marker of inflammation and can be of prognostic value in critically ill patients with multi-organ failure [37].…”

Immunotherapy strategies and prospects for acute lung injury: Focus on immune cells and cytokines

“…In addition, several other interleukins are associated with the progression of ALI. For example, blocking IL-3 and IL-5 can significantly reduce the hyperinflammatory response in ARDS models ( Wang H. et al, 2022 ). Of note is the self-sustaining IL-8 cycle driving the prethrombotic neutrophil phenotype in severe COVID-19 ( Kaiser et al, 2021 ).…”