Targeting GM-CSF in COVID-19 Pneumonia: Rationale and Strategies
COVID-19 is a clinical syndrome ranging from mild symptoms to severe pneumonia that often leads to respiratory failure, need for mechanical ventilation, and death. Most of the lung damage is driven by a surge in inflammatory cytokines [interleukin-6, interferon-γ, and granulocyte-monocyte stimulating factor (GM-CSF)]. Blunting this hyperinflammation with immunomodulation may lead to clinical improvement. GM-CSF is produced by many cells, including macrophages and T-cells. GM-CSF-derived signals are involved in differentiation of macrophages, including alveolar macrophages (AMs). In animal models of respiratory infections, the intranasal administration of GM-CSF increased the proliferation of AMs and improved outcomes. Increased levels of GM-CSF have been recently described in patients with COVID-19 compared to healthy controls. While GM-CSF might be beneficial in some circumstances as an appropriate response, in this case the inflammatory response is maladaptive by virtue of being later and disproportionate. The inhibition of GM-CSF signaling may be beneficial in improving the hyperinflammation-related lung damage in the most severe cases of COVID-19. This blockade can be achieved through antagonism of the GM-CSF receptor or the direct binding of circulating GM-CSF. Initial findings from patients with COVID-19 treated with a single intravenous dose of mavrilimumab, a monoclonal antibody binding GM-CSF receptor α, showed oxygenation improvement and shorter hospitalization. Prospective, randomized, placebo-controlled trials are ongoing. Anti-GM-CSF monoclonal antibodies, TJ003234 and gimsilumab, will be tested in clinical trials in patients with COVID-19, while lenzilumab received FDA approval for compassionate use. These trials will help inform whether blunting the inflammatory signaling provided by the GM-CSF axis in COVID-19 is beneficial.
CITE THIS COLLECTION
REFERENCES
- https://doi.org//10.1056/NEJMoa2002032
- https://doi.org//10.1097/FJC.0000000000000836
- https://doi.org//10.1016/S0140-6736(20)30628-0
- https://doi.org//10.1016/S0140-6736(20)30183-5
- https://doi.org//10.1002/jmv.25770
- https://doi.org//10.1101/2020.03.01.20029769
- https://doi.org//10.1007/s00134-020-05991-x
- https://doi.org//10.1001/jamainternmed.2020.0994
- https://doi.org//10.1007/s00011-020-01342-0
- https://doi.org//10.1016/S0140-6736(20)30566-3
- https://doi.org//10.1097/FJC.0000000000000717
- https://doi.org//10.1371/journal.ppat.1005973
- https://doi.org//10.1038/s41584-019-0277-8
- https://doi.org//10.1097/CCM.0000000000001402
SHARE
Usage metrics
Read the peer-reviewed publication
AUTHORS (12)
CATEGORIES
- Transplantation Immunology
- Tumour Immunology
- Immunology not elsewhere classified
- Immunology
- Veterinary Immunology
- Animal Immunology
- Genetic Immunology
- Applied Immunology (incl. Antibody Engineering, Xenotransplantation and T-cell Therapies)
- Autoimmunity
- Cellular Immunology
- Humoural Immunology and Immunochemistry
- Immunogenetics (incl. Genetic Immunology)
- Innate Immunity