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G-CSF and GM-CSF as therapeutic targets in rheumatoid arthritis

Abstract

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are well-recognized regulators of hematopoiesis and have an established role as growth factors in clinical practice. G-CSF and GM-CSF regulate myeloid cell production, differentiation and activation, and might also be important for driving inflammatory responses. Inappropriate engagement of this pathway could be a critical amplification mechanism when maladaptive immune responses predispose to autoimmunity and sterile tissue inflammation. We postulate that antagonism of G-CSF or GM-CSF could represent a novel therapeutic approach for a variety of autoimmune-mediated inflammatory diseases, including rheumatoid arthritis.

Key Points

  • Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are cytokines involved in the regulation of hematopoiesis, but can also have proinflammatory activities

  • G-CSF and GM-CSF administration can exacerbate rheumatoid arthritis (RA), and both cytokines are found in the joints of patients with RA

  • Antagonism of G-CSF or GM-CSF can markedly reduce established disease in mouse models of RA

  • GM-CSF antagonists have entered clinical trials, and antagonists of G-CSF are currently being developed

  • Antagonism of G-CSF or GM-CSF might be a safe and effective way of treating inflammatory disorders, such as RA

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Figure 1: Interactions between the innate and adaptive immune systems to generate immunopathology in RA.

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Acknowledgements

We gratefully acknowledge the longstanding support of the Reid Philanthropic Trusts for Rheumatology research at the Walter and Eliza Hall Institute, the support of the National Health & Medical Research Council of Australia (NHMRC Project Grant 461243, NHMRC Development Grant 305558, NHMRC Peter Doherty Fellowship 310608 [A. L. Cornish]; NHMRC Industry Fellowship 461287 [I. K. Campbell]; and NHMRC Clinical Practitioner Fellowship 461203 [I. P. Wicks]) and a Project Grant from Arthritis Australia.

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Correspondence to Ian P. Wicks.

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B. S. McKenzie is an employee of CSL Ltd.

I. K. Campbell is a National Health & Medical Research Council industry fellow based at the Walter and Eliza Hall Institute and CSL Ltd. He has received grant/research support (including clinical trials) from CSL Ltd and is a patent holder/applicant for a Walter and Eliza Hall Institute/CSL Ltd product. He is also a patent holder/applicant for a MorphoSystems AG product.

I. P. Wicks has received grant/research support from CSL Ltd and is a patent holder/applicant for a Walter and Eliza Hall Institute/CSL Ltd product.

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Cornish, A., Campbell, I., McKenzie, B. et al. G-CSF and GM-CSF as therapeutic targets in rheumatoid arthritis. Nat Rev Rheumatol 5, 554–559 (2009). https://doi.org/10.1038/nrrheum.2009.178

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