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
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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
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G-CSF and GM-CSF administration can exacerbate rheumatoid arthritis (RA), and both cytokines are found in the joints of patients with RA
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Antagonism of G-CSF or GM-CSF can markedly reduce established disease in mouse models of RA
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GM-CSF antagonists have entered clinical trials, and antagonists of G-CSF are currently being developed
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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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References
Spitzer, G. et al. Randomized comparison of G-CSF + GM-CSF vs G-CSF alone for mobilization of peripheral blood stem cells: effects on hematopoietic recovery after high-dose chemotherapy. Bone Marrow Transplant. 20, 921–930 (1997).
Eyles, J. L., Roberts, A. W., Metcalf, D. & Wicks, I. P. Granulocyte colony-stimulating factor and neutrophils—forgotten mediators of inflammatory disease. Nat. Clin. Pract. Rheumatol. 2, 500–510 (2006).
Hamilton, J. A. Colony-stimulating factors in inflammation and autoimmunity. Nat. Rev. Immunol. 8, 533–544 (2008).
Nicola, N. A. (Ed.) Guidebook to cytokines and their receptors (Oxford University Press, Oxford, UK, 1994).
Williamson, D. J., Begley, C. G., Vadas, M. A. & Metcalf, D. The detection and initial characterization of colony-stimulating factors in synovial fluid. Clin. Exp. Immunol. 72, 67–73 (1988).
Chu, C. Q. et al. Detection of cytokines at the cartilage/pannus junction in patients with rheumatoid arthritis: implications for the role of cytokines in cartilage destruction and repair. Br. J. Rheumatol. 31, 653–661 (1992).
Kawakami, M. et al. Levels of serum granulocyte colony-stimulating factor in patients with infections. Blood 76, 1962–1964 (1990).
Nakamura, H. et al. High serum and synovial fluid granulocyte colony stimulating factor (G-CSF) concentrations in patients with rheumatoid arthritis. Clin. Exp. Rheumatol. 18, 713–718 (2000).
Stark, M. A. et al. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 22, 285–294 (2005).
Smith, E. et al. IL-23 is required for neutrophil homeostasis in normal and neutrophilic mice. J. Immunol. 179, 8274–8279 (2007).
Nakae, S. et al. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17, 375–387 (2002).
von Vietinghoff, S. & Ley, K. IL-17A controls IL-17F production and maintains blood neutrophil counts in mice. J. Immunol. 183, 865–873 (2009).
Schwarzenberger, P. et al. Requirement of endogenous stem cell factor and granulocyte-colony-stimulating factor for IL-17-mediated granulopoiesis. J. Immunol. 164, 4783–4789 (2000).
Roberts, A. W. G-CSF: a key regulator of neutrophil production, but that's not all! Growth Factors 23, 33–41 (2005).
Wong, P. K. et al. SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1-dependent inflammatory arthritis. J. Clin. Invest. 116, 1571–1581 (2006).
Dancey, J. T., Deubelbeiss, K. A., Harker, L. A. & Finch, C. A. Neutrophil kinetics in man. J. Clin. Invest. 58, 705–715 (1976).
Lieschke, G. J. et al. Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood 84, 1737–1746 (1994).
Liu, F., Wu, H. Y., Wesselschmidt, R., Kornaga, T. & Link, D. C. Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice. Immunity 5, 491–501 (1996).
von Vietinghoff, S. & Ley, K. Homeostatic regulation of blood neutrophil counts. J. Immunol. 181, 5183–5188 (2008).
Gearing, D. P., King, J. A., Gough, N. M. & Nicola, N. A. Expression cloning of a receptor for human granulocyte-macrophage colony-stimulating factor. EMBO J. 8, 3667–3676 (1989).
Tortorella, C., Simone, O., Piazzolla, G., Stella, I. & Antonaci, S. Age-related impairment of GM-CSF-induced signaling in neutrophils: role of SHP-1 and SOCS proteins. Ageing Res. Rev. 6, 81–93 (2007).
Stanley, E. et al. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc. Natl Acad. Sci. USA 91, 5592–5596 (1994).
Dranoff, G. et al. Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Science 264, 713–716 (1994).
Sonderegger, I. et al. GM-CSF mediates autoimmunity by enhancing IL-6-dependent TH17 cell development and survival. J. Exp. Med. 205, 2281–2294 (2008).
Carulli, G. Effects of recombinant human granulocyte colony-stimulating factor administration on neutrophil phenotype and functions. Haematologica 82, 606–616 (1997).
McColl, S. R. et al. Treatment with anti-granulocyte antibodies inhibits the effector phase of experimental autoimmune encephalomyelitis. J. Immunol. 161, 6421–6426 (1998).
Mohr, W. & Menninger, H. Polymorphonuclear granulocytes at the pannus-cartilage junction in rheumatoid arthritis. Arthritis Rheum. 23, 1413–1414 (1980).
Ohtsu, S. et al. Enhanced neutrophilic granulopoiesis in rheumatoid arthritis. Involvement of neutrophils in disease progression. J. Rheumatol. 27, 1341–1351 (2000).
Bennouna, S. & Denkers, E. Y. Microbial antigen triggers rapid mobilization of TNF-α to the surface of mouse neutrophils transforming them into inducers of high-level dendritic cell TNF-α production. J. Immunol. 174, 4845–4851 (2005).
Gelderman, M. P. et al. Perpetuation of inflammation associated with experimental arthritis: the role of macrophage activation by neutrophilic myeloperoxidase. Mediators Inflamm. 7, 381–389 (1998).
Scapini, P. et al. G-CSF-stimulated neutrophils are a prominent source of functional BLyS. J. Exp. Med. 197, 297–302 (2003).
Schmielau, J. & Finn, O. J. Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of T-cell function in advanced cancer patients. Cancer Res. 61, 4756–4760 (2001).
Brennan, F. M. & McInnes, I. B. Evidence that cytokines play a role in rheumatoid arthritis. J. Clin. Invest. 118, 3537–3545 (2008).
Hamilton, J. A. & Tak, P. P. The dynamics of macrophage lineage populations in inflammatory and autoimmune diseases. Arthritis Rheum. 60, 1210–1221 (2009).
Fadok, V. A. et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J. Clin. Invest. 101, 890–898 (1998).
Torchinsky, M. B., Garaude, J., Martin, A. P. & Blander, J. M. Innate immune recognition of infected apoptotic cells directs TH17 cell differentiation. Nature 458, 78–82 (2009).
Michlewska, S., Dransfield, I., Megson, I. L. & Rossi, A. G. Macrophage phagocytosis of apoptotic neutrophils is critically regulated by the opposing actions of pro-inflammatory and anti-inflammatory agents: key role for TNF-α. FASEB J. 23, 844–854 (2009).
Eyles, J. L. et al. A key role for G-CSF-induced neutrophil production and trafficking during inflammatory arthritis. Blood 112, 5193–5201 (2008).
Lawlor, K. E. et al. Critical role for granulocyte colony-stimulating factor in inflammatory arthritis. Proc. Natl Acad. Sci. USA 101, 11398–11403 (2004).
Cook, A. D., Braine, E. L., Campbell, I. K., Rich, M. J. & Hamilton, J. A. Blockade of collagen-induced arthritis post-onset by antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF): requirement for GM-CSF in the effector phase of disease. Arthritis Res. 3, 293–298 (2001).
Plater-Zyberk, C. et al. GM-CSF neutralisation suppresses inflammation and protects cartilage in acute streptococcal cell wall arthritis of mice. Ann. Rheum. Dis. 66, 452–457 (2007).
Campbell, I. K., O'Donnell, K., Lawlor, K. E. & Wicks, I. P. Severe inflammatory arthritis and lymphadenopathy in the absence of TNF. J. Clin. Invest. 107, 1519–1527 (2001).
Rubbert-Roth, A. & Finckh, A. Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review. Arthritis Res. Ther. 11 (Suppl. 1), S1 (2009).
Plater-Zyberk, C. et al. Combined blockade of granulocyte-macrophage colony stimulating factor and interleukin 17 pathways potently suppresses chronic destructive arthritis in a tumour necrosis factor alpha-independent mouse model. Ann. Rheum. Dis. 68, 721–728 (2009).
Liang, M. et al. Internalization of the antibody (CAM-3001) following monocyte cell surface binding to the GM-CSFR alpha chain. Arthritis Rheum. 58, S181 (2008).
Medimmune LCC [online].
Morphosys AG [online].
KaloBios Pharmaceuticals [online].
Basu, S. et al. “Emergency” granulopoiesis in G-CSF-deficient mice in response to Candida albicans infection. Blood 95, 3725–3733 (2000).
Mannering, S. I., Zhan, Y., Gilbertson, B., Lieschke, G. J. & Cheers, C. T lymphocytes from granulocyte colony-stimulating factor−/− mice produce large quantities of interferon-gamma in a chronic infection model. Immunology 101, 132–139 (2000).
Bodey, G. P., Buckley, M., Sathe, Y. S. & Freireich, E. J. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann. Intern. Med. 64, 328–340 (1966).
Smith, T. J. et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J. Clin. Oncol. 24, 3187–3205 (2006).
Lester, S. E. et al. Treatment-induced stable, moderate reduction in blood cell counts correlate with disease control in early rheumatoid arthritis. Intern. Med. J. 39, 296–303 (2009).
Genovese, M. C. et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 58, 2968–2980 (2008).
Hamilton, J. A. Rheumatoid arthritis: opposing actions of haemopoietic growth factors and slow-acting anti-rheumatic drugs. Lancet 342, 536–539 (1993).
Trapnell, B. C., Whitsett, J. A. & Nakata, K. Pulmonary alveolar proteinosis. N. Engl. J. Med. 349, 2527–2539 (2003).
Uchida, K. et al. GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis. N. Engl. J. Med. 356, 567–579 (2007).
Uchida, K. et al. Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects. Blood 113, 2547–2556 (2009).
Robinson, T. E., Trapnell, B. C., Goris, M. L., Quittell, L. M. & Cornfield, D. N. Quantitative analysis of longitudinal response to aerosolized granulocyte-macrophage colony-stimulating factor in two adolescents with autoimmune pulmonary alveolar proteinosis. Chest 135, 842–848 (2009).
Gottlieb, A. et al. Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet 373, 633–640 (2009).
Bongartz, T. et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295, 2275–2285 (2006).
Smolen, J. S., Aletaha, D., Koeller, M., Weisman, M. H. & Emery, P. New therapies for treatment of rheumatoid arthritis. Lancet 370, 1861–1874 (2007).
Stabler, T., Piette, J. C., Chevalier, X., Marini-Portugal, A. & Kraus, V. B. Serum cytokine profiles in relapsing polychondritis suggest monocyte/macrophage activation. Arthritis Rheum. 50, 3663–3667 (2004).
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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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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DOI: https://doi.org/10.1038/nrrheum.2009.178
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