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  • Review Article
  • Published:

Targeting GM-CSF in inflammatory diseases

Key Points

  • GM-CSF (granulocyte-macrophage colony stimulating factor) is a multifunctional cytokine that regulates inflammatory responses, including emergency responses in the bone marrow

  • Mice deficient in GM-CSF develop normally, apart from displaying a lung phenotype similar to pulmonary alveolar proteinosis in humans

  • GM-CSF antagonism has beneficial effects in multiple autoimmune and inflammatory preclinical disease models, including inflammatory arthritis and inflammatory disease of the central nervous system

  • A monoclonal antibody specific to GM-CSFRα (GM-CSF ligand-binding α-chain) was well tolerated in early phase clinical trials in rheumatoid arthritis (RA), leading to impressive clinical responses that included rapid pain relief

  • Therapeutic agents targeting GM-CSF signalling are currently undergoing evaluation in a number of diseases, including RA and multiple sclerosis, among others

Abstract

Granulocyte-macrophage colony stimulating factor (GM-CSF) is a growth factor first identified as an inducer of differentiation and proliferation of granulocytes and macrophages derived from haematopoietic progenitor cells. Later studies have shown that GM-CSF is involved in a wide range of biological processes in both innate and adaptive immunity, with its production being tightly linked to the response to danger signals. Given that the functions of GM-CSF span multiple tissues and biological processes, this cytokine has shown potential as a new and important therapeutic target in several autoimmune and inflammatory disorders — particularly in rheumatoid arthritis. Indeed, GM-CSF was one of the first cytokines detected in human synovial fluid from inflamed joints. Therapies that target GM-CSF or its receptor have been tested in preclinical studies with promising results, further supporting the potential of targeting the GM-CSF pathway. In this Review, we discuss our expanding view of the biology of GM-CSF, outline what has been learnt about GM-CSF from studies of animal models and human diseases, and summarize the results of early phase clinical trials evaluating GM-CSF antagonism in inflammatory disorders.

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Figure 1: Structure of the GM-CSF receptor.
Figure 2: GM-CSF — a key player in inflammation and autoimmunity.

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References

  1. Metcalf, D. Hematopoietic cytokines. Blood 111, 485–491 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Metcalf, D. The colony-stimulating factors and cancer. Nat. Rev. Cancer 10, 425–434 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Xu, W. D., Firestein, G. S., Taetle, R., Kaushansky, K. & Zvaifler, N. J. Cytokines in chronic inflammatory arthritis. II. Granulocyte-macrophage colony-stimulating factor in rheumatoid synovial effusions. J. Clin. Invest. 83, 876–882 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cornish, A. L., Campbell, I. K., McKenzie, B. S., Chatfield, S. & Wicks, I. P. G-CSF and GM-CSF as therapeutic targets in rheumatoid arthritis. Nat. Rev. Rheumatol 5, 554–559 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Hamilton, J. A. Colony-stimulating factors in inflammation and autoimmunity. Nat. Rev. Immunol. 8, 533–544 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Shiomi, A. & Usui, T. Pivotal roles of GM-CSF in autoimmunity and inflammation. Mediators Inflamm. 2015, 568543 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. LeVine, A. M., Reed, J. A., Kurak, K. E., Cianciolo, E. & Whitsett, J. A. GM-CSF-deficient mice are susceptible to pulmonary group B streptococcal infection. J. Clin. Invest. 103, 563–569 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Stosser, S., Schweizerhof, M. & Kuner, R. Hematopoietic colony-stimulating factors: new players in tumor-nerve interactions. J. Mol. Med. (Berl.) 89, 321–329 (2011).

    Article  CAS  Google Scholar 

  10. Broughton, S. E. et al. The βc receptor family — structural insights and their functional implications. Cytokine 74, 247–258 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Hercus, T. R. et al. Signalling by the βc family of cytokines. Cytokine Growth Factor Rev. 24, 189–201 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Guthridge, M. A. & Lopez, A. F. Phosphotyrosine/phosphoserine binary switches: a new paradigm for the regulation of PI3K signalling and growth factor pleiotropy? Biochem. Soc. Trans. 35, 250–252 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Liontos, L. M. et al. The Src-like adaptor protein regulates GM-CSFR signaling and monocytic dendritic cell maturation. J. Immunol. 186, 1923–1933 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Bunda, S., Kommaraju, K., Heir, P. & Ohh, M. SOCS-1 mediates ubiquitylation and degradation of GM-CSF receptor. PLoS ONE 8, e76370 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Metcalf, D. et al. Aberrant hematopoiesis in mice with inactivation of the gene encoding SOCS-1. Leukemia 13, 926–934 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Wright, H. L., Thomas, H. B., Moots, R. J. & Edwards, S. W. RNA-seq reveals activation of both common and cytokine-specific pathways following neutrophil priming. PLoS ONE 8, e58598 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cowburn, A. S. et al. Granulocyte/macrophage colony-stimulating factor causes a paradoxical increase in the BH3-only pro-apoptotic protein Bim in human neutrophils. Am. J. Respir. Cell. Mol. Biol. 44, 879–887 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. 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).

    Article  CAS  PubMed  Google Scholar 

  19. Yong, K. L., Rowles, P. M., Patterson, K. G. & Linch, D. C. Granulocyte-macrophage colony-stimulating factor induces neutrophil adhesion to pulmonary vascular endothelium in vivo: role of beta 2 integrins. Blood 80, 1565–1575 (1992).

    CAS  PubMed  Google Scholar 

  20. Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Futosi, K., Fodor, S. & Mocsai, A. Neutrophil cell surface receptors and their intracellular signal transduction pathways. Int. Immunopharmacol. 17, 638–650 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yousefi, S., Mihalache, C., Kozlowski, E., Schmid, I. & Simon, H. U. Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps. Cell Death Differ. 16, 1438–1444 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Goldmann, O. & Medina, E. The expanding world of extracellular traps: not only neutrophils but much more. Front. Immunol. 3, 420 (2012).

    PubMed  Google Scholar 

  24. Curran, C. S. & Bertics, P. J. Lactoferrin regulates an axis involving CD11b and CD49d integrins and the chemokines MIP-1α and MCP-1 in GM-CSF-treated human primary eosinophils. J. Interferon Cytokine Res. 32, 450–461 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wong, C. K. et al. MicroRNA-21* regulates the prosurvival effect of GM-CSF on human eosinophils. Immunobiology 218, 255–262 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. Liu, L. Y., Wang, H., Xenakis, J. J. & Spencer, L. A. Notch signaling mediates granulocyte-macrophage colony-stimulating factor priming-induced transendothelial migration of human eosinophils. Allergy 70, 805–812 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. Hamilton, J. A. & Achuthan, A. Colony stimulating factors and myeloid cell biology in health and disease. Trends Immunol. 34, 81–89 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Mantovani, A., Sica, A. & Locati, M. Macrophage polarization comes of age. Immunity 23, 344–346 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Guilliams, M. & van de Laar, L. A. Hitchhiker's guide to myeloid cell subsets: practical implementation of a novel mononuclear phagocyte classification system. Front. Immunol. 6, 406 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fleetwood, A. J., Dinh, H., Cook, A. D., Hertzog, P. J. & Hamilton, J. A. GM-CSF- and M-CSF-dependent macrophage phenotypes display differential dependence on type I interferon signaling. J. Leukoc. Biol. 86, 411–421 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Akagawa, K. S. et al. Functional heterogeneity of colony-stimulating factor-induced human monocyte-derived macrophages. Respirology 11, S32–S36 (2006).

    Article  PubMed  Google Scholar 

  34. Joshi, S. et al. Rac2 controls tumor growth, metastasis and M1-M2 macrophage differentiation in vivo. PLoS ONE 9, e95893 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Martinez, F. O., Gordon, S., Locati, M. & Mantovani, A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J. Immunol. 177, 7303–7311 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Shibata, Y. et al. GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1. Immunity 15, 557–567 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Krausgruber, T. et al. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat. Immunol. 12, 231–238 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Sierra-Filardi, E. et al. Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers. Blood 117, 5092–5101 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Su, X. et al. Interferon-γ regulates cellular metabolism and mRNA translation to potentiate macrophage activation. Nat. Immunol. 16, 838–849 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Louis, C. et al. Specific contributions of CSF-1 and GM-CSF to the dynamics of the mononuclear phagocyte system. J. Immunol. 195, 134–144 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. Dai, X. M. et al. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood 99, 111–120 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Varol, C., Mildner, A. & Jung, S. Macrophages: development and tissue specialization. Annu. Rev. Immunol. 33, 643–675 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Wang, Y. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol. 13, 753–760 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).

    Article  CAS  PubMed  Google Scholar 

  46. Guilliams, M. et al. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J. Exp. Med. 210, 1977–1992 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Schneider, C. et al. Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages. Nat. Immunol. 15, 1026–1037 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Sakagami, T. et al. Human GM-CSF autoantibodies and reproduction of pulmonary alveolar proteinosis. N. Engl. J. Med. 361, 2679–2681 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bain, C. C. et al. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat. Immunol. 15, 929–937 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Misharin, A. V. et al. Nonclassical Ly6C monocytes drive the development of inflammatory arthritis in mice. Cell Rep. 9, 591–604 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tak, P. P. & Bresnihan, B. The pathogenesis and prevention of joint damage in rheumatoid arthritis: advances from synovial biopsy and tissue analysis. Arthritis Rheum. 43, 2619–2633 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Hamilton, J. A. & Tak, P. P. The dynamics of macrophage lineage populations in inflammatory and autoimmune diseases. Arthritis Rheum. 60, 1210–1221 (2009).

    Article  PubMed  Google Scholar 

  53. Schlitzer, A. & Ginhoux, F. Organisation of the mouse and human DC network. Curr. Opin. Immunol. 26, 90–99 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. King, I. L., Kroenke, M. A. & Segal, B. M. GM-CSF-dependent, CD103+ dermal dendritic cells play a critical role in Th effector cell differentiation after subcutaneous immunization. J. Exp. Med. 207, 953–961 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hirata, Y., Egea, L., Dann, S. M., Eckmann, L. & Kagnoff, M. F. GM-CSF-facilitated dendritic cell recruitment and survival govern the intestinal mucosal response to a mouse enteric bacterial pathogen. Cell Host Microbe 7, 151–163 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dabritz, J. Granulocyte macrophage colony-stimulating factor and the intestinal innate immune cell homeostasis in Crohn's disease. Am. J. Physiol. Gastrointest. Liver Physiol. 306, G455–G465 (2014).

    Article  CAS  PubMed  Google Scholar 

  57. Zhan, Y. et al. GM-CSF increases cross-presentation and CD103 expression by mouse CD8+ spleen dendritic cells. Eur. J. Immunol. 41, 2585–2595 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. Zhan, Y., Xu, Y. & Lew, A. M. The regulation of the development and function of dendritic cell subsets by GM-CSF: more than a hematopoietic growth factor. Mol. Immunol. 52, 30–37 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Esashi, E. et al. The signal transducer STAT5 inhibits plasmacytoid dendritic cell development by suppressing transcription factor IRF8. Immunity 28, 509–520 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gonzalez-Juarrero, M. et al. Disruption of granulocyte macrophage-colony stimulating factor production in the lungs severely affects the ability of mice to control Mycobacterium tuberculosis infection. J. Leukoc. Biol. 77, 914–922 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Riopel, J., Tam, M., Mohan, K., Marino, M. W. & Stevenson, M. M. Granulocyte-macrophage colony-stimulating factor-deficient mice have impaired resistance to blood-stage malaria. Infect. Immun. 69, 129–136 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Paine, R. et al. Granulocyte-macrophage colony-stimulating factor in the innate immune response to Pneumocystis carinii pneumonia in mice. J. Immunol. 164, 2602–2609 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Grau, G. E., Kindler, V., Piguet, P. F., Lambert, P. H. & Vassalli, P. Prevention of experimental cerebral malaria by anticytokine antibodies. Interleukin 3 and granulocyte macrophage colony-stimulating factor are intermediates in increased tumor necrosis factor production and macrophage accumulation. J. Exp. Med. 168, 1499–1504 (1988).

    Article  CAS  PubMed  Google Scholar 

  64. Campbell, I. K. et al. Differentiation of inflammatory dendritic cells is mediated by NF-κB1-dependent GM-CSF production in CD4 T cells. J. Immunol. 186, 5468–5477 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Naik, S. H. et al. Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes. Nat. Immunol. 7, 663–671 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Segura, E. & Amigorena, S. Inflammatory dendritic cells in mice and humans. Trends Immunol. 34, 440–445 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Segura, E. et al. Human inflammatory dendritic cells induce Th17 cell differentiation. Immunity 38, 336–348 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Caux, C. et al. CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNFα. J. Exp. Med. 184, 695–706 (1996).

    Article  CAS  PubMed  Google Scholar 

  69. Xu, Y., Zhan, Y., Lew, A. M., Naik, S. H. & Kershaw, M. H. Differential development of murine dendritic cells by GM-CSF versus Flt3 ligand has implications for inflammation and trafficking. J. Immunol. 179, 7577–7584 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. van Nieuwenhuijze, A. E. et al. Transgenic expression of GM-CSF in T cells causes disseminated histiocytosis. Am. J. Pathol. 184, 184–199 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Fleetwood, A. J., Lawrence, T., Hamilton, J. A. & Cook, A. D. Granulocyte-macrophage colony-stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities: implications for CSF blockade in inflammation. J. Immunol. 178, 5245–5252 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Ko, H. J. et al. GM-CSF-responsive monocyte-derived dendritic cells are pivotal in Th17 pathogenesis. J. Immunol. 192, 2202–2209 (2014).

    Article  CAS  PubMed  Google Scholar 

  73. Jiao, Z. et al. The closely related CD103+ dendritic cells (DCs) and lymphoid-resident CD8+ DCs differ in their inflammatory functions. PLoS ONE 9, e91126 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wang, J. et al. Transgenic expression of granulocyte-macrophage colony-stimulating factor induces the differentiation and activation of a novel dendritic cell population in the lung. Blood 95, 2337–2345 (2000).

    CAS  PubMed  Google Scholar 

  75. Teng, M. W. et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat. Med. 21, 719–729 (2015).

    Article  CAS  PubMed  Google Scholar 

  76. Codarri, L. et al. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat. Immunol. 12, 560–567 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Ruan, Q. et al. The Th17 immune response is controlled by the Rel–RORγ–RORγT transcriptional axis. J. Exp. Med. 208, 2321–2333 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Jeltsch, K. M. et al. Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote TH17 differentiation. Nat. Immunol. 15, 1079–1089 (2014).

    Article  CAS  PubMed  Google Scholar 

  79. Man, K. et al. The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells. Nat. Immunol. 14, 1155–1165 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Sheng, W. et al. STAT5 programs a distinct subset of GM-CSF-producing T helper cells that is essential for autoimmune neuroinflammation. Cell Res. 24, 1387–1402 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Noster, R. et al. IL-17 and GM-CSF expression are antagonistically regulated by human T helper cells. Sci. Transl. Med. 6, 241ra80 (2014).

    Article  CAS  PubMed  Google Scholar 

  82. Bar, E., Whitney, P. G., Moor, K., Reis e Sousa, C. & LeibundGut-Landmann, S. IL-17 regulates systemic fungal immunity by controlling the functional competence of NK cells. Immunity 40, 117–127 (2014).

    Article  CAS  PubMed  Google Scholar 

  83. Campbell, I. K. et al. Protection from collagen-induced arthritis in granulocyte-macrophage colony-stimulating factor-deficient mice. J. Immunol. 161, 3639–3644 (1998).

    CAS  PubMed  Google Scholar 

  84. Yang, Y. H. & Hamilton, J. A. Dependence of interleukin-1-induced arthritis on granulocyte-macrophage colony-stimulating factor. Arthritis Rheum. 44, 111–119 (2001).

    Article  PubMed  Google Scholar 

  85. Lawlor, K. E., Campbell, I. K., O'Donnell, K., Wu, L. & Wicks, I. P. Molecular and cellular mediators of interleukin-1-dependent acute inflammatory arthritis. Arthritis Rheum. 44, 442–450 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. 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).

    Article  CAS  PubMed  Google Scholar 

  87. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. El-Behi, M. et al. The encephalitogenicity of TH17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat. Immunol. 12, 568–575 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. van Nieuwenhuijze, A. et al. GM-CSF as a therapeutic target in inflammatory diseases. Mol. Immunol. 56, 675–682 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Egan, P. J., van Nieuwenhuijze, A., Campbell, I. K. & Wicks, I. P. Promotion of the local differentiation of murine Th17 cells by synovial macrophages during acute inflammatory arthritis. Arthritis Rheum. 58, 3720–3729 (2008).

    Article  CAS  PubMed  Google Scholar 

  91. Greter, M. et al. GM-CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable for the differentiation of inflammatory dendritic cells. Immunity 36, 1031–1046 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Croxford, A. L. et al. The cytokine GM-CSF drives the inflammatory signature of CCR2+ monocytes and licenses autoimmunity. Immunity 43, 502–514 (2015).

    Article  CAS  PubMed  Google Scholar 

  93. Rauch, P. J. et al. Innate response activator B cells protect against microbial sepsis. Science 335, 597–601 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Weber, G. F. et al. Pleural innate response activator B cells protect against pneumonia via a GM-CSF–IgM axis. J. Exp. Med. 211, 1243–1256 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Wang, M. et al. Interleukin-3/granulocyte macrophage colony-stimulating factor receptor promotes stem cell expansion, monocytosis, and atheroma macrophage burden in mice with hematopoietic ApoE deficiency. Arterioscler. Thromb. Vasc. Biol. 34, 976–984 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Hilgendorf, I. et al. Innate response activator B cells aggravate atherosclerosis by stimulating T helper-1 adaptive immunity. Circulation 129, 1677–1687 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Van Doornum, S., McColl, G. & Wicks, I. P. Accelerated atherosclerosis: an extraarticular feature of rheumatoid arthritis? Arthritis Rheum. 46, 862–873 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Uchida, K. et al. Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects. Blood 113, 2547–2556 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Browne, S. K. & Holland, S. M. Anticytokine autoantibodies in infectious diseases: pathogenesis and mechanisms. Lancet Infect. Dis. 10, 875–885 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Piccoli, L. et al. Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis. Nat. Commun. 6, 7375 (2015).

    Article  PubMed  Google Scholar 

  101. de la Rubia, J. et al. Administration of recombinant human granulocyte colony-stimulating factor to normal donors: results of the Spanish National Donor Registry. Bone Marrow Transplant. 24, 723–728 (1999).

    Article  CAS  PubMed  Google Scholar 

  102. Schweizerhof, M. et al. Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain. Nat. Med. 15, 802–807 (2009).

    Article  CAS  PubMed  Google Scholar 

  103. Cook, A. D. et al. Granulocyte-macrophage colony-stimulating factor is a key mediator in inflammatory and arthritic pain. Ann. Rheum. Dis. 72, 265–270 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Cook, A. D. et al. Granulocyte-macrophage colony-stimulating factor is a key mediator in experimental osteoarthritis pain and disease development. Arthritis Res. Ther. 14, R199 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Fiehn, C., Wermann, M., Pezzutto, A., Hufner, M. & Heilig, B. Plasma GM-CSF concentrations in rheumatoid arthritis, systemic lupus erythematosus and spondyloarthropathy. Z. Rheumatol. 51, 121–126 (in German) (1992).

    CAS  PubMed  Google Scholar 

  106. Field, M. & Clinton, L. Expression of GM-CSF receptor in rheumatoid arthritis. Lancet 342, 1244 (1993).

    Article  CAS  PubMed  Google Scholar 

  107. Hazenberg, B. P., Van Leeuwen, M. A., Van Rijswijk, M. H., Stern, A. C. & Vellenga, E. Correction of granulocytopenia in Felty's syndrome by granulocyte-macrophage colony-stimulating factor. Simultaneous induction of interleukin-6 release and flare-up of the arthritis. Blood 74, 2769–2770 (1989).

    CAS  PubMed  Google Scholar 

  108. Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–381 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Alvaro-Gracia, J. M., Zvaifler, N. J., Brown, C. B., Kaushansky, K. & Firestein, G. S. Cytokines in chronic inflammatory arthritis. VI. Analysis of the synovial cells involved in granulocyte-macrophage colony-stimulating factor production and gene expression in rheumatoid arthritis and its regulation by IL-1 and tumor necrosis factor-alpha. J. Immunol. 146, 3365–3371 (1991).

    CAS  PubMed  Google Scholar 

  110. Campbell, I. K., Novak, U., Cebon, J., Layton, J. E. & Hamilton, J. A. Human articular cartilage and chondrocytes produce hemopoietic colony-stimulating factors in culture in response to IL-1. J. Immunol. 147, 1238–1246 (1991).

    CAS  PubMed  Google Scholar 

  111. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 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 α-independent mouse model. Ann. Rheum. Dis. 68, 721–728 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. van Nieuwenhuijze, A. E. et al. Complementary action of granulocyte-macrophage colony-stimulating factor and interleukin-17A induces interleukin-23, receptor activator of nuclear factor-κB ligand and matrix metalloproteinases and drives bone and cartilage pathology in experimental arthritis: rationale for combination therapy in rheumatoid arthritis. Arthritis es. Ther. 17, 163 (2015).

    Article  CAS  Google Scholar 

  114. Shaw, O. M., Steiger, S., Liu, X., Hamilton, J. A. & Harper, J. L. Brief report: granulocyte-macrophage colony-stimulating factor drives monosodium urate monohydrate crystal-induced inflammatory macrophage differentiation and NLRP3 inflammasome up-regulation in an in vivo mouse model. Arthritis Rheumatol. 66, 2423–2428 (2014).

    Article  CAS  PubMed  Google Scholar 

  115. Ponomarev, E. D. et al. GM-CSF production by autoreactive T cells is required for the activation of microglial cells and the onset of experimental autoimmune encephalomyelitis. J. Immunol. 178, 39–48 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. King, I. L., Dickendesher, T. L. & Segal, B. M. Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood 113, 3190–3197 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Carrieri, P. B. et al. Profile of cerebrospinal fluid and serum cytokines in patients with relapsing-remitting multiple sclerosis: a correlation with clinical activity. Immunopharmacol. Immunotoxicol. 20, 373–382 (1998).

    Article  CAS  PubMed  Google Scholar 

  118. McQualter, J. L. et al. Granulocyte macrophage colony-stimulating factor: a new putative therapeutic target in multiple sclerosis. J. Exp. Med. 194, 873–882 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Haak, S. et al. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J. Clin. Invest. 119, 61–69 (2009).

    CAS  PubMed  Google Scholar 

  120. Benham, H. et al. Interleukin-23 mediates the intestinal response to microbial β-1,3-glucan and the development of spondyloarthritis pathology in SKG mice. Arthritis Rheumatol. 66, 1755–1767 (2014).

    Article  CAS  PubMed  Google Scholar 

  121. Shiomi, A. et al. GM-CSF but not IL-17 is critical for the development of severe interstitial lung disease in SKG mice. J. Immunol. 193, 849–859 (2014).

    Article  CAS  PubMed  Google Scholar 

  122. Willart, M. A. et al. Interleukin-1α controls allergic sensitization to inhaled house dust mite via the epithelial release of GM-CSF and IL-33. J. Exp. Med. 209, 1505–1517 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Vlahos, R. et al. Neutralizing granulocyte/macrophage colony-stimulating factor inhibits cigarette smoke-induced lung inflammation. Am. J. Respir. Crit. Care Med. 182, 34–40 (2010).

    Article  CAS  PubMed  Google Scholar 

  124. Botelho, F. M. et al. A mouse GM-CSF receptor antibody attenuates neutrophilia in mice exposed to cigarette smoke. Eur. Respir. J. 38, 285–294 (2011).

    Article  CAS  PubMed  Google Scholar 

  125. Yamashita, N. et al. Attenuation of airway hyperresponsiveness in a murine asthma model by neutralization of granulocyte-macrophage colony-stimulating factor (GM-CSF). Cell. Immunol. 219, 92–97 (2002).

    Article  CAS  PubMed  Google Scholar 

  126. Fahy, J. V. Eosinophilic and neutrophilic inflammation in asthma: insights from clinical studies. Proc. Am. Thorac Soc. 6, 256–259 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. Griseri, T. et al. Granulocyte macrophage colony-stimulating factor-activated eosinophils promote interleukin-23 driven chronic colitis. Immunity 43, 187–199 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Son, B. K. et al. Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma. Nat. Commun. 6, 6994 (2015).

    Article  CAS  PubMed  Google Scholar 

  129. Mellak, S. et al. Angiotensin II mobilizes spleen monocytes to promote the development of abdominal aortic aneurysm in Apoe−/− mice. Arterioscler. Thromb. Vasc. Biol. 35, 378–388 (2015).

    Article  CAS  PubMed  Google Scholar 

  130. Chen, L. et al. IL-23 activates innate lymphoid cells to promote neonatal intestinal pathology. Mucosal Immunol. 8, 390–402 (2015).

    Article  CAS  PubMed  Google Scholar 

  131. Dabritz, J. et al. Granulocyte macrophage colony-stimulating factor auto-antibodies and disease relapse in inflammatory bowel disease. Am. J. Gastroenterol. 108, 1901–1910 (2013).

    Article  CAS  PubMed  Google Scholar 

  132. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ryan, P. C. et al. Nonclinical safety of mavrilimumab, an anti-GMCSF receptor alpha monoclonal antibody, in cynomolgus monkeys: relevance for human safety. Toxicol. Appl. Pharmacol. 279, 230–239 (2014).

    Article  CAS  PubMed  Google Scholar 

  134. Liang, M. et al. Internalization of the antibody (CAM-3001) following monocyte cell surface binding to the GM-CSFR alpha chain. American College of Rheumatology [online], (2008).

    Google Scholar 

  135. Greven, D. E. et al. Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis. Ann. Rheum. Dis. 74, 1924–1930 (2014).

    Article  CAS  PubMed  Google Scholar 

  136. Burmester, G. R. et al. Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, Phase I, first-in-human study. Ann. Rheum. Dis. 70, 1542–1549 (2011).

    Article  CAS  PubMed  Google Scholar 

  137. Burmester, G. R. et al. Efficacy and safety of mavrilimumab in subjects with rheumatoid arthritis. Ann. Rheum. Dis. 72, 1445–1452 (2013).

    Article  CAS  PubMed  Google Scholar 

  138. Curtis, J. R. et al. Validation of a novel multibiomarker test to assess rheumatoid arthritis disease activity. Arthritis Care Res. (Hoboken) 64, 1794–1803 (2012).

    Article  Google Scholar 

  139. Takeuchi, T. et al. Efficacy and safety of mavrilimumab in Japanese subjects with rheumatoid arthritis: findings from a Phase IIa study. Mod. Rheumatol 25, 21–30 (2015).

    Article  CAS  PubMed  Google Scholar 

  140. McInnes, I. B. et al. Rapid onset of clinical benefit is associated with a reduction in validated biomarkers of disease in patients with rheumatoid arthritis treated with mavrilimumab, a monoclonal antibody targeting GM-CSFRα. ACRabstracts [online], (2014).

    Google Scholar 

  141. Burmester, G. et al. Efficacy and safety of mavrilimumab, a fully human GM-CSFR alpha monoclonal antibody in patients with rheumatoid arthritis: primary results from the earth explorer 1 study. Ann. Rheum. Dis. Abstr. 74, 78 (2015).

    Google Scholar 

  142. Steidl, S., Ratsch, O., Brocks, B., Durr, M. & Thomassen-Wolf, E. In vitro affinity maturation of human GM-CSF antibodies by targeted CDR-diversification. Mol. Immunol. 46, 135–144 (2008).

    Article  CAS  PubMed  Google Scholar 

  143. Behrens, F. et al. MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a Phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial. Ann. Rheum. Dis. 74, 1058–1064 (2015).

    Article  CAS  PubMed  Google Scholar 

  144. US National Library of Medicine. A Phase 1 MT203 single-dose study to evaluate safety, PK and PD. Clinicaltrials.gov[online], (2015).

  145. US National Library of Medicine. A Trial to evaluate the safety and tolerability of namilumab (MT203) in patients with mild to moderate rheumatoid arthritis (PRIORA). Clinicaltrials.gov[online], (2015).

  146. US National Library of Medicine. Efficacy and safety of namilumab (MT203) for plaque psoriasis. Clinicaltrials.gov[online], (2015).

  147. US National Library of Medicine. Namilumab vs adalimumab in participants with moderate to severe early rheumatoid arthritis inadequately responding to methotrexate (TELLUS). Clinicaltrials.gov[online], (2015).

  148. US National Library of Medicine. Dose finding study of namilumab in combination with methotrexate in participants with moderate to severe rheumatoid arthritis (RA). Clinicaltrials.gov[online], (2015).

  149. US National Library of Medicine. Safety and preliminary efficacy of MOR103 in patients with active rheumatoid arthritis. Clinicaltrials.gov[online], (2014).

  150. US National Library of Medicine. Phase Ib study to evaluate MOR103 in multiple sclerosis. Clinicaltrials.gov[online], (2014).

  151. US National Library of Medicine. Effect of KB003 in subjects with asthma inadequately controlled by corticosteroids (KB003-04). Clinicaltrials.gov[online], (2015).

  152. US National Library of Medicine. Study of KB003 in previously treated patients with chronic myelomonocytic leukemia (CMML). Clinicaltrials.gov[online], (2015).

  153. US National Library of Medicine. Safety and tolerability of MORAb-022 in healthy and rheumatoid arthritis subjects. Clinicaltrials.gov[online], (2015).

  154. US National Library of Medicine. A single dose study of the CAM-3001 in patients with rheumatoid arthritis. Clinicaltrials.gov[online], (2012).

  155. US National Library of Medicine. A study to evaluate the efficacy and safety of CAM-3001 (drug) in subjects with rheumatoid arthritis. Clinicaltrials.gov[online], (2014).

  156. US National Library of Medicine. A study of mavrilimumab versus anti tumor necrosis factor in subjects with rheumatoid arthritis. Clinicaltrials.gov[online], (2015).

  157. US National Library of Medicine. A study of mavrilimumab in subjects with moderate-to-severe rheumatoid arthritis. Clinicaltrials.gov[online], (2014).

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Acknowledgements

The work of the authors is supported by the Reid Charitable Trusts (Melbourne, Australia), the National Health and Medical Research Council (NHMRC), Canberra, Australia (I.P.W. Clinical Practitioner Fellowship 1023407 and A.W.R.107956), NHMRC Program Grant (1016647) funding to both authors, and operational infrastructure grants from the Victoria State Government. We thank all past and present members of our labs, and E. S. Prato for administrative assistance. This Review is dedicated to the memory of the late Donald Metcalf (1929–2014), a friend, colleague and mentor to both authors. Don was a pioneer of molecular haematology, who discovered GM-CSF, helped characterize the GM-CSF receptor and saw GM-CSF and G-CSF introduced into clinical practice as growth factors, to the benefit of many patients.

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Both authors contributed equally to all aspects of the manuscript (researching data for the article, discussions of its content, writing, review and editing of the manuscript before submission).

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Correspondence to Ian P. Wicks.

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I.P.W. declares that he collaborated with CSL Pty Ltd in the development of an anti-GM-CSF receptor antagonist program, which subsequently included a collaboration with MedImmune Pty Ltd. His lab has received funding from CSL and MedImmune for this program and for work on other colony-stimulating-factor (CSF) antagonists. A.W.R. has conducted two first-in-human clinical trials funded by CSL Pty Ltd.

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Wicks, I., Roberts, A. Targeting GM-CSF in inflammatory diseases. Nat Rev Rheumatol 12, 37–48 (2016). https://doi.org/10.1038/nrrheum.2015.161

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