Anti-colony-stimulating factor therapies for inflammatory and autoimmune diseases

Nature Reviews Drug Discovery

Volumn 16, Issue 1, 2016, Pages 53-70

  Hamilton, John A ^a   Cook, Andrew D ^a   Tak, Paul P ^b  

^a UNIVERSITY OF MELBOURNE   (Australia)

^b GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

COLONY STIMULATING FACTOR 1; FPA 008; GRANULOCYTE COLONY STIMULATING FACTOR; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; GSK 3196165; INTERLEUKIN 3; JNJ 40346527; LENZILUMAB; MAVRILIMUMAB; MCS 110; NAMILUMAB; PD 0360324; PLX 5622; UNCLASSIFIED DRUG; COLONY STIMULATING FACTOR;

ASTHMA; AUTOIMMUNE DISEASE; B LYMPHOCYTE; CLINICAL RESEARCH; DISEASE MODEL; DRUG TARGETING; GIANT CELL TUMOR; HELPER CELL; HUMAN; INFLAMMATORY DISEASE; LUNG SARCOIDOSIS; MULTIPLE SCLEROSIS; NERVOUS SYSTEM; NONHUMAN; OSTEOARTHRITIS; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PIGMENTED VILLONODULAR SYNOVITIS; PRIORITY JOURNAL; PROTEIN FUNCTION; PSORIASIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RHEUMATOID ARTHRITIS; SKIN LUPUS ERYTHEMATOSUS; ANIMAL; ANTAGONISTS AND INHIBITORS; AUTOIMMUNE DISEASES; CLINICAL TRIAL (TOPIC); INFLAMMATION; METABOLISM;

ANIMALS; AUTOIMMUNE DISEASES; CLINICAL TRIALS AS TOPIC; COLONY-STIMULATING FACTORS; HUMANS; INFLAMMATION; INTERLEUKIN-3;

EID: 85007507906     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd.2016.231     Document Type: Review

References (265)

1. Burgess A. W, & Metcalf D. The nature and action of granulocyte-macrophage colony stimulating factors. Blood 56, 947-958 (1980).
2. Metcalf D. Hematopoietic cytokines. Blood 111, 485-491 (2008).
3. Hamilton J. A. Colony-stimulating factors in inflammation and autoimmunity. Nat. Rev. Immunol. 8, 533-544 (2008).
4. Hamilton J. A, Stanley E. R, Burgess A. W, & Shadduck R. K. Stimulation of macrophage plasminogen activator activity by colony-stimulating factors. J. Cell. Physiol. 103, 435-445 (1980).
5. Masek-Hammerman K, et al. Monoclonal antibody against macrophage colony-stimulating factor suppresses circulating monocytes and tissue macrophage function but does not alter cell infiltration/activation in cutaneous lesions or clinical outcomes in patients with cutaneous lupus erythematosus. Clin. Exp. Immunol. 183, 258-270 (2016).
6. Molfino N. A, et al. Phase 2, randomised placebo-controlled trial to evaluate the efficacy and safety of an anti GM CSF antibody (KB003) in patients with inadequately controlled asthma. BMJ Open 6, e007709 (2016).
7. Genovese M. C, et al. Results from a phase IIa parallel group study of JNJ 40346527, an oral CSF 1R inhibitor, in patients with active rheumatoid arthritis despite disease-modifying antirheumatic drug therapy. J. Rheumatol. 42, 1752-1760 (2015).
8. Burmester G, et al. Long-Term safety and efficacy of Mavrilimumab, a fully human granulocyte-macrophage colony-stimulating factor receptor α (GM CSFR α) monoclonal antibody, in patients with rheumatoid arthritis (RA). Arthritis Rheumatol. 67 (Suppl. 10), abstr. 3111 (2015).
9. Hamilton J. A, & Achuthan A. Colony stimulating factors and myeloid cell biology in health and disease. Trends Immunol. 34, 81-89 (2013).
10. Broughton S. E, et al. The βc receptor family-structural insights and their functional implications. Cytokine 74, 247-258 (2015).
11. Hamilton J. A. GM CSF as a target in inflammatory/.autoimmune disease: current evidence and future therapeutic potential. Expert Rev. Clin. Immunol. 11, 457-465 (2015).
12. Wicks I. P, & Roberts A. W. Targeting GM CSF in inflammatory diseases. Nat. Rev. Rheumatol. 12, 37-48 (2016).
13. 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).
14. Ghirelli C, Zollinger R, & Soumelis V. Systematic cytokine receptor profiling reveals GM CSF as a novel TLR-independent activator of human plasmacytoid predendritic cells. Blood 115, 5037-5040 (2010).
15. Min L, et al. Cutting edge: granulocyte-macrophage colony-stimulating factor is the major CD8+ T cell-derived licensing factor for dendritic cell activation. J. Immunol. 184, 4625-4629 (2010).
16. Hamilton J. A. Rheumatoid arthritis: opposing actions of haemopoietic growth factors and slow-Acting anti-rheumatic drugs. Lancet 342, 536-539 (1993).
17. 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).
18. 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).
19. Croxford A. L, et al. The cytokine GM CSF drives the inflammatory signature of CCR2+ monocytes and licenses autoimmunity. Immunity 43, 502-514 (2015).
20. Su S, Wu W, He C, Liu Q, & Song E. Breaking the vicious cycle between breast cancer cells and tumor-Associated macrophages. Oncoimmunology 3, e953418 (2014).
21. Wu L, et al. Pathogenic IL 23 signaling is required to initiate GM CSF-driven autoimmune myocarditis in mice. Eur. J. Immunol. 46, 582-592 (2016).
22. Hansen G, et al. The structure of the GM CSF receptor complex reveals a distinct mode of cytokine receptor activation. Cell 134, 496-507 (2008).
23. Broughton S. E, et al. Conformational changes in the GM CSF receptor suggest a molecular mechanism for affinity conversion and receptor signaling. Structure 24, 1271-1281 (2016).
24. van de Laar L, Coffer P. J, & Woltman A. M. Regulation of dendritic cell development by GM CSF: molecular control and implications for immune homeostasis and therapy. Blood 119, 3383-3393 (2012).
25. Raza S, et al. Analysis of the transcriptional networks underpinning the activation of murine macrophages by inflammatory mediators. J. Leukoc. Biol. 96, 167-183 (2014).
26. Campbell I. K, Bendele A, Smith D. A, & Hamilton J. A. Granulocyte-macrophage colony stimulating factor exacerbates collagen induced arthritis in mice. Ann. Rheum. Dis. 56, 364-368 (1997).
27. Llop-Guevara A, et al. A GM CSF/IL 33 pathway facilitates allergic airway responses to sub-Threshold house dust mite exposure. PLoS ONE 9, e88714 (2014).
28. van Nieuwenhuijze A. E, et al. Transgenic expression of GM CSF in T cells causes disseminated histiocytosis. Am. J. Pathol. 184, 184-199 (2014).
29. Egea L, Hirata Y, & Kagnoff M. F. GM CSF: a role in immune and inflammatory reactions in the intestine. Expert Rev. Gastroenterol. Hepatol. 4, 723-731 (2010).
30. Bhattacharya P, et al. GM CSF: an immune modulatory cytokine that can suppress autoimmunity. Cytokine 75, 261-271 (2015).
31. Campbell I. K, et al. Protection from collagen-induced arthritis in granulocyte-macrophage colony-stimulating factor-deficient mice. J. Immunol. 161, 3639-3644 (1998).
32. 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).
33. 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).
34. Lam R. S, et al. GM CSF and uPA are required for Porphyromonas gingivalis-induced alveolar bone loss in a mouse periodontitis model. Immunol. Cell Biol. 93, 705-715 (2015).
35. Son B. K, et al. Granulocyte macrophage colony-stimulating factor is required for aortic dissection/.intramural haematoma. Nat. Commun. 6, 6994 (2015).
36. 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).
37. 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-?B ligand, and matrix metalloproteinases and drives bone and cartilage pathology in experimental arthritis: rationale for combination therapy in rheumatoid arthritis. Arthritis Res. Ther. 17, 163 (2015).
38. Xu Y, Hunt N. H, & Bao S. The role of granulocyte-macrophage colony-stimulating factor in acute intestinal inflammation. Cell Res. 18, 1220-1229 (2008).
39. Samarakoon A, et al. CD45 regulates GM CSF, retinoic acid and T cell homing in intestinal inflammation. Mucosal Immunol. 9, 1514-1527 (2016).
40. Khajah M, Millen B, Cara D. C, Waterhouse C, & McCafferty D. M. Granulocyte-macrophage colony-stimulating factor (GM CSF): a chemoattractive agent for murine leukocytes in vivo. J. Leukoc. Biol. 89, 945-953 (2011).
41. Griseri T, McKenzie B. S, Schiering C, & Powrie F. Dysregulated hematopoietic stem and progenitor cell activity promotes interleukin 23 driven chronic intestinal inflammation. Immunity 37, 1116-1129 (2012).
42. Griseri T, et al. Granulocyte macrophage colony-stimulating factor-Activated eosinophils promote interleukin 23 driven chronic colitis. Immunity 43, 187-199 (2015).
43. Song C, et al. Unique and redundant functions of NKp46+ ILC3s in models of intestinal inflammation. J. Exp. Med. 212, 1869-1882 (2015).
44. Pearson C, et al. ILC3 GM CSF production and mobilisation orchestrate acute intestinal inflammation. eLife 5, e10066 (2016).
45. del Rio M. L, Bernhardt G, Rodriguez-Barbosa J. I, & Forster R. Development and functional specialization of CD103+ dendritic cells. Immunol. Rev. 234, 268-281 (2010).
46. 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).
47. 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).
48. Edelson B. T, et al. Batf3 dependent CD11blow/-peripheral dendritic cells are GM CSF-independent and are not required for Th cell priming after subcutaneous immunization. PLoS ONE 6, e25660 (2011).
49. 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).
50. Campbell I. K, et al. Differentiation of inflammatory dendritic cells is mediated by NF ?B1 dependent GM CSF production in CD4 T cells. J. Immunol. 186, 5468-5477 (2011).
51. Ko H. J, et al. GM CSF-responsive monocyte-derived dendritic cells are pivotal in Th17 pathogenesis. J. Immunol. 192, 2202-2209 (2014).
52. Naik S. H, et al. Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes. Nat. Immunol. 7, 663-671 (2006).
53. 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).
54. Helft J, et al. GM CSF mouse bone marrow cultures comprise a heterogeneous population of CD11c+MHCII+ macrophages and dendritic cells. Immunity 42, 1197-1211 (2015).
55. Achuthan A, et al. Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation. J. Clin. Invest. 126, 3453-3466 (2016).
56. Hamilton J. A, & Tak P. P. The dynamics of macrophage lineage populations in inflammatory and autoimmune diseases. Arthritis Rheum. 60, 1210-1221 (2009).
57. Soler Palacios B, et al. Macrophages from the synovium of active rheumatoid arthritis exhibit an activin A dependent pro-inflammatory profile. J. Pathol. 235, 515-526 (2015).
58. Ilmarinen P, Moilanen E, & Kankaanranta H. Regulation of spontaneous eosinophil apoptosis-A neglected area of importance. J. Cell Death 7, 1-9 (2014).
59. Singh P, et al. GM CSF enhances macrophage glycolytic activity in vitro and improves detection of inflammation in vivo. J. Nucl. Med. 57, 1428-1435 (2016).
60. Subramanian M, Thorp E, & Tabas I. Identification of a non-growth factor role for GM CSF in advanced atherosclerosis: promotion of macrophage apoptosis and plaque necrosis through IL 23 signaling. Circ. Res. 116, e13-e24 (2015).
61. Krausgruber T, et al. IRF5 promotes inflammatory macrophage polarization and TH1 TH17 responses. Nat. Immunol. 12, 231-238 (2011).
62. Fleetwood A. J, Lawrence T, Hamilton J. A, & Cook A. D. GM CSF and M CSF (CSF 1)-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities-implications for CSF blockade in inflammation. J. Immunol. 178, 5245-5252 (2007).
63. Verreck F. A, et al. Human IL 23 producing type 1 macrophages promote but IL 10 producing type 2 macrophages subvert immunity to (myco)bacteria. Proc. Natl Acad. Sci. USA 101, 4560-4565 (2004).
64. 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).
65. Cates E. C, et al. Intranasal exposure of mice to house dust mite elicits allergic airway inflammation via a GM CSF-mediated mechanism. J. Immunol. 173, 6384-6392 (2004).
66. Sielska M, et al. Distinct roles of CSF family cytokines in macrophage infiltration and activation in glioma progression and injury response. J. Pathol. 230, 310-321 (2013).
67. Egea L, et al. GM CSF produced by nonhematopoietic cells is required for early epithelial cell proliferation and repair of injured colonic mucosa. J. Immunol. 190, 1702-1713 (2013).
68. Huen S. C, et al. GM CSF promotes macrophage alternative activation after renal ischemia/reperfusion injury. J. Am. Soc. Nephrol. 26, 1334-1345 (2015).
69. Bernasconi E, D?Angelo F, Michetti P, & Velin D. Critical role of the GM CSF signaling pathway in macrophage pro-repair activities. Pathobiology 81, 183-189 (2014).
70. 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).
71. Lacey D. C, et al. Defining GM CSF-And macrophage-CSF-dependent macrophage responses by in vitro models. J. Immunol. 188, 5752-5765 (2012).
72. Murray P. J, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14-20 (2014).
73. 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).
74. 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).
75. Noster R, et al. IL 17 and GM CSF expression are antagonistically regulated by human T helper cells. Sci. Transl. Med. 6, 241ra80 (2014).
76. Carbajal K. S, et al. Th cell diversity in experimental autoimmune encephalomyelitis and multiple sclerosis. J. Immunol. 195, 2552-2559 (2015).
77. Grifka-Walk H. M, Giles D. A, & Segal B. M. IL 12 polarized Th1 cells produce GM CSF and induce EAE independent of IL 23. Eur. J. Immunol. 45, 2780-2786 (2015).
78. Cao Y, et al. Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis. Sci. Transl. Med. 7, 287ra74 (2015).
79. Vogel D. Y, et al. GM CSF promotes migration of human monocytes across the blood brain barrier. Eur. J. Immunol. 45, 1808-1819 (2015).
80. Hamilton J. A. Colony stimulating factors, cytokines and monocyte-macrophages-some controversies. Immunol. Today 14, 18-24 (1993).
81. Piper C, et al. T cell expression of granulocyte-macrophage colony-stimulating factor in juvenile arthritis is contingent upon Th17 plasticity. Arthritis Rheumatol. 66, 1955-1960 (2014).
82. Reynolds G, et al. Synovial CD4+ T cell-derived GM CSF supports the differentiation of an inflammatory dendritic cell population in rheumatoid arthritis. Ann. Rheum. Dis. 75, 899-907 (2015).
83. 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 (2015).
84. Rauch P. J, et al. Innate response activator B cells protect against microbial sepsis. Science 335, 597-601 (2012).
85. 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).
86. Hilgendorf I, et al. Innate response activator B cells aggravate atherosclerosis by stimulating T helper 1 adaptive immunity. Circulation 129, 1677-1687 (2014).
87. Li R, et al. Proinflammatory GM CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci. Transl. Med. 7, 310ra166 (2015).
88. Magri G, et al. Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells. Nat. Immunol. 15, 354-364 (2014).
89. Kelso M. L, Elliott B. R, Haverland N. A, Mosley R. L, & Gendelman H. E. Granulocyte-macrophage colony stimulating factor exerts protective and immunomodulatory effects in cortical trauma. J. Neuroimmunol. 278, 162-173 (2015).
90. Schabitz W. R, et al. A neuroprotective function for the hematopoietic protein granulocyte-macrophage colony stimulating factor (GM CSF). J. Cereb. Blood Flow Metab. 28, 29-43 (2008).
91. Schweizerhof M, et al. Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain. Nat. Med. 15, 802-807 (2009).
92. Bali K. K, et al. Transcriptional mechanisms underlying sensitization of peripheral sensory neurons by granulocyte-/granulocyte-macrophage colony stimulating factors. Mol. Pain 9, 48 (2013).
93. Ridwan S, Bauer H, Frauenknecht K, von Pein H, & Sommer C. J. Distribution of granulocyte-monocyte colony-stimulating factor and its receptor α-subunit in the adult human brain with specific reference to Alzheimer?s disease. J. Neural Transm. (Vienna) 119, 1389-1406 (2012).
94. 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).
95. 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).
96. Reed J. A, et al. GM CSF action in the CNS decreases food intake and body weight. J. Clin. Invest. 115, 3035-3044 (2005).
97. Hamilton J. A, Davis J, Pobjoy J, & Cook A. D. GM CSF is not essential for optimal fertility or for weight control. Cytokine 57, 30-31 (2012).
98. Kim D. H, et al. The role of GM CSF in adipose tissue inflammation. Am. J. Physiol. Endocrinol. Metab. 295, E1038-E1046 (2008).
99. Robertson S. A, Roberts C. T, Farr K. L, Dunn A. R, & Seamark R. F. Fertility impairment in granulocyte-macrophage colony-stimulating factor-deficient mice. Biol. Reprod. 60, 251-261 (1999).
100. 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).
101. Burmester G. R, et al. Efficacy and safety of mavrilimumab in subjects with rheumatoid arthritis. Ann. Rheum. Dis. 72, 1445-1452 (2013).
102. 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).
103. Burmester G. R, et al. Efficacy and safety of mavrilimumab, a fully human GM CSFR-α monoclonal antibody in patients with rheumatoid arthritis: primary results from the earth explorer 1 study. Ann. Rheum. Dis. 74 (Suppl 2), 78 (2015).
104. McInnes I. B, et al. Rapid onset of clinical benefit in patients with RA treated with mavrilimumab, a fully human monoclonal antibody targeting GM CSFR-α: subanalysis of the phase IIb earth explorer 1 study. Ann. Rheum. Dis. 74 (Suppl 2), 723 (2015).
105. Kremer J. M, et al. Patient-reported outcomes (PROS) during treatment with mavrilimumab, a fully human monoclonal antibody targeting GM CSFR-α, in the phase IIb earth explorer 1 study. Ann. Rheum. Dis. 74 (Suppl 2), 483 (2015).
106. Kremer J. M, et al. Analysis of patient reported outcomes during treatment with mavrilimumab, a human monoclonal antibody targeting GM CSFRa, in the randomized phase IIb earth explorer 1 study. ACR abstr. 1485 (2014).
107. Piccoli L, et al. Neutralization and clearance of GM CSF by autoantibodies in pulmonary alveolar proteinosis. Nat. Commun. 6, 7375 (2015).
108. 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).
109. Constantinescu C. S, et al. Randomized phase 1b trial of MOR103, a human antibody to GM CSF, in multiple sclerosis. Neurol. Neuroimmunol. Neuroinflamm. 2, e117 (2015).
110. Huizinga T. W, Batalov A, Yablanski K, Stoilov R, & Lloyd E. W. T. First in patient study of Namilumab, an anti GM CSF monoclonal antibody, in active rheumatoid arthritis: results of the Priora Phase 1B study. Ann. Rheum. Dis. 74 (Suppl. 2), 733 (2015)
111. Huizinga T. W. J, et al. Namilumab, an anti-granulocyte macrophage-colony stimulating factor (GM CSF) monoclonal antibody: results of the first study in patients with mild to moderate rheumatoid arthritis (RA). Arthritis Rheumatol. 67 (Suppl. 10), abstr. 969 (2015).
112. Kokkonen H, et al. Up regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthritis Rheum. 62, 383-391 (2010).
113. Deane K. D, et al. The number of elevated cytokines and chemokines in preclinical seropositive rheumatoid arthritis predicts time to diagnosis in an age-dependent manner. Arthritis Rheum. 62, 3161-3172 (2010).
114. Raza K, et al. Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res. Ther. 7, R784-R795 (2005).
115. Hume D. A, & MacDonald K. P. Therapeutic applications of macrophage colony-stimulating factor 1 (CSF 1) and antagonists of CSF 1 receptor (CSF 1R) signaling. Blood 119, 1810-1820 (2012).
116. Ginhoux F, & Guilliams M. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44, 439-449 (2016).
117. Sauter K. A, et al. Pleiotropic effects of extended blockade of CSF1R signaling in adult mice. J. Leukoc. Biol. 96, 265-274 (2014).
118. Lenzo J. C, et al. Control of macrophage lineage populations by CSF 1 receptor and GM CSF in homeostasis and inflammation. Immunol. Cell Biol. 90, 429-440 (2012).
119. MacDonald K. P, et al. An antibody against the colony-stimulating factor 1 receptor depletes the resident subset of monocytes and tissue-And tumor-Associated macrophages but does not inhibit inflammation. Blood 116, 3955-3963 (2010).
120. Muller P. A, et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 158, 300-313 (2014).
121. Akcora D, et al. The CSF 1 receptor fashions the intestinal stem cell niche. Stem Cell Res. 10, 203-212 (2013).
122. Jenkins S. J, et al. IL 4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF 1. J. Exp. Med. 210, 2477-2491 (2013).
123. Davies L. C, et al. Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation. Nat. Commun. 4, 1886 (2013).
124. Jenkins S. J, et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332, 1284-1288 (2011).
125. Davies L. C, et al. A quantifiable proliferative burst of tissue macrophages restores homeostatic macrophage populations after acute inflammation. Eur. J. Immunol. 41, 2155-2164 (2011).
126. Mossadegh-Keller N, et al. M CSF instructs myeloid lineage fate in single haematopoietic stem cells. Nature 497, 239-243 (2013).
127. Rieger M. A, Hoppe P. S, Smejkal B. M, Eitelhuber A. C, & Schroeder T. Hematopoietic cytokines can instruct lineage choice. Science 325, 217-218 (2009).
128. Hashimoto D, et al. Pretransplant CSF 1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation. J. Exp. Med. 208, 1069-1082 (2011).
129. Rademakers R, et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat. Genet. 44, 200-205 (2012).
130. Nicholson A. M, et al. CSF1R mutations link POLD and HDLS as a single disease entity. Neurology 80, 1033-1040 (2013).
131. Foulds N, et al. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia caused by a novel R782G mutation in CSF1R. Sci. Rep. 5, 10042 (2015).
132. Hofer T. P, et al. Slan-defined subsets of CD16 positive monocytes: impact of granulomatous inflammation and M CSF receptor mutation. Blood 126, 2601-2610 (2015).
133. Chitu V, et al. Phenotypic characterization of a Csf1r haploinsufficient mouse model of adult-onset leukodystrophy with axonal spheroids and pigmented glia (ALSP). Neurobiol. Dis. 74, 219-228 (2015).
134. Stanley E. R, & Chitu V. CSF 1 receptor signaling in myeloid cells. Cold Spring Harb. Perspect. Biol. 6, a021857 (2014).
135. Felix J, et al. Structure and assembly mechanism of the signaling complex mediated by human CSF 1. Structure 23, 1621-1631 (2015).
136. Ma X, et al. Structural basis for the dual recognition of helical cytokines IL 34 and CSF 1 by CSF 1R. Structure 20, 676-687 (2012).
137. Liu H, et al. The mechanism of shared but distinct CSF 1R signaling by the non-homologous cytokines IL 34 and CSF 1. Biochim. Biophys. Acta 1824, 938-945 (2012).
138. Masteller E. L, & Wong B. R. Targeting IL 34 in chronic inflammation. Drug Discov. Today 19, 1212-1216 (2014).
139. Nandi S, et al. Receptor-Type protein-Tyrosine phosphatase ? is a functional receptor for interleukin 34. J. Biol. Chem. 288, 21972-21986 (2013).
140. Toh M. L, et al. Bone-And cartilage-protective effects of a monoclonal antibody against colony-stimulating factor 1 receptor in experimental arthritis. Arthritis Rheumatol. 66, 2989-3000 (2014).
141. Chitu V, & Stanley E. R. Colony-stimulating factor 1 in immunity and inflammation. Curr. Opin. Immunol. 18, 39-48 (2006).
142. Patel S, & Player M. R. Colony-stimulating factor 1 receptor inhibitors for the treatment of cancer and inflammatory disease. Curr. Top. Med. Chem. 9, 599-610 (2009).
143. Ghia J. E, et al. Role of M CSF dependent macrophages in colitis is driven by the nature of the inflammatory stimulus. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G770-G777 (2008).
144. Segawa M, et al. Suppression of macrophage functions impairs skeletal muscle regeneration with severe fibrosis. Exp. Cell Res. 314, 3232-3244 (2008).
145. Garcia S, et al. Colony-stimulating factor (CSF) 1 receptor blockade reduces inflammation in human and murine models of rheumatoid arthritis. Arthritis Res. Ther. 18, 75 (2016).
146. Alvarado-Vazquez P. A, et al. Intra-Articular administration of an antibody against CSF 1 receptor reduces pain-related behaviors and inflammation in CFA-induced knee arthritis. Neurosci. Lett. 584, 39-44 (2015).
147. Park S. J, et al. 2-(trimethylammonium) ethyl (R)-3 methoxy 3 oxo 2 stearamidopropyl phosphate suppresses osteoclast maturation and bone resorption by targeting macrophage-colony stimulating factor signaling. Mol. Cells 37, 628-635 (2014).
148. Chalmers S. A, et al. Macrophage depletion ameliorates nephritis induced by pathogenic antibodies. J. Autoimmun. 57, 42-52 (2015).
149. Leblond A. L, et al. Systemic and cardiac depletion of M2 macrophage through CSF 1R signaling inhibition alters cardiac function post myocardial infarction. PLoS ONE 10, e0137515 (2015).
150. Ries C. H, et al. Targeting tumor-Associated macrophages with anti-CSF 1R antibody reveals a strategy for cancer therapy. Cancer Cell 25, 846-859 (2014).
151. Swierczak A, et al. The promotion of breast cancer metastasis caused by inhibition of CSF 1R/CSF 1 signaling is blocked by targeting the G CSF receptor. Cancer Immunol. Res. 2, 765-776 (2014).
152. Chitu V, Gokhan S, Nandi S, Mehler M. F, & Stanley E. R. Emerging roles for CSF 1 receptor and its ligands in the nervous system. Trends Neurosci. 39, 378-393 (2016).
153. Gomez-Nicola D, Fransen N. L, Suzzi S, & Perry V. H. Regulation of microglial proliferation during chronic neurodegeneration. J. Neurosci. 33, 2481-2493 (2013).
154. Olmos-Alonso A, et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer?s like pathology. Brain 139, 891-907 (2016).
155. Dagher N. N, et al. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg AD mice. J. Neuroinflammation 12, 139 (2015).
156. Luo J, et al. Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival. J. Exp. Med. 210, 157-172 (2013).
157. Erblich B, Zhu L, Etgen A. M, Dobrenis K, & Pollard J. W. Absence of colony stimulation factor 1 receptor results in loss of microglia, disrupted brain development and olfactory deficits. PLoS ONE 6, e26317 (2011).
158. Guan Z, et al. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12 dependent pain. Nat. Neurosci. 19, 94-101 (2016).
159. Okubo M, et al. Macrophage-colony stimulating factor derived from injured primary afferent induces proliferation of spinal microglia and neuropathic pain in rats. PLoS ONE 11, e0153375 (2016).
160. Klein D, et al. Targeting the colony stimulating factor 1 receptor alleviates two forms of Charcot-Marie-Tooth disease in mice. Brain 138, 3193-3205 (2015).
161. Groh J, Basu R, Stanley E. R, & Martini R. Cell-surface and secreted isoforms of CSF 1 exert opposing roles in macrophage-mediated neural damage in Cx32 deficient mice. J. Neurosci. 36, 1890-1901 (2016).
162. Campbell I. K, Rich M. J, Bischof R. J, & Hamilton J. A. The colony-stimulating factors and collagen-induced arthritis: exacerbation of disease by M CSF and G CSF and requirement for endogenous M CSF. J. Leukoc. Biol. 68, 144-150 (2000).
163. Hamilton J. A, et al. Hypoxia enhances the proliferative response of macrophages to CSF 1 and their pro-survival response to TNF. PLoS ONE 7, e45853 (2012).
164. Satoh T, et al. The Jmjd3 Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat. Immunol. 11, 936-944 (2010).
165. Clavel C, Ceccato L, Anquetil F, Serre G, & Sebbag M. Among human macrophages polarised to different phenotypes, the M CSF-oriented cells present the highest pro-inflammatory response to the rheumatoid arthritis-specific immune complexes containing ACPA. Ann. Rheum. Dis. http://dx.doi. org/10.1136/annrheumdis-2015-208887 (2016).
166. Vogelpoel L. T, et al. Fc gamma receptor-TLR cross-Talk elicits pro-inflammatory cytokine production by human M2 macrophages. Nat. Commun. 5, 5444 (2014).
167. Jenkins S. J, & Hume D. A. Homeostasis in the mononuclear phagocyte system. Trends Immunol. 35, 358-367 (2014).
168. Zhang M. Z, et al. CSF 1 signaling mediates recovery from acute kidney injury. J. Clin. Invest. 122, 4519-4532 (2012).
169. Wang Y, et al. Proximal tubule-derived colony stimulating factor 1 mediates polarization of renal macrophages and dendritic cells, and recovery in acute kidney injury. Kidney Int. 88, 1274-1282 (2015).
170. Stutchfield B. M, et al. CSF1 restores innate immunity after liver injury in mice and serum levels indicate outcomes of patients with acute liver failure. Gastroenterology 149, 1896-1909 (2015).
171. Sauter K. A, et al. Macrophage colony-stimulating factor (CSF1) controls monocyte production and maturation and the steady-state size of the liver in pigs. Am. J. Physiol. Gastrointest. Liver Physiol. 311, G533-G547 (2016).
172. Alexander K. A, et al. CSF 1 dependant donor-derived macrophages mediate chronic graft-versus-host disease. J. Clin. Invest. 124, 4266-4280 (2014).
173. Yang P. T, et al. Increase in the level of macrophage colony-stimulating factor in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 67, 429-430 (2008).
174. Tian S, et al. Urinary levels of RANTES and M CSF are predictors of lupus nephritis flare. Inflamm. Res. 56, 304-310 (2007).
175. Menke J, et al. Colony-stimulating factor 1: a potential biomarker for lupus nephritis. J. Am. Soc. Nephrol. 26, 379-389 (2015).
176. Korkosz M, Bukowska-Strakova K, Sadis S, Grodzicki T, & Siedlar M. Monoclonal antibodies against macrophage colony-stimulating factor diminish the number of circulating intermediate and nonclassical (CD14++CD16+/CD14+CD16++) monocytes in rheumatoid arthritis patient. Blood 119, 5329-5330 (2012).
177. Tap W. D, et al. Structure-guided blockade of CSF1R Kinase in tenosynovial giant-cell tumor. N. Engl. J. Med. 373, 428-437 (2015).
178. Butowski N, et al. Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an ivy foundation early phase clinical trials consortium phase II study. Neuro Oncol. 18, 557-564 (2016).
179. 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).
180. 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).
181. Wright H. L, Moots R. J, & Edwards S. W. The multifactorial role of neutrophils in rheumatoid arthritis. Nat. Rev. Rheumatol. 10, 593-601 (2014).
182. Dalhoff K, et al. Inhibition of neutrophil apoptosis and modulation of the inflammatory response by granulocyte colony-stimulating factor in healthy and ethanol-Treated human volunteers. J. Infect. Dis. 178, 891-895 (1998).
183. Stark M. A, et al. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL 23 and IL 17. Immunity 22, 285-294 (2005).
184. Hartung T. Anti-inflammatory effects of granulocyte colony-stimulating factor. Curr. Opin. Hematol. 5, 221-225 (1998).
185. Joshi A, et al. Transcription factor, promoter, and enhancer utilization in human myeloid cells. J. Leukoc. Biol. 97, 985-995 (2015).
186. Mehta H. M, Glaubach T, & Corey S. J. Systems approach to phagocyte production and activation: neutrophils and monocytes. Adv. Exp. Med. Biol. 844, 99-113 (2014).
187. Roberts A. W. G CSF: a key regulator of neutrophil production, but that?s not all! Growth Factors 23, 33-41 (2005).
188. McMullin M. F, & Finch M. B. Felty?s syndrome treated with rhG-CSF associated with flare of arthritis and skin rash. Clin. Rheumatol. 14, 204-208 (1995).
189. Hayat S. Q, Hearth-Holmes M, & Wolf R. E. Flare of arthritis with successful treatment of Felty?s syndrome with granulocyte colony stimulating factor (GCSF). Clin. Rheumatol. 14, 211-212 (1995).
190. Lawlor K. E, et al. Critical role for granulocyte colony-stimulating factor in inflammatory arthritis. Proc. Natl Acad. Sci. USA 101, 11398-11403 (2004).
191. Eyles J. L, et al. A key role for G CSF-induced neutrophil production and trafficking during inflammatory arthritis. Blood 112, 5193-5201 (2008).
192. Christensen A. D, Haase C, Cook A. D, & Hamilton J. A. Granulocyte colony-stimulating factor (G CSF) plays an important role in immune complex-mediated arthritis. Eur. J. Immunol. 46, 1235-1245 (2016).
193. Christensen A. D, Skov S, & Haase C. The role of neutrophils and G CSF in DNFB-induced contact hypersensitivity in mice. Immun. Inflamm. Dis. 2, 21-34 (2014).
194. Rumble J. M, et al. Neutrophil-related factors as biomarkers in EAE and MS. J. Exp. Med. 212, 23-35 (2015).
195. Goldberg G. L, et al. G CSF and neutrophils are nonredundant mediators of murine experimental autoimmune uveoretinitis. Am. J. Pathol. 186, 172-184 (2016).
196. Bagaitkar J, et al. NADPH oxidase controls neutrophilic response to sterile inflammation in mice by regulating the IL 1α/G CSF axis. Blood 126, 2724-2733 (2015).
197. Swierczak A, Mouchemore K. A, Hamilton J. A, & Anderson R. L. Neutrophils: important contributors to tumor progression and metastasis. Cancer Metastasis Rev. 34, 735-751 (2015).
198. Coffelt S. B, et al. IL 17 producing γd T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522, 345-348 (2015).
199. Brotfain E, et al. Neutrophil functions in morbidly obese subjects. Clin. Exp. Immunol. 181, 156-163 (2015).
200. Ryder E, et al. Association of obesity with leukocyte count in obese individuals without metabolic syndrome. Diabetes Metab. Syndr. 8, 197-204 (2014).
201. Daltro P. S, et al. Administration of granulocyte-colony stimulating factor accompanied with a balanced diet improves cardiac function alterations induced by high fat diet in mice. BMC Cardiovasc. Disord. 15, 162 (2015).
202. Egi H, et al. Regulation of T helper type 1 immunity in hapten-induced colitis by host pretreatment with granulocyte colony-stimulating factor. Cytokine 23, 23-30 (2003).
203. Kudo T, et al. Recombinant human granulocyte colony-stimulating factor reduces colonic epithelial cell apoptosis and ameliorates murine dextran sulfate sodium-induced colitis. Scand. J. Gastroenterol. 43, 689-697 (2008).
204. 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).
205. Basu S, et al. Emergency" granulopoiesis in G CSF-deficient mice in response to Candida albicans infection. Blood 95, 3725-3733 (2000).
206. Basu S, Hodgson G, Katz M, & Dunn A. R. Evaluation of role of G CSF in the production, survival, and release of neutrophils from bone marrow into circulation. Blood 100, 854-861 (2002).
207. Hibbs M. L, et al. Mice lacking three myeloid colony-stimulating factors (G CSF, GM CSF, and M CSF) still produce macrophages and granulocytes and mount an inflammatory response in a sterile model of peritonitis. J. Immunol. 178, 6435-6443 (2007).
208. Bugl S, et al. Steady-state neutrophil homeostasis is dependent on TLR4/TRIF signaling. Blood 121, 723-733 (2013).
209. Campbell I. K, et al. Therapeutic targeting of the G-CSF receptor reduces neutrophil trafficking and joint inflammation in antibody-mediated inflammatory arthritis. J. Immunol. 197, 4392-4402 (2016).
210. Meshkibaf S, Martins A. J, Henry G. T, & Kim S. O. Protective role of G CSF in dextran sulfate sodium-induced acute colitis through generating gut-homing macrophages. Cytokine 78, 69-78 (2016).
211. Dejaco C, et al. An open-label pilot study of granulocyte colony-stimulating factor for the treatment of severe endoscopic postoperative recurrence in Crohn?s disease. Digestion 68, 63-70 (2003).
212. Wallner S, et al. The granulocyte-colony stimulating factor has a dual role in neuronal and vascular plasticity. Front. Cell Dev. Biol. 3, 48 (2015).
213. Stosser S, Schweizerhof M, & Kuner R. Hematopoietic colony-stimulating factors: new players in tumor-nerve interactions. J. Mol. Med. (Berl.) 89, 321-329 (2011).
214. Carvalho T. T, et al. Granulocyte-colony stimulating factor (G CSF) induces mechanical hyperalgesia via spinal activation of MAP kinases and PI3K in mice. Pharmacol. Biochem. Behav. 98, 188-195 (2011).
215. Carvalho T. T, et al. Granulocyte-colony stimulating factor (G CSF)-induced mechanical hyperalgesia in mice: role for peripheral TNFα, IL 1β and IL 10. Eur. J. Pharmacol. 749, 62-72 (2015).
216. Liou J. T, Lui P. W, Liu F. C, Lai Y. S, & Day Y. J. Exogenous granulocyte colony-stimulating factor exacerbate pain-related behaviors after peripheral nerve injury. J. Neuroimmunol. 232, 83-93 (2011).
217. Chao P. K, et al. Early systemic granulocyte-colony stimulating factor treatment attenuates neuropathic pain after peripheral nerve injury. PLoS ONE 7, e43680 (2012).
218. Kato K, et al. Intravenous administration of granulocyte colony-stimulating factor for treating neuropathic pain associated with compression myelopathy: a phase I and IIa clinical trial. Eur. Spine J. 22, 197-204 (2013).
219. Schneider A, et al. The hematopoietic factor G CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J. Clin. Invest. 115, 2083-2098 (2005).
220. Diederich K, Schabitz W. R, & Minnerup J. Seeing old friends from a different angle: novel properties of hematopoietic growth factors in the healthy and diseased brain. Hippocampus 22, 1051-1057 (2012).
221. Broughton S. E, et al. Dual mechanism of interleukin 3 receptor blockade by an anti-cancer antibody. Cell Rep. 8, 410-419 (2014).
222. Carr P. D, et al. Crystal structure of the mouse interleukin 3 β-receptor: insights into interleukin 3 binding and receptor activation. Biochem. J. 463, 393-403 (2014).
223. Hara T, & Miyajima A. Two distinct functional high affinity receptors for mouse interleukin 3 (IL 3). EMBO J. 11, 1875-1884 (1992).
224. Ihle J. N. Interleukin 3 and hematopoiesis. Chem. Immunol. 51, 65-106 (1992).
225. Lantz C. S, et al. Role for interleukin 3 in mast-cell and basophil development and in immunity to parasites. Nature 392, 90-93 (1998).
226. Kim S, et al. Cutting edge: basophils are transiently recruited into the draining lymph nodes during helminth infection via IL 3, but infection-induced Th2 immunity can develop without basophil lymph node recruitment or IL 3. J. Immunol. 184, 1143-1147 (2010).
227. Broughton S. E, et al. The GM CSF/IL 3/IL 5 cytokine receptor family: from ligand recognition to initiation of signaling. Immunol. Rev. 250, 277-302 (2012).
228. Esnault S, et al. IL 3 maintains activation of the p90S6K/RPS6 pathway and increases translation in human eosinophils. J. Immunol. 195, 2529-2539 (2015).
229. Luo X. J, et al. The interleukin 3 gene (IL3) contributes to human brain volume variation by regulating proliferation and survival of neural progenitors. PLoS ONE 7, e50375 (2012).
230. Hercus T. R, et al. Signalling by the βc family of cytokines. Cytokine Growth Factor Rev. 24, 189-201 (2013).
231. Ebner S, et al. A novel role for IL 3: human monocytes cultured in the presence of IL 3 and IL 4 differentiate into dendritic cells that produce less IL 12 and shift Th cell responses toward a Th2 cytokine pattern. J. Immunol. 168, 6199-6207 (2002).
232. Elliott M. J, et al. Recombinant human interleukin 3 and granulocyte-macrophage colony-stimulating factor show common biological effects and binding characteristics on human monocytes. Blood 74, 2349-2359 (1989).
233. Hart P. H, Whitty G. A, Burgess D. R, & Hamilton J. A. Regulation by interleukin 3 of human monocyte pro-inflammatory mediators. Similarities with granulocyte-macrophage colony-stimulating factor. Immunology 71, 76-82 (1990).
234. Andrade P. R, Amadeu T. P, Nery J. A, Pinheiro R. O, & Sarno E. N. CD123, the plasmacytoid dendritic cell phenotypic marker, is abundant in leprosy type 1 reaction. Br. J. Dermatol. 172, 268-271 (2015).
235. Firestein G. S, et al. Cytokines in chronic inflammatory arthritis. I. Failure to detect T cell lymphokines (interleukin 2 and interleukin 3) and presence of macrophage colony-stimulating factor (CSF 1) and a novel mast cell growth factor in rheumatoid synovitis. J. Exp. Med. 168, 1573-1586 (1988).
236. Heller R. A, et al. Discovery and analysis of inflammatory disease-related genes using cDNA microarrays. Proc. Natl Acad. Sci. USA 94, 2150-2155 (1997).
237. Ferraccioli G, et al. Circulating levels of interleukin 10 and other cytokines in rheumatoid arthritis treated with cyclosporin A or combination therapy. J. Rheumatol. 25, 1874-1879 (1998).
238. Yamada R, et al. Association between a single-nucleotide polymorphism in the promoter of the human interleukin 3 gene and rheumatoid arthritis in Japanese patients, and maximum-likelihood estimation of combinatorial effect that two genetic loci have on susceptibility to the disease. Am. J. Hum. Genet. 68, 674-685 (2001).
239. Oren H, Erbay A. R, Balci M, & Cehreli S. Role of novel biomarkers of inflammation in patients with stable coronary heart disease. Angiology 58, 148-155 (2007).
240. Xiu M. H, et al. Increased IL 3 serum levels in chronic patients with schizophrenia: associated with psychopathology. Psychiatry Res. 229, 225-229 (2015).
241. Piguet P. F, Grau G. E, Hauser C, & Vassalli P. Tumor necrosis factor is a critical mediator in hapten induced irritant and contact hypersensitivity reactions. J. Exp. Med. 173, 673-679 (1991).
242. Mach N, et al. Involvement of interleukin 3 in delayed-Type hypersensitivity. Blood 91, 778-783 (1998).
243. Bruhl H, et al. Important role of interleukin 3 in the early phase of collagen-induced arthritis. Arthritis Rheum. 60, 1352-1361 (2009).
244. Srivastava R. K, et al. IL 3 attenuates collagen-induced arthritis by modulating the development of Foxp3+ regulatory T cells. J. Immunol. 186, 2262-2272 (2011).
245. Yogesha S. D, et al. IL 3 inhibits TNF-α-induced bone resorption and prevents inflammatory arthritis. J. Immunol. 182, 361-370 (2009).
246. Renner K, et al. IL 3 contributes to development of lupus nephritis in MRL/lpr mice. Kidney Int. 88, 1088-1098 (2015).
247. Weber G. F, et al. Interleukin 3 amplifies acute inflammation and is a potential therapeutic target in sepsis. Science 347, 1260-1265 (2015).
248. Chousterman B. G, & Swirski F. K. Innate response activator B cells: origins and functions. Int. Immunol. 27, 537-541 (2015).
249. Zambrano A, Otth C, Mujica L, Concha I. I, & Maccioni R. B. Interleukin 3 prevents neuronal death induced by amyloid peptide. BMC Neurosci. 8, 82 (2007).
250. Rojo L. E, Fernandez J. A, Maccioni A. A, Jimenez J. M, & Maccioni R. B. Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer?s disease. Arch. Med. Res. 39, 1-16 (2008).
251. Asquith K. L, et al. The IL 3/IL 5/GM CSF common receptor plays a pivotal role in the regulation of Th2 immunity and allergic airway inflammation. J. Immunol. 180, 1199-1206 (2008).
252. Panousis C, et al. CSL311, a novel, potent, therapeutic monoclonal antibody for the treatment of diseases mediated by the common β chain of the IL 3, GM CSF and IL 5 receptors. MAbs 8, 436-453 (2016).
253. Sun Q, et al. Simultaneous antagonism of interleukin 5, granulocyte-macrophage colony-stimulating factor, and interleukin 3 stimulation of human eosinophils by targetting the common cytokine binding site of their receptors. Blood 94, 1943-1951 (1999).
254. Owczarek C. M, et al. Novel anti βc receptor antibody targets multiple effector cell populations in human nasal polyps transplanted into immunodeficient transgenic human interleukin 3 (IL 3)/granulocyte-macrophage colony stimulating factor (GM CSF) knock in mice. Am. Thorac. Soc. Meet. 31 abstr. A7903 (2016).
255. Munoz L, et al. Interleukin 3 receptor alpha chain (CD123) is widely expressed in hematologic malignancies. Haematologica 86, 1261-1269 (2001).
256. He S. Z, et al. A Phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia. Leuk. Lymphoma 56, 1406-1415 (2015).
257. Busfield S. J, et al. Targeting of acute myeloid leukemia in vitro and in vivo with an anti CD123 mAb engineered for optimal ADCC. Leukemia 28, 2213-2221 (2014).
258. Smith B. D, et al. First in man, phase 1 study of CSL362 (anti IL3Rα /.anti CD123 monoclonal antibody) in patients with CD123+ acute myeloid leukemia (AML) in CR at high risk for early relapse. Blood 124, 120 (2014).
259. Oon S, et al. A cytotoxic anti IL 3Rα antibody targets key cells and cytokines implicated in systemic lupus erythematosus. JCI Insight 1, e86131 (2016).
260. Frankel A. E, et al. Activity of SL 401, a targeted therapy directed to interleukin 3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients. Blood 124, 385-392 (2014).
261. Sun Q, et al. Monoclonal antibody 7G3 recognizes the N terminal domain of the human interleukin 3 (IL 3) receptor α-chain and functions as a specific IL 3 receptor antagonist. Blood 87, 83-92 (1996).
262. Jin L, et al. Monoclonal antibody-mediated targeting of CD123, IL 3 receptor α chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell 5, 31-42 (2009).
263. van Vollenhoven R. F, Nagy G, & Tak P. P. Early start and stop of biologics: has the time come? BMC Med. 12, 25 (2014).
264. Hamilton J. A. Coordinate and noncoordinate colony stimulating factor formation by human monocytes. J. Leukoc. Biol. 55, 355-361 (1994).
265. Santiago E, et al. Granulocyte colony-stimulating factor induces neutrophils to secrete macrophage colony-stimulating factor. Cytokine 15, 299-304 (2001).