The role of granulocyte-macrophage colony-stimulating growth factor in inflammatory bowel diseases


V. Pershko, Сandidate of Medical Sciences; Associate Professor I. Yarovenko, Сandidate of Medical Sciences; Professor A. Pershko, MD
S.M. Kirov Military Medical Academy, Saint Petersburg

Inflammatory bowel diseases, which include ulcerative colitis and Crohn's disease, are chronic immune-inflammatory diseases of the intestine that are increasing in prevalence and incidence worldwide. They are progressive, with the need for lifelong therapy, a high risk of surgical interventions and a decrease in the quality of life of patients. The results of clinical and population studies indicate that the possibilities of modern therapy for inflammatory bowel diseases have reached their maximum. Its effectiveness in achieving complete clinical and endoscopic remission, despite the use of genetically engineered biological drugs, is estimated at 35-40%, which is obviously insufficient. A possible solution to this problem could be the inclusion of granulocyte-macrophage colony-stimulating factors in treatment regimens for inflammatory bowel diseases in combination with glucocorticosteroids, cytostatics and biological therapy drugs. A review of a number of experimental and clinical studies that confirmed the clinical effectiveness of macrophage growth factors is the subject of this article.

granulocyte-macrophage colony-stimulating factor
inflammatory bowel disease
ulcerative colitis
Crohn's disease

  1. Cosnes J., Gower-Rousseau C., Seksik P. et al. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 2011; 140 (6): 1785–94. DOI: 10.1053/j.gastro.2011.01.055
  2. Dignass A., Eliakim R., Magro F. et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis. J Crohns Colitis. 2012; 6 (10): 965–90. DOI: 10.1016/j.crohns.2012.09.003
  3. Wright S.S., Trauernicht A., Bonkowski E. et al. Familial Association of Granulocyte-Macrophage Colony-Stimulating Factor Autoantibodies in Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr. 2018; 66 (5): 767–72. DOI: 10.1097/MPG.0000000000001851
  4. Molodecky N.A., Soon I.S., Rabi D.M. et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012; 142 (1): 46–54. DOI: 10.1053/j.gastro.2011.10.001
  5. Rubin G.P., Hungin A.P., Kelly P.J. Inflammatory bowel disease: epidemiology and management in an English general practice population. Aliment Pharmacol Ther. 2000; 14 (12): 1553–9. DOI: 10.1046/j.1365-2036.2000.00886.x
  6. Singh S., Fumery M., Sandborn W.J. First- and Second-line Pharmacotherapy for Moderate-severe Ulcerative Colitis. Aliment Pharmacol Ther. 2018; 47 (2): 162–75. DOI: 10.1111/apt.14422
  7. Yang E., Panaccione N., Whitmire N. et al. Efficacy and Safety of Simultaneous Treatment With Two Biologic Medications in Refractory Crohn's Disease. Aliment Pharmacol Ther. 2020; 51 (11): 1031–8. DOI: 10.1111/apt.15719
  8. Першко А.М. Клинико-морфологические варианты неспецифического язвенного колита: прогнозирование течения и подходы к терапии (клинико-экспериментальное исследование). Автореф. Дисс. … д-ра мед. наук. СПб, 2000; 38 с. [Pershko A.M. Kliniko-morfologicheskie varianty nespetsificheskogo yazvennogo kolita: prognozirovanie techeniya i podkhody k terapii (kliniko-eksperimental'noe issledovanie). Avtoref. Diss. … d-ra med. nauk. SPb, 2000; 38 р. (in Russ.)].
  9. Cleynen I., Boucher G., Jostins L. et al. International Inflammatory Bowel Disease Genetics Consortium. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet. 2016; 387 (10014): 156–67. DOI: 10.1016/S0140-6736(15)00465-1
  10. Fukuzawa H., Sawada M., Kayahara T. et al. Identification of GM-CSF in Paneth cells using single-cell RT-PCR. Biochem Biophys Res Commun. 2003; 312 (4): 897–902. DOI: 10.1016/j.bbrc.2003.11.009
  11. Hansen G., Hercus T.R., McClure B.J. et al. The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation. Cell. 2008; 134 (3): 496–507. DOI: 10.1016/j.cell.2008.05.053
  12. Sartor R.B. Mechanisms of Disease: pathogenesis of Crohn's disease and ulcerative colitis. Nat Clin Prac Gastroenterol Hepatol. 2006; 3 (7): 390–407. DOI: 10.1038/ncpgasthep0528
  13. Bogunovic M., Ginhoux F., Helft J. et al. Origin of the lamina propria dendritic cell network. Immunity. 2009; 31 (3): 513–25. DOI: 10.1016/j.immuni.2009.08.010
  14. Coombes J.L., Siddiqui K.R, Arancibia-Carcamo C.V. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007; 204 (8): 1757–64. DOI: 10.1084/jem.20070590
  15. Hamilton J.A. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol. 2008; 8 (7): 533–44. DOI: 10.1038/nri2356
  16. Martinez-Moczygemba M., Huston D.P. Biology of common β receptor-signaling cytokines: IL-3, IL-5, and GM-CSF. J Allergy Clin Immunol. 2003; 112 (4): 653–65. DOI: 10.1016/S0091
  17. Burbelo P.D., Browne S.K., Sampaio E.P. et al. Anti-cytokine autoantibodies are associated with opportunistic infection in patients with thymic neoplasia. Blood. 2010; 116 (23): 4848–58. DOI: 10.1182/blood-2010-05-286161
  18. Karner J., Meager A., Laan M. et al. Anti-cytokine autoantibodies suggest pathogenetic links with autoimmune regulator deficiency in humans and mice. Clin Exp Immunol. 2013; 171 (3): 263–72. DOI: 10.1111/cei.12024
  19. Hamilton J.A. GM-CSF in inflammation and autoimmunity. Trends Immunol. 2002; 23 (8): 403–8. DOI: 10.1016/s1471-4906(02)02260-3
  20. Uchida K., Nakata K., Suzuki T. et al. Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects. Blood. 2009; 113 (11): 2547–56. DOI: 10.1182/blood-2009-05-155689
  21. Denson L.A., Jurickova I., Karns R. et al. Genetic and transcriptomic variation linked to neutrophil granulocyte-macrophage colony-stimulating factor signaling in pediatric Crohn's disease. Inflamm Bowel Dis. 2019; 25 (3): 547–60. DOI: 10.1093/ibd/izy265
  22. Han X., Uchida K., Jurickova I. et al. Granulocyte-macrophage colony-stimulating factor autoantibodies in murine ileitis and progressive ileal Crohn's disease. Gastroenterology. 2009; 136 (4): 1261–71. DOI: 10.1053/j.gastro.2008.12.046
  23. Nylund C.M., D'Mello S., Kim M.-O. et al. Granulocyte macrophage-colony-stimulating factor autoantibodies and increased intestinal permeability in Crohn disease. J Pediatr Gastroenterol Nutr. 2011; 52 (5): 542–8. DOI: 10.1097/MPG.0b013e3181fe2d93
  24. Tai S., Remark R., Laface I. et al. A5 gm-csf autoantibodies: predictors of crohn’s disease development and a novel therapeutic approach. J Can Assoc Gastroenterol. 2021; 4 (1): 5–6. DOI:10.1093/jcag/gwab002.004
  25. Porter C.K., Riddle M.S., Gutierrez R.L. et al. PREDICTS study team. Cohort profile of the PRoteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects (PREDICTS) study: Rationale, organization, design, and baseline characteristics. Contemp Clin Trials Commun. 2019; 14: 100345. DOI: 10.1016/j.conctc.2019.100345
  26. Ferguson L.R. Fundamental and Molecular Mechanisms of Mutagenesis. Mutation Research. 2010; 690: 3–11.
  27. Jurickova I., Collins M.H., Chalk C. et al. Paediatric Crohn disease patients with stricturing behaviour exhibit ileal granulocyte–macrophage colony-stimulating factor (GM-CSF) autoantibody production and reduced neutrophil bacterial killing and GM-CSF bioactivity. Clin Exp Immunol. 2013; 172 (3): 455–65. DOI: 10.1111/cei.12076
  28. Samson C.M., Jurickova I., Molden E. et al. Granulocyte-macrophage colony stimulating factor blockade promotes ccr9(+) lymphocyte expansion in Nod2 deficient mice. Inflamm Bowel Dis. 2011; 17 (12): 2443–55. DOI: 10.1002/ibd.21672
  29. Dabritz J., Bonkowski E., Chalk C. et al. Granulocyte macrophage colony-stimulating factor auto-antibodies and disease relapse in inflammatory bowel disease. Am J Gastroenterol. 2013; 108 (12): 1901–10. DOI: 10.1038/ajg.2013.360
  30. Gathungu G., Zhang Y., Tian X. et al. Impaired granulocyte-macrophage colony-stimulating factor bioactivity accelerates surgical recurrence in ileal Crohn's disease. World J Gastroenterol. 2018; 24 (5): 623–30. DOI: 10.3748/wjg.v24.i5.623
  31. Svenson M., Hansen M.B., Ross C. et al. Antibody to granulocyte-macrophage colony-stimulating factor is a dominant anti-cytokine activity in human IgG preparations. Blood. 1998; 91 (6): 2054–61.
  32. Uchida K., Beck D.C., Yamamoto T. et al. GM-CSF Autoantibodies and Neutrophil Dysfunction in Pulmonary Alveolar Proteinosis. N Engl J Med. 2007; 356 (6): 567–79. DOI: 10.1056/NEJMoa062505
  33. Watanabe M., Uchida K., Nakagaki K. et al. Anti-cytokine autoantibodies are ubiquitous in healthy individuals. FEBS Lett. 2007; 581 (DOI: 10.1016/j.febslet.2007.04.029): 2017–21. DOI: 10.1016/j.febslet.2007.04.029
  34. Watanabe M., Uchida K., Nakagaki K. et al. High avidity cytokine autoantibodies in health and disease: pathogenesis and mechanisms. Cytokine Growth Factor Rev. 2010; 21 (4): 263–73. DOI: 10.1016/j.cytogfr.2010.03.003
  35. Blech M., Seeliger D., Kistler B. et al. Molecular structure of human GM-CSF in complex with a disease-associated anti-human GM-CSF autoantibody and its potential biological implications. Biochem J. 2012; 447 (2): 205–15. DOI: 10.1042/BJ20120884
  36. Wang Y., Thomson C.A., Allan L.L. et al. Characterization of pathogenic human monoclonal autoantibodies against GM-CSF. Proc Natl Acad Sci USA. 2013; 110 (19): 7832–7. DOI: 10.1073/pnas.1216011110
  37. Gregersen P.K., Diamond B., Plenge R.M. GWAS implicates a role for quantitative immune traits and threshold effects in risk for human autoimmune disorders. Curr Opin Immunol. 2012; 24 (5): 538–43. DOI: 10.1016/j.coi.2012.09.003
  38. Dieckgraefe B.K., Korzenik J.R. Treatment of active Crohn's disease with recombinant human granulocyte-macrophage colony-stimulating factor. Lancet. 2002; 360 (9344): 1478–80. DOI: 10.1016/S0140-6736(02)11437-1
  39. Korzenik J.R., Dieckgraefe B.K., Valentine J.F. et al. Sargramostim for Active Crohn's Disease. N Engl J Med. 2005; 352 (21): 2193–201. DOI: 10.1056/NEJMoa041109
  40. Xu Y., Hunt N.H., Bao S. The role of granulocyte macrophage-colony-stimulating factor in acute intestinal inflammation. Cell Res. 2008; 18 (12): 1220–9. DOI: 10.1038/cr.2008.310
  41. Egea L., Hirata Y., Kagnoff M.F. GM-CSF: a role in immune and inflammatory reactions in the intestine. Expert Rev Gastroenterol Hepatol. 2010; 4 (6): 723–31. DOI: 10.1586/egh.10.73
  42. Bernasconi E., Favre L., Maillard M.H. et al. Granulocyte-macrophage colony-stimulating factor elicits bone marrow-derived cells that promote efficient colonic mucosal healing. Inflamm Bowel Dis. 2010; 16 (3): 428–41. DOI: 10.1002/ibd.21072
  43. Sainathan S.K., Hanna E.M., Gong Q. et al. Granulocyte macrophage colony-stimulating factor ameliorates DSS-induced experimental colitis. Inflamm Bowel Dis. 2008; 14 (1): 88–99. DOI: 10.1002/ibd.20279
  44. Valentine J.F., Fedorak R.N., Feagan B. et al. Steroid-sparing properties of sargramostim in patients with corticosteroid-dependent Crohn's disease: a randomised, double-blind, placebo-controlled, phase 2 study. Gut. 2009; 58 (10): 1354–62. DOI: 10.1136/gut.2008.165738
  45. Osterweil N. Steroids and G-CSF Improve 90-day Survival in Severe Alcoholic Hepatitis. Conference AASLD. November 09, 2022.