Anti-IL-6 receptor monoclonal antibody as a new treatment of endometriosis

Many pro-inflammatory cytokines especially tumor necrotic factor alpha (TNFα), interleukin (IL)-1β, and IL-6 have crucial role in the pathogenesis of endometriosis. In this study, we investigated the immune-modulatory role of humanized anti-IL-6 receptor monoclonal antibodies in the treatment of endometriosis. This is a prospective, randomized, controlled, blinded study in which Sprague Dawley rats were used as animal model of endometriosis. Animals were randomly divided into two groups, a test group which received tocilizumab (Actemra; Roche, Switzerland) and a control group which received saline. Afterwards, a comparison was done between the eutopic and ectopic endometrium that was excised from both groups, histopathologically and immune-histochemically. Histopathologic assessment and immune-histochemical staining were performed using antibodies against IL-6. Tocilizumab significantly suppressed the volume of endometriotic lesions compared with non-treated rats (P = 0.006) and atrophied the ectopic endometrial-like epithelium (in 42.8% of treated rats vs 0% in the control group). Tocilizumab also decreased the anti-IL-6 receptor immune-histochemical staining intensity in ectopic endometrium (from non to +++ in the test group vs ++ or more in the control group), with no apparent difference in the eutopic one reflecting the down-regulation of IL-6-producing cells in ectopic endometriotic lesions. In rats with induced endometriosis, anti-IL-6 receptor monoclonal antibodies could offer a new horizon of usage of this immune-modulatory biologic drug, used in other autoimmune diseases, in treatment of endometriosis. Similar content being viewed by others Data availability Are confirmed.

Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–79. Vinatier D, Orazi G, Cosson M, Dufour P. Theories of endometriosis. Eur J Obstet Gynecol Reprod Biol. 2001;96(1):21–34. Gargett CE, Schwab KE, Zillwood RM, Nguyen HP, Wu D. Isolation and culture of epithelial progenitors and mesenchymal stem cells from human endometrium. Biol Reprod. 2009;80(6):1136–45. Symons LK, Miller JE, Kay VR, Marks RM, Liblik K, Koti M, et al. The immunopathophysiology of endometriosis. Trends Mol Med. 2018;24(9):748–62. Wickiewicz D, Chrobak A, Gmyrek GB, Halbersztadt A, Gabrys MS, Goluda M, et al. Diagnostic accuracy of interleukin-6 levels in peritoneal fluid for detection of endometriosis. Arch Gynecol Obstet. 2013;288(4):805–14. Malutan AM, Drugan T, Costin N, Ciortea R, Bucuri C, Rada MP, et al. Pro-inflammatory cytokines for evaluation of inflammatory status in endometriosis. Cent Eur J Immunol. 2015;40(1):96–102. Maggio M, Guralnik JM, Longo DL, Ferrucci L. Interleukin-6 in aging and chronic disease: a magnificent pathway. J Gerontol A Biol Sci Med Sci. 2006;61(6):575–84. Dyson MT, Bulun SE. Cutting SRC-1 down to size in endometriosis. Nat Med. 2012;18(7):1016–8. Woo JH, Yang YI, Ahn JH, Choi YS, Choi JH. Interleukin 6 secretion from alternatively activated macrophages promotes the migration of endometriotic epithelial cells. Biol Reprod. 2017;97(5):660–70. Lin YH, Chen YH, Chang HY, Au HK, Tzeng CR, Huang YH. Chronic niche inflammation in endometriosis-associated infertility: current understanding and future therapeutic strategies. Int J Mol Sci. 2018 Aug 13;19(8):2385. Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362(25):2389–98. Lebovic DI, Kir M, Casey CL. Peroxisome proliferator-activated receptor-gamma induces regression of endometrial explants in a rat model of endometriosis. Fertil Steril. 2004;82(Suppl 3):1008–13. Podgaec S, Abrao MS, Dias JA Jr, Rizzo LV, de Oliveira RM, Baracat EC. Endometriosis: an inflammatory disease with a Th2 immune response component. Hum Reprod. 2007;22(5):1373–9. Podgaec S, Dias Junior JA, Chapron C, Oliveira RM, Baracat EC, Abrao MS. Th1 and Th2 immune responses related to pelvic endometriosis. Rev Assoc Med Bras. 2010;56(1):92–8. Tsukamoto H, Senju S, Matsumura K, Swain SL, Nishimura Y. IL-6-mediated environmental conditioning of defective Th1 differentiation dampens antitumour immune responses in old age. Nat Commun. 2015;6:6702–5. Herington JL, Bruner-Tran KL, Lucas JA, Osteen KG. Immune interactions in endometriosis. Expert Rev Clin Immunol. 2011;7(5):611–26. Sharpe-Timms KL, Zimmer RL, Ricke EA, Piva M, Horowitz GM. Endometriotic haptoglobin binds to peritoneal macrophages and alters their function in women with endometriosis. Fertil Steril. 2002;78(4):810–9. Gazvani R, Templeton A. Peritoneal environment, cytokines and angiogenesis in the pathophysiology of endometriosis. Reproduction. 2002;123(2):217–26. Khan KN, Masuzaki H, Fujishita A, Kitajima M, Hiraki K, Sekine I, et al. Interleukin-6- and tumour necrosis factor alpha-mediated expression of hepatocyte growth factor by stromal cells and its involvement in the growth of endometriosis. Hum Reprod. 2005;20(10):2715–23. Li S, Fu X, Wu T, Yang L, Hu C, Wu R. Role of interleukin-6 and its receptor in endometriosis. Med Sci Monit. 2017;23:3801–7. Quattrone F, Sanchez AM, Pannese M, Hemmerle T, Vigano P, Candiani M, et al. The targeted delivery of interleukin 4 inhibits development of endometriotic lesions in a mouse model. Reprod Sci. 2015;22(9):1143–52. Szymanowski K, Niepsuj-Binias J, Dera-Szymanowska A, Wolun-Cholewa M, Yantczenko A, Florek E, et al. An influence of immunomodulation on Th1 and Th2 immune response in endometriosis in an animal model. Biomed Res Int. 2013;201:849492. Falconer H, Mwenda JM, Chai DC, Wagner C, Song XY, Mihalyi A, et al. Treatment with anti-TNF monoclonal antibody (c5N) reduces the extent of induced endometriosis in the baboon. Hum Reprod. 2006;21(7):1856–62. Zulfikaroglu E, Kilic S, Islimye M, Aydin M, Zergeroglu S, Batioglu S. Efficacy of anti-tumor necrosis factor therapy on endometriosis in an experimental rat model. Arch Gynecol Obstet. 2011;283(4):799–804. Taskin MI, Gungor AC, Adali E, Yay A, Onder GO, Inceboz U. A humanized anti-interleukin 6 receptor monoclonal antibody, tocilizumab, for the treatment of endometriosis in a rat model. Reprod Sci. 2016;23(5):662–9. Funding This project was supported financially by the Mansoura University Fund, Egypt. Author information Authors and Affiliations Corresponding author Ethics declarations Conflict of interest The authors declare that they have no conflict of interest. Ethical approval The study was approved by the Mansoura Faculty of Medicine Institutional Research Board (MFM-IRB). Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions About this article Cite this article El-Zayadi, A.A., Mohamed, S.A., Arafa, M. et al. Anti-IL-6 receptor monoclonal antibody as a new treatment of endometriosis. Immunol Res 68, 389–397 (2020). https://doi.org/10.1007/s12026-020-09153-5 Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s12026-020-09153-5