Cytokine production in thyroid eye disease: in vitro effects of dexamethasone and IL-6 blockade with tocilizumab

• Published in: Graefe's archive for clinical and experimental ophthalmology Vol. 257; no. 10; pp. 2307 - 2314
• Main Authors: Leszczynska, Anna, Molins, Blanca, Fernández, Estrella, Adán, Alfredo, Ortiz-Perez, Santiago
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2019; Springer Nature B.V
• Subjects: Adult; Aged; Antibodies, Monoclonal, Humanized - therapeutic use; Cell culture; Cells, Cultured; Cytokines - biosynthesis; Dexamethasone; Dexamethasone - therapeutic use; Enzyme-Linked Immunosorbent Assay; Eye diseases; Female; Follow-Up Studies; Glucocorticoids - therapeutic use; Graves Ophthalmopathy - diagnosis; Graves Ophthalmopathy - drug therapy; Graves Ophthalmopathy - metabolism; Humans; Immunosuppressive agents; Interleukin 17; Interleukin 6; Interleukin-6 - antagonists & inhibitors; Leukocytes (mononuclear); Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - pathology; Male; Medicine; Medicine & Public Health; Middle Aged; Monoclonal antibodies; Oculoplastics and Orbit; Ophthalmology; Peripheral blood mononuclear cells; Prospective Studies; Steroid hormones; Steroids; Thyroid; Thyroid gland; Tomography, X-Ray Computed; Treatment Outcome; Interleukin 6; Dexamethasone; Interleukin 6 receptor; Thyroid eye disease; Tocilizumab
• ISSN: 0721-832X; 1435-702X; 1435-702X
• DOI: 10.1007/s00417-019-04419-7

Purpose To compare IL-6, sIL-6R, and IL-17 secretion in peripheral blood mononuclear cells (PBMCs) cultured with tocilizumab (a humanized monoclonal antibody against the interleukin-6 receptor), dexamethasone, and placebo, obtained from patients with thyroid eye disease (TED) and healthy controls. Methods The study was a prospective proof of concept test. We cultured peripheral blood mononuclear cells from TED patients and healthy controls with tocilizumab, dexamethasone, and placebo. IL-6, sIL-6R, and IL-17 levels in supernatants obtained from PBMCs cultures were analyzed by ELISA. Results We included seventeen patients with thyroid eye disease (12 females and five males). The mean age was 49 years. Both dexamethasone and tocilizumab influenced IL-6 and IL-6Rs levels in patients’ group. Supernatants obtained from PBMCs treated with dexamethasone showed 77.2% and 82.8% lower IL-6 levels compared with those cultured with placebo and tocilizumab, respectively. Furthermore, overnight culture of PBMCs with dexamethasone showed significantly lower sIL-6R secretion compared with untreated (33.71%, p  = 0.04) and tocilizumab treated (58.21%, p  = 0.01) PBMCs. Neither dexamethasone nor tocilizumab affected IL-17 concentrations in PBMCs cultures. Conclusions Both dexamethasone and tocilizumab affect the IL-6/sIL-6R system. Specifically, dexamethasone reduces and tocilizumab increases the levels of these cytokines in PBMCs cultures. These results strengthen the molecular rationale for interrogating the efficacy of tocilizumab in steroid-resistant TED, as IL-6 seems to be a common target for both anti-IL-6R antibody and steroids.