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

  • Oculoplastics and Orbit
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Abstract

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.

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Funding

This study was financially supported by a grant from Hospital Clinic de Barcelona (Emili Letang Award for Best Investigations Projects, 2013/2014).

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Authors and Affiliations

  1. Faculty of Medicine. “Medicine and Translational Research” Doctorate Program, University of Barcelona, Barcelona, Spain

    Anna Leszczynska, Alfredo Adán & Santiago Ortiz-Perez

  2. Division of Biological Aggression and Response Mechanisms, August Pi I Sunyer Biomedical Research Institute, Barcelona, Spain

    Blanca Molins

  3. Hospital Clinic de Barcelona, Institut Clinic d’Oftalmologia, Barcelona, Spain

    Blanca Molins, Estrella Fernández, Alfredo Adán & Santiago Ortiz-Perez

Authors
  1. Anna Leszczynska
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  2. Blanca Molins
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  3. Estrella Fernández
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  4. Alfredo Adán
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  5. Santiago Ortiz-Perez
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Corresponding author

Correspondence to Santiago Ortiz-Perez.

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Conflict of interest

Anna Leszczynska was an employee at Esteve Pharmaceuticals from June 2017 until December 2018.

Alfredo Adan participated in advisory boards for Allergan, AbbVie Inc., Santen Pharmaceutical Co., Ltd., Novartis, and Alimera Sciences; delivered lectures for Allergan, AbbVie Inc., Santen Pharmaceuticals Co., Ltd., and Novartis; and received grants from F. Hoffmann-La Roche Ltd., Allergan, Bayer AG, and Novartis.

Santiago Ortiz provided consultations for Laboratoires THEA and Alcon Healthcare.

Blanca Molins declares that she has no conflict of interest.

Estrella Fernández declares that she has no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Human and animal rights and informed consent

Informed consent was obtained from all individual participants included in the study. This article does not contain any studies with animals performed by any of the authors.

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Leszczynska, A., Molins, B., Fernández, E. et al. Cytokine production in thyroid eye disease: in vitro effects of dexamethasone and IL-6 blockade with tocilizumab. Graefes Arch Clin Exp Ophthalmol 257, 2307–2314 (2019). https://doi.org/10.1007/s00417-019-04419-7

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  • DOI: https://doi.org/10.1007/s00417-019-04419-7

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