Abstract
Myasthenia gravis (MG) is an autoantibody-mediated autoimmune disease characterized by skeletal muscle weakness exacerbated with exercise. There is a need for novel drugs effective in refractory MG. We aimed to test the potential of teriflunomide, an immunomodulatory drug currently used in rheumatoid arthritis and multiple sclerosis treatment, in a murine experimental autoimmune myasthenia gravis (EAMG) model. EAMG was induced by immunizations with recombinant acetylcholine receptor (AChR). Teriflunomide treatment (10 mg/kg/day, intraperitoneal) was initiated to one group of mice (n = 21) following the third immunization and continued for 5 weeks. The disease control group (n = 19) did not receive medication. Naïve mice (n = 10) received only mock immunization. In addition to the clinical scorings, the numbers of B cells and T cells, and cytokine profiles of T cells were examined by flow cytometry. Anti-AChR-specific antibodies in the peripheral blood serum were quantified by ELISA. Teriflunomide significantly reduced clinical disease scores and the absolute numbers of CD4+ T cells and some of their cytokine-producing subgroups (IFN-γ, IL 2, IL22, IL-17A, GM-CSF) in the spleen and the lymph nodes. The thymic CD4+ T cells were also significantly reduced. Teriflunomide mostly spared CD8+ T cells’ numbers and cytokine production, while reducing CD138+CD19+lambda+ plasma B cells’ absolute numbers and CD138 mean fluorescent intensities, probably decreasing the number of IgG secreting more mature plasma cells. It also led to some selective changes in the measurements of anti-AChR-specific antibodies in the serum. Our results showed that teriflunomide may be beneficial in the treatment of MG in humans.
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Acknowledgements
We thank Erciyes University DEKAM vivarium and administrative personnel of GENKOK.
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This study was supported by Erciyes University Scientific Research Council- Doctoral Research Grant (#: TDK-2019-9670) to Sabahattin Muhtaroglu.
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EK, AE and SM conceived the study. SM provided funding. EK carried out all the experiments. EK and AE performed first immunizations. EK, AE and NS killed the mice and harvested the organs. AE supervised all the experimental procedures post-killing and flow cytometry operation. NS helped clinical scoring. Data generation and analyses were performed by EK, GZ and AE. Flow cytometric data analyses on FlowJo and generation of flow plots were performed by AE. All the figures of the manuscript were generated by Emel Koseoglu, except Fig. 1, Supplementary Figs. 13, 14, 15, which were generated by AE. Interpretation of data was performed by EK and AE together. The manuscript was written by AE and EK. All the authors read and contributed to the manuscript preparation, critical reading and approved the submitted version of the manuscript.
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Koseoglu, E., Sungur, N., Muhtaroglu, S. et al. The Beneficial Clinical Effects of Teriflunomide in Experimental Autoimmune Myasthenia Gravis and the Investigation of the Possible Immunological Mechanisms. Cell Mol Neurobiol 43, 2071–2087 (2023). https://doi.org/10.1007/s10571-022-01286-5
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DOI: https://doi.org/10.1007/s10571-022-01286-5