Fingolimod Increases Brain-Derived Neurotrophic Factor Level Secretion from Circulating T Cells of Patients with Multiple Sclerosis

Abstract

Background

The pathophysiology of multiple sclerosis involves an autoimmune and a neurodegenerative mechanism. Central nervous system-infiltrating immune cells in multiple sclerosis also possess a neuroprotective activity through secretion of neurotrophins, such as brain-derived neurotrophic factor. Fingolimod was shown to slow the progression of disability and loss of brain volume.

Objective

The objective of this study was to explore whether fingolimod induces secretion of neurotrophins by immune cells.

Methods

Blood was drawn from 21 patients before the initiation of treatment with fingolimod and at 6 and 12 months of follow-up. The levels of the neurotrophic factors brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, β-nerve growth factor, neurotrophin-3, neurotrophin-4, basic fibroblast growth factor, epidermal growth factor, and vascular endothelial growth factor were screened in the supernatants of separated T cells and monocyte cultures using a customized, multiplex enzyme-linked immunosorbent assay. Brain-derived neurotrophic factor levels were further validated by a specific enzyme-linked immunosorbent assay.

Results

Treatment with fingolimod significantly increased brain-derived neurotrophic factor secretion from T cells. A specific enzyme-linked immunosorbent assay confirmed these results in the supernatant of T cells after 6 and 12 months of therapy.

Conclusions

T cells that reach the bloodstream of fingolimod-treated patients with multiple sclerosis may contribute to the neuroprotective effect of this therapy by increased secretion of brain-derived neurotrophic factor. This mechanism of action of fingolimod in patients with multiple sclerosis has not been previously reported.

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Acknowledgements

We thank Esther Eshkol, institutional medical copy editor of Tel Aviv Sourasky Medical Center, for assistance in drafting the manuscript.

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Correspondence to Arnon Karni.

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Funding

Novartis AG partially supported the study.

Conflict of interest

Maya Golan, Karin Mausner-Fainberg, Bassima Ibrahim, Moshe Benhamou, Adi Wilf-Yarkoni, Hadar Kolb, Keren Regev, and Arnon Karni have no conflicts of interest that are directly relevant to the content of this study.

Ethics Approval

The study was approved by the local institutional review board in Helsinki (Research No. 0584-13-TLV).

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All the participants in the study signed an informed consent form upon enrollment.

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Golan, M., Mausner-Fainberg, K., Ibrahim, B. et al. Fingolimod Increases Brain-Derived Neurotrophic Factor Level Secretion from Circulating T Cells of Patients with Multiple Sclerosis. CNS Drugs 33, 1229–1237 (2019). https://doi.org/10.1007/s40263-019-00675-7

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