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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2019

Open Access 01-12-2019 | Multiple Sclerosis | Research

Clinical and immunological control of experimental autoimmune encephalomyelitis by tolerogenic dendritic cells loaded with MOG-encoding mRNA

Authors: Judith Derdelinckx, María José Mansilla, Maxime De Laere, Wai-Ping Lee, Juan Navarro-Barriuso, Inez Wens, Irene Nkansah, Jasmijn Daans, Hans De Reu, Aneta Jolanta Keliris, Johan Van Audekerke, Verdi Vanreusel, Zoë Pieters, Annemie Van der Linden, Marleen Verhoye, Geert Molenberghs, Niel Hens, Herman Goossens, Barbara Willekens, Patrick Cras, Peter Ponsaerts, Zwi N. Berneman, Eva María Martínez-Cáceres, Nathalie Cools

Published in: Journal of Neuroinflammation | Issue 1/2019

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Abstract

Background

Although effective in reducing relapse rate and delaying progression, current therapies for multiple sclerosis (MS) do not completely halt disease progression. T cell autoimmunity to myelin antigens is considered one of the main mechanisms driving MS. It is characterized by autoreactivity to disease-initiating myelin antigen epitope(s), followed by a cascade of epitope spreading, which are both strongly patient-dependent. Targeting a variety of MS-associated antigens by myelin antigen-presenting tolerogenic dendritic cells (tolDC) is a promising treatment strategy to re-establish tolerance in MS. Electroporation with mRNA encoding myelin proteins is an innovative technique to load tolDC with the full spectrum of naturally processed myelin-derived epitopes.

Methods

In this study, we generated murine tolDC presenting myelin oligodendrocyte glycoprotein (MOG) using mRNA electroporation and we assessed the efficacy of MOG mRNA-electroporated tolDC to dampen pathogenic T cell responses in experimental autoimmune encephalomyelitis (EAE). For this, MOG35–55-immunized C57BL/6 mice were injected intravenously at days 13, 17, and 21 post-disease induction with 1α,25-dihydroxyvitamin D3-treated tolDC electroporated with MOG-encoding mRNA. Mice were scored daily for signs of paralysis. At day 25, myelin reactivity was evaluated following restimulation of splenocytes with myelin-derived epitopes. Ex vivo magnetic resonance imaging (MRI) was performed to assess spinal cord inflammatory lesion load.

Results

Treatment of MOG35–55-immunized C57BL/6 mice with MOG mRNA-electroporated or MOG35–55-pulsed tolDC led to a stabilization of the EAE clinical score from the first administration onwards, whereas it worsened in mice treated with non-antigen-loaded tolDC or with vehicle only. In addition, MOG35–55-specific pro-inflammatory pathogenic T cell responses and myelin antigen epitope spreading were inhibited in the peripheral immune system of tolDC-treated mice. Finally, magnetic resonance imaging analysis of hyperintense spots along the spinal cord was in line with the clinical score.

Conclusions

Electroporation with mRNA is an efficient and versatile tool to generate myelin-presenting tolDC that are capable to stabilize the clinical score in EAE. These results pave the way for further research into mRNA-electroporated tolDC treatment as a patient-tailored therapy for MS.
Appendix
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Metadata
Title
Clinical and immunological control of experimental autoimmune encephalomyelitis by tolerogenic dendritic cells loaded with MOG-encoding mRNA
Authors
Judith Derdelinckx
María José Mansilla
Maxime De Laere
Wai-Ping Lee
Juan Navarro-Barriuso
Inez Wens
Irene Nkansah
Jasmijn Daans
Hans De Reu
Aneta Jolanta Keliris
Johan Van Audekerke
Verdi Vanreusel
Zoë Pieters
Annemie Van der Linden
Marleen Verhoye
Geert Molenberghs
Niel Hens
Herman Goossens
Barbara Willekens
Patrick Cras
Peter Ponsaerts
Zwi N. Berneman
Eva María Martínez-Cáceres
Nathalie Cools
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2019
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-019-1541-1

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