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Title: | Clinical and immunological control of experimental autoimmune encephalomyelitis by tolerogenic dendritic cells loaded with MOG-encoding mRNA | Authors: | Derdelinckx, Judith Mansila, Maria José De Laere, Maxime Lee, Wai-Ping Navaro-Barriuso, Juan WENS, Inez Nkansah, Irene Daans, Jasmijn De Reu, Hans Keliris, Aneta Jolanta Van Audekerke, Johan Vanreusel, Verdi PIETERS, Zoe Van der Linden, Annemie Verhoye, Marleen MOLENBERGHS, Geert HENS, Niel Goosens, Herman Willekens, Barbara Cras, Patrick Ponsaerts, Peter Berneman, Zwi N. Martínez-Cáceres, Eva María Cools, Nathalie |
Issue Date: | 2019 | Source: | Journal of neuroinflammation, 16(1) (Art N° 167) | 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 MSassociated 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. | Keywords: | Messenger RNA electroporation;Tolerogenic dendritic cells;Antigen-specific treatment;Experimental autoimmune encephalomyelitis;Multiple sclerosis;Tolerance induction | Document URI: | http://hdl.handle.net/1942/29655 | e-ISSN: | 1742-2094 | DOI: | 10.1186/s12974-019-1541-1 | ISI #: | 000481905900001 | Rights: | The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2020 |
Appears in Collections: | Research publications |
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