Título:
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Clinical and immunological control of experimental autoimmune encephalomyelitis by tolerogenic dendritic cells loaded with MOG-encoding mRNA
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Autor/a:
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Derdelinckx, Judith; Mansilla Lopez, Maria Jose; De Laere, Maxime; Lee, Wai-Ping; Navarro-Barriuso, Juan; Wens, Inez; Nkansah, Irene; Daans, Jasmijn; De Reu, Hans; Jolanta Keliris, Aneta; Van Audekerke, Johan; Vanreusel, Verdi; Pieters, Zoë; Van Der Linden, Annemie; Verhoye, Maraleen; Molenberghs, Geert; Hens, Niel; Goossens, Herman; Willekens, Barbara; Cras, Patrick; Ponsaerts, Peter; Berneman, Zwi; Martínez Cáceres, Eva María; Cools, Nathalie
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Abstract:
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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, MOG-immunized C57BL/6 mice were injected intravenously at days 13, 17, and 21 post-disease induction with 1α,25-dihydroxyvitamin D-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 MOG-immunized C57BL/6 mice with MOG mRNA-electroporated or MOG-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, MOG-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. |
Materia(s):
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-Messenger RNA electroporation -Tolerogenic dendritic cells -Antigen-specific treatment -Experimental autoimmune encephalomyelitis -Multiple sclerosis -Tolerance induction |
Derechos:
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open access
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Article |
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Uri:
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https://ddd.uab.cat/record/223975
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