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Title:
Clinical and immunological control of experimental autoimmune encephalomyelitis by tolerogenic dendritic cells loaded with MOG-encoding mRNA | Journal of Neuroinflammation
Description:
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.
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Keywords {🔍}
toldc, mog, cells, mrna, mice, pubmed, eae, article, treatment, google, scholar, electroporation, clinical, cell, splenocytes, mrnaelectroporated, myelin, epitope, dendritic, cas, spreading, disease, spinal, model, multiple, analysis, autoimmune, mdc, sclerosis, score, additional, murine, protein, number, cord, results, extracellular, research, day, central, fig, data, performed, van, antigen, demonstrated, belgium, group, tolerance, effect,
Topics {✒️}
}_i}{1+\exp \left[-\frac{t_{ij}-\left messenger rna electroporation sig-full length mog-lamp-3 ]}+{\varepsilon}_{ij} $$ sig-extracellular mog-lamp mrna mog35–55-specific pro-inflammatory response sig-extracellular mog-lamp-3 constructs mog35–55-specific pro-inflammatory pathogenic pro-inflammatory cytokine gm-csf mrna encoding full-length 75 μg sig-mog-lamp mrna ifn-γ spot-forming cells full size image sig-mog-lamp mrna electroporation antigen-specific cell-based approach full-length mog mrna extracellular mog-encoding mrna sig-extracellular mog-lamp relapsing-remitting multiple sclerosis mog-specific splenocyte hyporesponsiveness allo-tolerogenic dendritic cells murine nir815 dye-labeled vitd3-treated mog40–55-loaded toldc sfc spot-forming cells mog-specific proliferation assay sig-mog-lamp mrna peter ponsaerts sig-lamp mrna sequence specific t-cell proliferation thyroglobulin-specific cd4+cd25+ complex multi-epitope-targeted loss pelco® cryo-embedding compound primary immunodeficiency—lessons learned lymph node-derived lymphocytes anti-cd1d-alexa fluor 647 anti-cd27-alexa fluor 647 pfa-fixed spinal cords low-voltage electrical field cytokine secretion profile juan navarro-barriuso mog35–55-pulsed toldc-treated groups bonferroni post-hoc test article download pdf generate myelin-presenting toldc mog35–55-specific splenocyte reactivity individual disease profiles full size table mediate toldc-induced tolerance 5 mmol gadoteric acid/ml administering antigen-loaded toldc
Questions {❓}
- Dendritic cells in multiple sclerosis: key players in the immunopathogenesis, key players for new cellular immunotherapies?
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headline:Clinical and immunological control of experimental autoimmune encephalomyelitis by tolerogenic dendritic cells loaded with MOG-encoding mRNA
description: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. 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. 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. 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.
datePublished:2019-08-15T00:00:00Z
dateModified:2019-08-15T00:00:00Z
pageStart:1
pageEnd:20
license:http://creativecommons.org/publicdomain/zero/1.0/
sameAs:https://doi.org/10.1186/s12974-019-1541-1
keywords:
Messenger RNA electroporation
Tolerogenic dendritic cells
Antigen-specific treatment
Experimental autoimmune encephalomyelitis
Multiple sclerosis
Tolerance induction
Neurosciences
Neurology
Neurobiology
Immunology
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headline:Clinical and immunological control of experimental autoimmune encephalomyelitis by tolerogenic dendritic cells loaded with MOG-encoding mRNA
description: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. 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. 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. 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.
datePublished:2019-08-15T00:00:00Z
dateModified:2019-08-15T00:00:00Z
pageStart:1
pageEnd:20
license:http://creativecommons.org/publicdomain/zero/1.0/
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keywords:
Messenger RNA electroporation
Tolerogenic dendritic cells
Antigen-specific treatment
Experimental autoimmune encephalomyelitis
Multiple sclerosis
Tolerance induction
Neurosciences
Neurology
Neurobiology
Immunology
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name:L-BioStat, I-BioStat, KU Leuven, Leuven, Belgium
name:Center for Statistics, I-Biostat, Hasselt University, Diepenbeek, Belgium
name:Centre for Health Economics Research and Modelling Infectious Diseases (CHERMID), Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
name:Laboratory of Medical Microbiology, Faculty of Medicine and Health Sciences, Vaccine and Infectious Disease Institute (VaxInfectio), University of Antwerp, Antwerp, Belgium
name:Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, Vaccine and Infectious Disease Institute (VaxInfectio), University of Antwerp, Antwerp University Hospital (UZA), Edegem, Belgium
name:Division of Neurology, Antwerp University Hospital, Edegem, Belgium
name:Division of Neurology, Antwerp University Hospital, Edegem, Belgium
name:Born Bunge Institute, Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
name:Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, Vaccine and Infectious Disease Institute (VaxInfectio), University of Antwerp, Antwerp University Hospital (UZA), Edegem, Belgium
name:Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, Vaccine and Infectious Disease Institute (VaxInfectio), University of Antwerp, Antwerp University Hospital (UZA), Edegem, Belgium
name:Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem, Belgium
name:Division of Immunology, Germans Trias i Pujol University Hospital and Research Institute, Badalona, Spain
name:Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain
name:Laboratory of Experimental Hematology, Faculty of Medicine and Health Sciences, Vaccine and Infectious Disease Institute (VaxInfectio), University of Antwerp, Antwerp University Hospital (UZA), Edegem, Belgium
name:Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem, Belgium
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