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| Home > Articles > Published articles > Targeting aryl hydrocarbon receptor functionally restores tolerogenic dendritic cells derived from patients with multiple sclerosis |
(Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)| Date: | 2024 |
| Abstract: | Multiple sclerosis (MS) is a chronic disease characterized by dysregulated self-reactive immune responses that damage the neurons' myelin sheath, leading to progressive disability. The primary therapeutic option, immunosuppressants, inhibits pathogenic anti-myelin responses but depresses the immune system. Antigen-specific monocyte-derived autologous tolerogenic dendritic cells (tolDCs) offer alternative therapeutic approaches to restore tolerance to autoantigens without causing generalized immunosuppression. However, immune dysregulation in MS could impact the properties of the monocytes used as starting material for this cell therapy. Here, we characterized CD14+ monocytes, mature dendritic cells, and vitamin D3-tolDCs (VitD3-tolDCs) from active, treatment-naive MS patients and healthy donors (HDs). Using multiomics, we identified a switch in these cell types toward proinflammatory features characterized by alterations in the aryl hydrocarbon receptor (AhR) and NF-κB pathways. MS patient-derived VitD3-tolDCs showed reduced tolerogenic properties compared with those from HDs, which were fully restored through direct AhR agonism and by use of in vivo or in vitro dimethyl fumarate (DMF) supplementation. Additionally, in the experimental autoimmune encephalomyelitis mouse model, combined therapy of DMF and VitD3-tolDCs was more efficient than monotherapies in reducing the clinical score of mice. We propose that a combined therapy with DMF and VitD3-tolDCs offers enhanced therapeutic potential in treating MS. |
| Grants: | Instituto de Salud Carlos III PI17/01521 Instituto de Salud Carlos III PI20/01313 Instituto de Salud Carlos III PI21/00944 Agencia Estatal de Investigación PID2020-117212RB-I00 |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | Adult ; Animals ; Basic Helix-Loop-Helix Transcription Factors ; Cholecalciferol ; Dendritic Cells ; Encephalomyelitis, Autoimmune, Experimental ; Female ; Humans ; Immune Tolerance ; Male ; Mice ; Middle Aged ; Monocytes ; Multiple Sclerosis ; NF-kappa B ; Receptors, Aryl Hydrocarbon |
| Published in: | The journal of clinical investigation, Vol. 134 Núm. 21 (january 2024) , p. e178949, ISSN 1558-8238 |
