Targeting aryl hydrocarbon receptor functionally restores tolerogenic dendritic cells derived from patients with multiple sclerosis
Federico Fondelli, … , Esteban Ballestar, Eva Martínez-Cáceres
Federico Fondelli, … , Esteban Ballestar, Eva Martínez-Cáceres
Published September 17, 2024
Citation Information: J Clin Invest. 2024;134(21):e178949. https://doi.org/10.1172/JCI178949.
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Research Article Autoimmunity Therapeutics

Targeting aryl hydrocarbon receptor functionally restores tolerogenic dendritic cells derived from patients with multiple sclerosis

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.

Authors

Federico Fondelli, Jana Willemyns, Roger Domenech-Garcia, Maria José Mansilla, Gerard Godoy-Tena, Anna G. Ferreté-Bonastre, Alex Agúndez-Moreno, Silvia Presas-Rodriguez, Cristina Ramo-Tello, Esteban Ballestar, Eva Martínez-Cáceres

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Figure 9

In vivo administration of DMF to MS patients restores fully functional tolDCs.

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In vivo administration of DMF to MS patients restores fully functional t...
(A) Box plots reporting percentages of classical, intermediate, and non-classical monocytes among HD and MS patients without treatment (MS) or treated with DMF (DMF), with respect to total monocytes as parent gate (top row), or reporting percentages of CD45RA+ (middle row) or CD40+ (bottom row) classical, intermediate, and non-classical monocytes. P values from Kruskal-Wallis test with Dunn’s multiple comparisons are shown. n = 7 or n = 4 depending on the sample group. Percentages of monocyte subpopulations from HD and MS patient groups are also presented in Figure 1B. Here, new statistical tests have been applied to include a cohort of DMF-treated patients. (B) Box plots showing flow cytometry data relative to the percentage of CD83+CD86+ and CD14+ cells after 6-day in vitro differentiation among MS tolDCs and among tolDCs isolated from patients undergoing DMF treatment (MS tolDCs DMF). Unpaired, 2-tailed t tests were used to calculate P values (Mann-Whitney tests). n = 4 in each sample group. (C) Proliferation of allogeneic PBMCs with tolDCs from HDs, treatment-naive MS patients (MS tolDCs), or patients undergoing DMF treatment (MS tolDCs DMF) or with tolDCs from MS patients differentiated in the presence of DMF in vitro (MS tolDCs + DMF). Inhibition of proliferation was assessed as described earlier. One-way ANOVA with multiple comparisons was used to calculate significant differences among groups (Kruskal-Wallis test), reported as P values. n = 4–8 depending on the sample group.