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

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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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 auto-antigens 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 (mDCs) and Vitamin-D3-tolDCs (VitD3-tolDCs) from active, treatment-naive MS patients and healthy donors (HD). Using multi-omics, we identified a switch in these cell types towards proinflammatory features characterized by alterations in the AhR and NF-kB pathways. MS patient-derived VitD3-tolDCs showed reduced tolerogenic properties compared to those from HD, which were fully restored through direct AhR agonism and using in vivo or in vitro Dimethyl Fumarate (DMF) supplementation. Additionally, in the experimental autoimmune encephalomyelitis (EAE) 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.
靶向芳基烃受体可恢复多发性硬化症患者的耐受性树突状细胞功能。
多发性硬化症(MS)是一种慢性疾病,其特点是自我调节失调的免疫反应损害神经元的髓鞘,导致进行性残疾。免疫抑制剂是主要的治疗选择,它能抑制致病性抗髓鞘反应,但会抑制免疫系统。抗原特异性单核细胞衍生的自体耐受性树突状细胞(tolDCs)提供了替代治疗方法,可在不引起全身免疫抑制的情况下恢复对自身抗原的耐受性。然而,多发性硬化症的免疫失调可能会影响作为细胞疗法起始材料的单核细胞的特性。在这里,我们对来自活跃的、未经治疗的多发性硬化症患者和健康供体(HD)的 CD14+ 单核细胞、成熟树突状细胞(mDCs)和维生素-D3-tolDCs(VitD3-tolDCs)进行了鉴定。通过多组学研究,我们确定了这些细胞类型向以 AhR 和 NF-kB 通路的改变为特征的促炎特征的转变。与来自 HD 的 VitD3-tolDCs 相比,MS 患者衍生的 VitD3-tolDCs 显示出较低的耐受性,而通过直接 AhR 激动以及体内或体外富马酸二甲酯(DMF)补充,这些耐受性得到了完全恢复。此外,在实验性自身免疫性脑脊髓炎(EAE)小鼠模型中,DMF和VitD3-tolDCs联合疗法在降低小鼠临床评分方面比单一疗法更有效。我们认为,DMF 和 VitD3-tolDCs 联合疗法在治疗多发性硬化症方面具有更大的治疗潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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