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Introduction: IgE-mediated peanut allergy is an important public health problem of increasing prevalence leading to anaphylactic reactions both in children and adults. Allergen-specific oral immunotherapy (OIT) is the single treatment with the potential capacity to modify the course of the disease, but it still faces some drawbacks in terms of efficacy, safety, patients' adherence, and cost. Alternative strategies, including the use of novel adjuvants, to overcome such limitations are highly demanded. The main aim of this study was to search for potential novel adjuvants for peanut OIT by assessing the capacity of free purified mannan and different toll-like receptor ligands (TLR-Ls) to immunomodulate the responses of human monocyte-derived dendritic cells (hmoDCs) to peanut allergens., Methods: Monocytes were isolated from PBMCs of healthy donors and differentiated into hmoDCs. Flow cytometry, ELISA, coculture, and suppression assay were performed to assess the effects of TLR-Ls, mannan, and crude peanut extract (CPE) in hmoDCs., Results: Purified free mannan increased the expression levels of HLA-DR, CD86, CD83, and PD-L1 and induced a higher IL-10/IL-6 cytokine ratio in hmoDCs compared to the stimulation with different TLR-Ls. Mannan significantly increased the expression of HLA-DR, the maturation marker CD83, the tolerogenic marker PD-L1, as well as the production of IL-10, IL-6, and TNF-α in CPE-stimulated hmoDCs. Supporting these tolerogenic properties, mannan also significantly increased the frequency of FOXP3+ regulatory T cells generated by CPE-treated hmoDCs with functional suppressive capacity., Conclusions: We uncover that purified free mannan induces tolerogenic responses in human DCs stimulated with peanut allergens, suggesting mannan as a suitable potential novel adjuvant to be exploited in the context of OIT for peanut allergy., (© 2024 S. Karger AG, Basel.)