Allergoid–mannan conjugates reprogram monocytes into tolerogenic dendritic cells via epigenetic and metabolic rewiring

Benito-Villalvilla, Cristina; Pérez‐Diego, Mario; Angelina, Alba; Kisand, Kai; Rebane, Ana; Subiza, José Luis; Palomares, Óscar

doi:10.1016/j.jaci.2021.06.012

Cited by 47 publications

(43 citation statements)

References 49 publications

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“…In this study, we initially sought to assess the potential capacity of the synthetic cannabinoid WIN55212‐2 to interfere with the polarizing effects imprinted by CPE on human DCs. For that, we employed a well‐defined co‐culture experimental model of hmoDCs and allogeneic naïve CD4 + T cells, which allowed us to study how human DCs condition T‐cell polarization in a non‐antigen‐specific manner 33–35 …”

Section: Discussionmentioning

confidence: 99%

“…the synthetic cannabinoid WIN55212-2 to interfere with the polarizing effects imprinted by CPE on human DCs. For that, we employed a well-defined co-culture experimental model of hmoDCs and allogeneic naïve CD4 + T cells, which allowed us to study how human DCs condition T-cell polarization in a non-antigen-specific manner [33][34][35]. WIN55212-2 significantly impairs the expression of costimulatory molecules and proinflammatory cytokines induced by CPE-stimulated hmoDCs.…”

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confidence: 99%

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Cannabinoid WIN55212‐2 impairs peanut‐allergic sensitization and promotes the generation of allergen‐specific regulatory T cells

Angelina

Jiménez‐Saiz

Pérez‐Diego

et al. 2022

Clin Experimental Allergy

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Background: Cannabinoids are lipid-derived mediators with anti-inflammatory properties in different diseases. WIN55212-2, a non-selective synthetic cannabinoid, reduces immediate anaphylactic reactions in a mouse model of peanut allergy, but its capacity to prevent peanut-allergic sensitization and the underlying mechanisms remains largely unknown.Objective: To investigate the capacity of WIN55212-2 to immunomodulate peanutstimulated human dendritic cells (DCs) and peanut-allergic sensitization in mice. Methods: Surface markers and cytokines were quantified by flow cytometry, ELISA and qPCR in human monocyte-derived DCs (hmoDCs) and T-cell cocultures after stimulation with peanut alone or in the presence of WIN55212-2. Mice were epicutaneously sensitized with peanut alone or peanut/WIN55212-2. After peanut challenge, drop in body temperature, haematocrit, clinical symptoms, peanut-specific antibodies in serum and FOXP3 + regulatory (Treg) cells in spleen and lymph nodes were quantified. Splenocytes were stimulated in vitro with peanut to analyse allergen-specific T-cell responses. Results: WIN55212-2 reduced peanut-induced hmoDC activation and promoted the generation of CD4 + CD127 − CD25 + FOXP3 + Treg cells, while reducing the induction of IL-5-producing T cells. In vivo, WIN55212-2 impaired the peanut-induced migration of DCs to lymph nodes and their maturation. WIN55212-2 significantly reduced the induction of peanut-specific IgE and IgG 1 antibodies in serum during epicutaneous peanut sensitization, reduced the clinical symptoms score upon peanut challenge and promoted the generation of allergen-specific FOXP3 + Treg cells. Conclusions:The synthetic cannabinoid WIN55212-2 interferes with peanut sensitization and promotes tolerogenic responses, which might well pave the way for the development of novel prophylactic and therapeutic strategies for peanut allergy.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Cannabinoid WIN55212‐2 impairs peanut‐allergic sensitization and promotes the generation of allergen‐specific regulatory T cells

Angelina

Jiménez‐Saiz

Pérez‐Diego

et al. 2022

Clin Experimental Allergy

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“…14 In addition of being hypoallergenic, 14,15 PM-allergoids target dendritic cells by binding to C-type lectin receptors through their mannan moiety, which are rapidly and efficiently taken up by these cells. 16,17 Preclinical data indicate that PM-allergoids induce tolerogenic dendritic cells and macrophages capable of promoting Treg-cell responses in vitro 15,[18][19][20] and in vivo, whether administered subcutaneously (SC) 15,20 or sublingually (SL), 17 thus, with promising potential for AIT. 21 A pilot study in veterinary medicine indicated that SC immunotherapy with PM-allergoids (D. farinae) was safe and successful in the treatment of canine atopic dermatitis.…”

Section: G R a P H I C A L Abstractmentioning

confidence: 99%

First‐in‐human phase 2 trial with mite allergoids coupled to mannan in subcutaneous and sublingual immunotherapy

Nieto

Mazón

Nieto

et al. 2022

Allergy

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Background Polymerized allergens conjugated to non‐oxidized mannan (PM‐allergoids) are novel vaccines targeting dendritic cells (DCs). Previous experimental data indicate that PM‐allergoids are readily taken up by DCs and induce Treg cells. This first‐in‐human study was aimed to evaluate safety and to find the optimal dose of house dust mite PM‐allergoid (PM‐HDM) administered subcutaneously (SC) or sublingually (SL). Methods In a randomized, double‐blind, double‐dummy, placebo‐controlled trial, 196 subjects received placebo or PM‐HDM at 500, 1000, 3000, or 5000 mannan‐conjugated therapeutic units (mTU)/mL in 9‐arm groups for 4 months. All subjects received 5 SC doses (0.5 ml each) every 30 days plus 0.2 ml SL daily. The primary efficacy outcome was the improvement of titrated nasal provocation tests (NPT) with D. pteronyssinus at baseline and at the end of the study. All adverse events and reactions were recorded and assessed. Secondary outcomes were the combination of symptom and medication scores (CSMS) and serological markers. Results No moderate or severe adverse reactions were reported. Subjects improving the NPT after treatment ranged from 45% to 62% in active SC, 44% to 61% in active SL and 16% in placebo groups. Statistical differences between placebo and active groups were all significant above 500 mTU, being the highest with 3000 mTU SL (p = 0.004) and 5000 mTU SC (p = 0.011). CSMS improvement over placebo reached 70% (p < 0.001) in active 3000 mTU SC and 40% (p = 0.015) in 5000 mTU SL groups. Conclusions PM‐HDM immunotherapy was safe and successful in achieving primary and secondary clinical outcomes in SC and SL at either 3000 or 5000 mTU/ml.

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“…2,3 We recently demonstrated that PM reprogram monocytes from healthy donors and allergic patients into tolerogenic DCs via epigenetic and metabolic reprogramming. 4 However, their capacity to regulate macrophage polarization remains unknown. Macrophages (MØ) exhibit sufficient cell plasticity to be able to polarize into different phenotypes, from pro-inflammatory, pathogen-eliminating, and subsequent tissue-damaging to antiinflammatory or more regulatory profiles.…”

Section: Allergoid-mannan Conjugates Imprint Tolerogenic Features In ...mentioning

confidence: 99%

“…Cluster analysis is a popular unsupervised machine learning (ML) method for discovering previously undetected data patterns. 4 ML-based cluster analysis has been used in several diseases for the identification and characterization of patient subgroups. 5,6 As of now, no study has attempted to identify CU subtypes with this method.…”

Section: S U Pp O Rti N G I N Fo R M Ati O Nmentioning

confidence: 99%

Allergoid‐mannan conjugates imprint tolerogenic features in human macrophages

Benito-Villalvilla

Pérez‐Diego

Subiza

et al. 2021

Allergy

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Allergoid–mannan conjugates reprogram monocytes into tolerogenic dendritic cells via epigenetic and metabolic rewiring

Abstract: DCs: Dendritic cells; SOCS: Suppressor of cytokine signaling; HDACs: Histone deacetylases;Mannan-tolDCs: Tolerogenic DCs generated by allergoid-mannan conjugates Allergoid-mannan conjugates reprogram monocytes into tolerogenic DCsT cell naïve

Cited by 47 publications

References 49 publications

Cannabinoid WIN55212‐2 impairs peanut‐allergic sensitization and promotes the generation of allergen‐specific regulatory T cells

Cannabinoid WIN55212‐2 impairs peanut‐allergic sensitization and promotes the generation of allergen‐specific regulatory T cells

First‐in‐human phase 2 trial with mite allergoids coupled to mannan in subcutaneous and sublingual immunotherapy

Allergoid‐mannan conjugates imprint tolerogenic features in human macrophages

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