Department of Biochemistry and Molecular Biology, School of Chemistry, Complutense University, Madrid, Spain.
Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
J Allergy Clin Immunol. 2022 Jan;149(1):212-222.e9. doi: 10.1016/j.jaci.2021.06.012. Epub 2021 Jun 18.
Allergoid-mannan conjugates are novel vaccines for allergen-specific immunotherapy being currently assayed in phase 2 clinical trials. Allergoid-mannan conjugates target dendritic cells (DCs) and generate functional forkhead box P3 (FOXP3)-positive Treg cells, but their capacity to reprogram monocyte differentiation remains unknown.
We studied whether allergoid-mannan conjugates could reprogram monocyte differentiation into tolerogenic DCs and the underlying molecular mechanisms.
Monocytes from nonatopic and allergic subjects were differentiated into DCs under conventional protocols in the absence or presence of allergoid-mannan conjugates. ELISA, real-time quantitative PCR, coculture, flow cytometry, and suppression assay were performed. Metabolic and epigenetic techniques were also used.
Monocyte differentiation from nonatopic and allergic subjects into DCs in the presence of allergoid-mannan conjugates yields stable tolerogenic DCs. Lipopolysaccharide-stimulated mannan-tolDCs show a significantly lower cytokine production, lower TNF-α/IL-10 ratio, and higher expression of the tolerogenic molecules PDL1, IDO, SOCS1, SOCS3, and IL10; and they induce higher numbers of functional FOXP3 Treg cells than conventional DC counterparts. Mannan-tolDCs shift glucose metabolism from Warburg effect and lactate production to mitochondrial oxidative phosphorylation. They also display epigenetic reprogramming involving specific histone marks within tolerogenic loci and lower expression levels of histone deacetylase genes. Mannan-tolDCs significantly increase the expression of the anti-inflammatory miRNA-146a/b and decrease proinflammatory miRNA-155.
Allergoid-mannan conjugates reprogram monocyte differentiation into stable tolerogenic DCs via epigenetic and metabolic reprogramming. Our findings shed light on the novel mechanisms by which allergoid-mannan conjugates might contribute to allergen tolerance induction during allergen-specific immunotherapy.
变应原甘露聚糖缀合物是目前正在进行 2 期临床试验的新型变应原特异性免疫治疗疫苗。变应原甘露聚糖缀合物靶向树突状细胞（DC）并产生功能性叉头框 P3（FOXP3）阳性 Treg 细胞，但它们改变单核细胞分化的能力尚不清楚。
我们研究了变应原甘露聚糖缀合物是否可以将单核细胞分化为耐受性 DC，并探讨其潜在的分子机制。
非变应性和变应性个体的单核细胞在无变应原甘露聚糖缀合物或存在变应原甘露聚糖缀合物的情况下，根据常规方案分化为 DC。进行 ELISA、实时定量 PCR、共培养、流式细胞术和抑制试验。还使用了代谢和表观遗传技术。
非变应性和变应性个体的单核细胞在变应原甘露聚糖缀合物存在下分化为 DC 可产生稳定的耐受性 DC。脂多糖刺激的甘露聚糖-tolDC 表现出明显较低的细胞因子产生、较低的 TNF-α/IL-10 比值和较高的耐受性分子 PDL1、IDO、SOCS1、SOCS3 和 IL10 表达；并且与传统 DC 相比，它们诱导更多数量的功能性 FOXP3 Treg 细胞。甘露聚糖-tolDC 将葡萄糖代谢从瓦伯格效应和乳酸产生转变为线粒体氧化磷酸化。它们还显示出表观遗传重编程，涉及耐受性基因座中的特定组蛋白标记和组蛋白去乙酰化酶基因的较低表达水平。甘露聚糖-tolDC 显著增加抗炎 miRNA-146a/b 的表达并降低促炎 miRNA-155 的表达。
变应原甘露聚糖缀合物通过表观遗传和代谢重编程将单核细胞分化为稳定的耐受性 DC。我们的发现揭示了变应原甘露聚糖缀合物在变应原特异性免疫治疗期间诱导变应原耐受的新机制。
