BackgroundApproximately 70% of individuals allergic to birch pollen (Bet v 1.01 [Bet]) develop a secondary food allergy (e.g., hazelnut: Cor a 1.04 [Cor]), due to allergen cross‐reactivity. However, standard immunotherapy for type I allergies often does not improve the food allergy sufficiently. We analyzed the allergen‐specific and cross‐reactive suppressive capacity of primary human regulatory T cells (Treg) induced by autologous IL‐10‐modulated dendritic cells (IL‐10 DC) in vitro and in vivo.MethodsCD4+ T cells of patients with birch pollen and associated hazelnut allergies were differentiated into Bet‐specific or non‐specific induced Treg (iTreg). After Bet‐ or Cor‐specific restimulation the phenotype, proliferation, and suppressive capacity of iTreg subsets were analyzed. iTreg function was further investigated in humanized mouse models of airway and intestinal allergy, generated by engraftment of peripheral blood mononuclear cells from allergic donors into immunodeficient animals.ResultsAfter IL‐10 DC priming and allergen‐specific restimulation (Bet or Cor), non‐specific control iTreg remained anergic, whereas Bet‐specific iTreg proliferated extensively and exhibited a regulatory phenotype (enhanced expression of CTLA‐4, PD‐1, TNFR2, IL‐10). Accordingly, activated Bet‐specific iTreg displayed a high capacity to suppress Bet‐ and Cor‐induced responder Th2 cell responses in vitro, indicating induction of both allergen‐specific (birch) and cross‐reactive tolerance (hazelnut). In vivo, the beneficial effect of Bet‐specific iTreg was verified in humanized mouse models of allergic airway and intestinal inflammation, resulting in reduced allergen‐induced clinical symptoms, and immune responses.ConclusionHuman IL‐10 DC‐induced iTreg facilitate allergen‐specific and cross‐reactive tolerance. Therefore, they are potential candidates for regulatory cell therapy in allergic and autoimmune diseases.

中文翻译：

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来自桦树花粉和榛子过敏患者的 IL-10 调节的树突状细胞促进了 Treg 介导的过敏原特异性和交叉反应性耐受性


背景由于过敏原交叉反应性，大约 70% 对桦树花粉过敏的个体 （Bet v 1.01 [Bet]） 会发展为继发性食物过敏（例如，榛子：Cor a 1.04 [Cor]）。然而，针对 I 型过敏的标准免疫疗法通常不能充分改善食物过敏。我们分析了自体 IL-10 调节的树突状细胞 （IL-10 DC） 在体外和体内诱导的原代人调节性 T 细胞 （Treg） 的过敏原特异性和交叉反应性抑制能力。方法将桦树花粉和相关榛子过敏患者的 CD4+ T 细胞分化为 Bet 特异性或非特异性诱导的 Treg （iTreg）。在 Bet 或 Cor-特异性再刺激后，分析 iTreg 亚群的表型、增殖和抑制能力。在气道和肠道过敏的人源化小鼠模型中进一步研究了 iTreg 功能，该模型是通过将过敏供体的外周血单核细胞植入免疫缺陷动物体内产生的。结果IL-10 DC 启动和过敏原特异性再刺激 （Bet 或 Cor） 后，非特异性对照 iTreg 保持无能状态，而 Bet 特异性 iTreg 广泛增殖并表现出调节表型 （CTLA-4 、 PD-1 、 TNFR2 、 IL-10 的表达增强）。因此，激活的 Bet 特异性 iTreg 在体外显示出抑制 Bet 和 Cor 诱导的反应性 Th2 细胞反应的高能力，表明诱导过敏原特异性（桦木）和交叉反应性耐受（榛子）。在体内，Bet 特异性 iTreg 的有益作用在过敏性气道和肠道炎症的人源化小鼠模型中得到验证，从而减少过敏原诱导的临床症状和免疫反应。结论人 IL-10 DC 诱导的 iTreg 促进过敏原特异性和交叉反应性耐受。因此，它们是过敏和自身免疫性疾病中调节细胞治疗的潜在候选者。