Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
J Allergy Clin Immunol. 2017 May;139(5):1608-1620.e3. doi: 10.1016/j.jaci.2016.07.042. Epub 2016 Oct 26.
Anaphylaxis is a life-threatening condition for which we have limited therapeutic options. Although specific immunotherapy for food allergies is becoming more effective, it is still laborious and carries substantial risk of adverse events. On the other hand, regulatory dendritic cell (DC) therapy is effective in mouse models of allergic disease and has been shown to work with T2 cells from atopic asthmatic patients.
We assessed whether DC immunotherapy could reverse food allergen sensitivity in mouse models to provide proof of concept relating to their use in the clinic.
We generated and characterized mature retinoic acid-skewed dendritic cells (DC-RAs) and assessed their abilities to reverse ovalbumin or peanut allergies in mouse models, as well as their operative mechanisms.
DC-RAs displayed a mature yet tolerogenic phenotype, expressing IL-10, TGF-β, IL-27, and aldehyde dehydrogenase 1A2 but not IL-12 or IL-35; IL-10 and TGF-β together drove their suppression of T2 cell proliferation. Delivery of specific allergen-presenting DC-RAs to half-maximally sensitized mice with ovalbumin or peanut allergy reduced anaphylactic responses to oral allergen challenge by 84% to 90%, as well as diarrhea, mast cell activation, and T2 cytokine responses and serum allergen-specific IgE/IgG levels. DC-RA expression of IL-27 was important to their induction of CD25 lymphocyte activation gene 3 (LAG3), CD49b, forkhead box P3 (Foxp3) regulatory T cells in vitro, such that β subunit of IL-27 (Ebi) (ie, IL-27-incompetent) DC-RAs were ineffective in inducing food allergen tolerance.
Our data indicate that regulatory DC immunotherapy can be effective for food allergies and suggest that induction of Foxp3 regulatory T cells might be a useful strategy for tolerance induction in this context.
过敏反应是一种危及生命的疾病，我们的治疗选择有限。虽然针对食物过敏的特异性免疫疗法越来越有效，但它仍然很繁琐，并且有发生不良事件的实质性风险。另一方面，调节树突状细胞（DC）疗法在过敏性疾病的小鼠模型中有效，并已证明可与特应性哮喘患者的 T2 细胞一起发挥作用。
我们评估了 DC 免疫疗法是否可以逆转食物过敏原敏感性，为其在临床上的应用提供概念验证。
我们生成并表征了成熟的视黄酸倾斜的树突状细胞（DC-RAs），并评估了它们在小鼠模型中逆转卵清蛋白或花生过敏的能力，以及它们的作用机制。
DC-RAs 表现出成熟但耐受的表型，表达 IL-10、TGF-β、IL-27 和醛脱氢酶 1A2，但不表达 IL-12 或 IL-35；IL-10 和 TGF-β 共同驱动其抑制 T2 细胞增殖。将特异性过敏原呈递的 DC-RAs 递送至半最大程度致敏的卵清蛋白或花生过敏小鼠中，可将口服过敏原挑战的过敏反应降低 84%至 90%，同时减少腹泻、肥大细胞活化和 T2 细胞因子反应以及血清过敏原特异性 IgE/IgG 水平。IL-27 的 DC-RA 表达对于诱导 CD25 淋巴细胞激活基因 3（LAG3）、CD49b、叉头框 P3（Foxp3）调节性 T 细胞至关重要，因此，IL-27 的β亚基（Ebi）（即，IL-27 无功能）DC-RAs 无法有效诱导食物过敏原耐受。
我们的数据表明，调节性 DC 免疫疗法可有效治疗食物过敏，并表明诱导 Foxp3 调节性 T 细胞可能是这种情况下诱导耐受的一种有用策略。
