Vonk Marlotte M, Wagenaar Laura, Pieters Raymond H H, Knippels Leon M J, Willemsen Linette E M, Smit Joost J, van Esch Betty C A M, Garssen Johan
Department of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
Immunology Platform, Nutricia Research, Utrecht, The Netherlands.
Clin Transl Allergy. 2017 Sep 29;7:35. doi: 10.1186/s13601-017-0170-y. eCollection 2017.
Antigen-specific immunotherapy (AIT) is a promising therapeutic approach for both cow's milk allergy (CMA) and peanut allergy (PNA), but needs optimization in terms of efficacy and safety.
Compare oral immunotherapy (OIT) and subcutaneous immunotherapy (SCIT) in murine models for CMA and PNA and determine the dose of allergen needed to effectively modify parameters of allergy.
Female C3H/HeOuJ mice were sensitized intragastrically (i.g.) to whey or peanut extract with cholera toxin. Mice were treated orally (5 times/week) or subcutaneously (3 times/week) for three consecutive weeks. Hereafter, the acute allergic skin response, anaphylactic shock symptoms and body temperature were measured upon intradermal (i.d.) and intraperitoneal (i.p.) challenge, and mast cell degranulation was measured upon i.g. challenge. Allergen-specific IgE, IgG1 and IgG2a were measured in serum at different time points. Single cell suspensions derived from lymph organs were stimulated with allergen to induce cytokine production and T cell phenotypes were assessed using flow cytometry.
Both OIT and SCIT decreased clinically related signs upon challenge in the CMA and PNA model. Interestingly, a rise in allergen-specific IgE was observed during immunotherapy, hereafter, treated mice were protected against the increase in IgE caused by allergen challenge. Allergen-specific IgG1 and IgG2a increased due to both types of AIT. In the CMA model, SCIT and OIT reduced the percentage of activated Th2 cells and increased the percentage of activated Th1 cells in the spleen. OIT increased the percentage of regulatory T cells (Tregs) and activated Th2 cells in the MLN. Th2 cytokines IL-5, IL-13 and IL-10 were reduced after OIT, but not after SCIT. In the PNA model, no differences were observed in percentages of T cell subsets. SCIT induced Th2 cytokines IL-5 and IL-10, whereas OIT had no effect.
We have shown clinical protection against allergic manifestations after OIT and SCIT in a CMA and PNA model. Although similar allergen-specific antibody patterns were observed, differences in T cell and cytokine responses were shown. Whether these findings are related to a different mechanism of AIT in CMA and PNA needs to be elucidated.
抗原特异性免疫疗法（AIT）是一种针对牛奶过敏（CMA）和花生过敏（PNA）都很有前景的治疗方法，但在疗效和安全性方面需要优化。
在CMA和PNA的小鼠模型中比较口服免疫疗法（OIT）和皮下免疫疗法（SCIT），并确定有效改变过敏参数所需的过敏原剂量。
将雌性C3H/HeOuJ小鼠通过胃内（i.g.）给予乳清或花生提取物并添加霍乱毒素进行致敏。小鼠连续三周每周口服（5次/周）或皮下注射（3次/周）进行治疗。此后，在皮内（i.d.）和腹腔内（i.p.）激发后测量急性过敏皮肤反应、过敏性休克症状和体温，并在胃内（i.g.）激发后测量肥大细胞脱颗粒。在不同时间点测量血清中的过敏原特异性IgE、IgG1和IgG2a。用过敏原刺激来自淋巴器官的单细胞悬液以诱导细胞因子产生，并使用流式细胞术评估T细胞表型。
在CMA和PNA模型中，OIT和SCIT在激发后均降低了临床相关体征。有趣的是，在免疫治疗期间观察到过敏原特异性IgE升高，此后，治疗后的小鼠对过敏原激发引起的IgE增加具有保护作用。由于两种类型的AIT，过敏原特异性IgG1和IgG2a均增加。在CMA模型中，SCIT和OIT降低了脾脏中活化Th2细胞的百分比并增加了活化Th1细胞的百分比。OIT增加了肠系膜淋巴结（MLN）中调节性T细胞（Tregs）和活化Th2细胞的百分比。OIT后Th2细胞因子IL-5、IL-13和IL-10减少，但SCIT后未减少。在PNA模型中，未观察到T细胞亚群百分比的差异。SCIT诱导Th2细胞因子IL-5和IL-10，而OIT无作用。
我们已经证明在CMA和PNA模型中，OIT和SCIT后对过敏表现具有临床保护作用。尽管观察到相似的过敏原特异性抗体模式，但T细胞和细胞因子反应存在差异。这些发现是否与CMA和PNA中AIT的不同机制相关需要进一步阐明。
