Kostadinova Atanaska I, Pablos-Tanarro Alba, Diks Mara A P, van Esch Betty C A M, Garssen Johan, Knippels Léon M J, Willemsen Linette E M
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.
Department of Immunology, Nutricia Research, Utrecht, Netherlands.
Front Immunol. 2017 Oct 23;8:1303. doi: 10.3389/fimmu.2017.01303. eCollection 2017.
Cow's milk allergy (CMA) prevails in infants and brings increased risk of developing other allergic diseases. Oral administration of specific β-lactoglobulin (BLG)-derived peptides (PepMix) and a specific blend of short- and long-chain fructo-oligosaccharides and M-16V (FF/) was found to partially prevent CMA development in mice. In this study, we aimed to expand the knowledge on the preventive potential and the underlying mechanisms of this approach. Three-week-old female C3H/HeOuJ mice were orally exposed to PepMix±FF/ prior to a 5-week oral sensitization with whole whey and cholera toxin as an adjuvant. The acute allergic skin response was determined after an intradermal challenge with whole whey protein. Following an oral challenge with whey, regulatory T cells (T) in the small intestine lamina propria (SI-LP) and mRNA expression of immune markers in the Peyer's patches (PP) were investigated. The early impact of PepMix and FF/ interventions on the immune system during the oral tolerance (OT) induction phase was investigated after the last OT administration. Pre-exposing mice to PepMix+FF/ partially prevented the acute allergic skin response compared to PBS and increased T and activated T cells in the SI-LP compared to sham-sensitized mice. It also increased the mRNA expression of Tbet over GATA3 in the PP of whey-sensitized mice. Directly upon the 6-day OT phase, FF/ intervention enhanced cecal content levels of propionic and butyric acid in PepMix-fed mice and the former was positively correlated with Foxp3 cell numbers in the colon. In the PP of PepMix+FF/-exposed mice, IL-22 mRNA expression increased and IL-10 followed the same tendency, while the Foxp3 expression was increased over GATA3 and RorγT. In the colon, the Tbet mRNA expression increased over GATA3, while IL-22 decreased. In addition, the Foxp3/GATA3 and regulatory/effector T cell ratios in the mesenteric lymph nodes and the CD11b/CD11b conventional dendritic cells ratio in the SI-LP were increased. In conclusion, the FF/ diet facilitates the capacity of the specific BLG-peptides to partially prevent the allergic response after sensitization to whole whey protein, possibly by creating a tolerance-prone environment during the OT phase. Such a dietary intervention might contribute to tailoring successful strategies for CMA prevention.
牛奶过敏（CMA）在婴儿中普遍存在，并增加了患其他过敏性疾病的风险。研究发现，口服特定的β-乳球蛋白（BLG）衍生肽（PepMix）以及短链和长链低聚果糖与M-16V的特定混合物（FF/）可部分预防小鼠发生CMA。在本研究中，我们旨在扩展对该方法预防潜力及其潜在机制的认识。将3周龄雌性C3H/HeOuJ小鼠在以全乳清和霍乱毒素作为佐剂进行为期5周的口服致敏之前，口服给予PepMix±FF/。在用全乳清蛋白进行皮内激发后，测定急性过敏性皮肤反应。在用乳清进行口服激发后，研究小肠固有层（SI-LP）中的调节性T细胞（T）以及派尔集合淋巴结（PP）中免疫标志物的mRNA表达。在最后一次口服耐受（OT）给药后，研究PepMix和FF/干预对OT诱导期免疫系统的早期影响。与PBS相比，预先将小鼠暴露于PepMix+FF/可部分预防急性过敏性皮肤反应，并且与假致敏小鼠相比，SI-LP中的T细胞和活化T细胞增加。它还增加了乳清致敏小鼠PP中Tbet相对于GATA3的mRNA表达。在6天的OT期刚结束时，FF/干预提高了PepMix喂养小鼠盲肠内容物中丙酸和丁酸的水平，并且前者与结肠中Foxp3细胞数量呈正相关。在暴露于PepMix+FF/的小鼠的PP中，IL-22 mRNA表达增加，IL-10呈现相同趋势，而Foxp3表达相对于GATA3和RorγT增加。在结肠中，Tbet mRNA表达相对于GATA3增加，而IL-22减少。此外，肠系膜淋巴结中的Foxp3/GATA3以及调节性/效应性T细胞比率和SI-LP中的CD11b/CD11b传统树突状细胞比率增加。总之，FF/饮食可能通过在OT期创造一个易于产生耐受的环境，促进特定BLG肽部分预防对全乳清蛋白致敏后的过敏反应的能力。这种饮食干预可能有助于制定成功的CMA预防策略。
