Division of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.
Front Immunol. 2023 Jan 6;13:1053107. doi: 10.3389/fimmu.2022.1053107. eCollection 2022.
Cow's milk allergy is a common food allergy among infants. Improved hygiene conditions and loss of microbial diversity are associated with increased risk of allergy development. The intestinal immune system is essential for oral tolerance induction. In this respect, bacterial CpG DNA is known to drive Th1 and regulatory T-cell (Treg) development Toll-Like-Receptor 9 (TLR-9) signaling, skewing away from the allergic Th2 phenotype. We aimed to induce allergen specific tolerance oral delivery of poly (lactic-co-glycolic acid) nanoparticles (NP) co-encapsulated with a selected β-lactoglobulin derived peptide (BLG-Pep) and TLR-9 ligand CpG oligodeoxynucleotide (CpG). , 3-4-week-old female C3H/HeOuJ mice housed in individually ventilated cages received 6-consecutive-daily gavages of either PBS, whey, BLG-Pep/NP, CpG/NP, a mixture of BLG-Pep/NP plus CpG/NP or co-encapsulated BLG-Pep+CpG/NP, before 5-weekly oral sensitizations with whey plus cholera toxin (CT) or only CT (sham) and were challenged with whey 5 days after the last sensitization. The co-encapsulated BLG-Pep+CpG/NP pretreatment, but not BLG-Pep/NP, CpG/NP or the mixture of BLG-Pep/NP plus CpG/NP, prevented the whey-induced allergic skin reactivity and prevented rise in serum BLG-specific IgE compared to whey-sensitized mice. Importantly, co-encapsulated BLG-Pep+CpG/NP pretreatment reduced dendritic cell (DC) activation and lowered the frequencies of PD-L1+ DC in the mesenteric lymph nodes compared to whey-sensitized mice. By contrast, co-encapsulated BLG-Pep+CpG/NP pretreatment increased the frequency of splenic PD-L1+ DC compared to the BLG-Pep/NP plus CpG/NP recipients, in association with lower Th2 development and increased Treg/Th2 and Th1/Th2 ratios in the spleen. Oral administration of PLGA NP co-encapsulated with BLG-Pep and CpG prevented rise in serum BLG-specific IgE and symptom development while lowering splenic Th2 cell frequency in these mice which were kept under strict hygienic conditions.
牛奶过敏是婴儿常见的食物过敏。卫生条件的改善和微生物多样性的丧失与过敏发展风险的增加有关。肠道免疫系统对于诱导口服耐受至关重要。在这方面，细菌 CpG DNA 已知可驱动 Th1 和调节性 T 细胞（Treg）的发育，从而偏向于非过敏的 Th2 表型。我们旨在通过口服递送聚（乳酸-共-乙醇酸）纳米颗粒（NP）来诱导过敏原特异性耐受，该 NP 共包封了选定的β-乳球蛋白衍生肽（BLG-Pep）和 Toll 样受体 9（TLR-9）配体 CpG 寡脱氧核苷酸（CpG）。3-4 周龄的雌性 C3H/HeOuJ 小鼠饲养在单独通风的笼子中，接受 6 次连续每日灌胃 PBS、乳清蛋白、BLG-Pep/NP、CpG/NP、BLG-Pep/NP 加 CpG/NP 的混合物或共包封的 BLG-Pep+CpG/NP，然后用乳清蛋白加霍乱毒素（CT）或仅 CT（假）进行 5 周的口服致敏，并在最后一次致敏后 5 天用乳清蛋白进行攻毒。与仅用乳清蛋白致敏的小鼠相比，共包封的 BLG-Pep+CpG/NP 预处理而不是 BLG-Pep/NP、CpG/NP 或 BLG-Pep/NP 加 CpG/NP 的混合物，可预防乳清诱导的过敏皮肤反应，并可预防血清 BLG 特异性 IgE 的升高。重要的是，与用乳清蛋白致敏的小鼠相比，共包封的 BLG-Pep+CpG/NP 预处理可降低肠系膜淋巴结中树突状细胞（DC）的激活，并降低 PD-L1+DC 的频率。相比之下，与 BLG-Pep/NP 加 CpG/NP 受者相比，共包封的 BLG-Pep+CpG/NP 预处理增加了脾 PD-L1+DC 的频率，与较低的 Th2 发育和增加的脾 Treg/Th2 和 Th1/Th2 比值有关。在这些严格保持卫生条件的小鼠中，口服给予共包封 BLG-Pep 和 CpG 的 PLGA NP 可预防血清 BLG 特异性 IgE 的升高和症状的发展，同时降低脾 Th2 细胞的频率。
