Huanjin Liao, Xia Peng, Yue Yin, Yiqing Ge, Yanning Li, Juan Wang, Jia Li, Lihui Lin, Li Li, Guogang Xie
Department of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
Department of Laboratory Medicine, Shanghai Chest Hospital Affiliated Shanghai Jiao Tong University, Shanghai, 200030, China.
Inflammation. 2025 May 14. doi: 10.1007/s10753-025-02307-3.
Allergen immunotherapy (AIT) is the only treatment that can alter the course of allergic diseases by inducing immune tolerance through long-term, repeated low-dose allergen exposure. Nonetheless, AIT persistently faces challenges necessitating resolution, particularly in relation to treatment duration, the incidence of adverse reactions, and patient adherence. Extracellular vesicles (EVs) are promising drug delivery carriers for medications, vaccines, and targeted antibodies. Previously, we demonstrated that intravenous bone marrow-derived mast cell EVs (BMMC-EVs) can reduce allergic airway inflammation in asthmatic mice by interacting with free IgE. This study explores the potential of intranasally administered BMMC-EVs loaded with dermatophagoides farinae extracts to induce local immune tolerance and more effectively alleviate allergic asthma in mice. BMMC were co-cultured with the crude extract of dermatophagoides farina (DfE). BMMC-EVs-DfE were obtained and analyzed for the presence and concentration of DfE. The allergic asthma model was sensitized by intraperitoneal injection of DfE and Al(OH) in BALB/c mice. Mice were immunized with PBS, BMMC-EVs-DfE, BMMC-EVs, and DfE intranasally. Then, mice were challenged with DfE after treatment. Effects of immunization were analyzed based on lung histology, bronchoalveolar lavage cell counts, lung cytokine levels, and plasma antibody levels. There were no deaths or signs of systemic toxicity noted in association with the BMMC-EVs-DfE, BMMC-EVs, and DfE immunized mice. BMMC-EVs-DfE immunization could decrease the total cells, macrophages and eosinophils number in bronchoalveolar lavage fluid (BALF), and attenuate goblet cell hyperplasia and MUC5AC expression in lung tissue. DfE specific IgE and IgG3 antibody, and histamine levels were significantly suppressed by BMMC-EVs-DfE immunization, while DfE specific IgG1 and IgG2a levels were increased. Moreover, BMMC-EVs-DfE can regulate the Th1/Th2 balance toward Th1 via increasing the IFN-γ and decreasing the IL-4 levels. We demonstrate here that BMMC-EVs-DfE could efficiently prevent allergic asthma inflammation, rebuild Th1/Th2 balance, reduce goblet hyperplasia and mucus production. BMMC-EVs-DfE as a platform for allergen delivery that effectively inhibits asthma airway inflammation.
变应原免疫疗法（AIT）是唯一一种可通过长期、反复低剂量接触变应原诱导免疫耐受来改变过敏性疾病病程的治疗方法。尽管如此，AIT一直面临着亟待解决的挑战，尤其是在治疗持续时间、不良反应发生率和患者依从性方面。细胞外囊泡（EVs）是用于药物、疫苗和靶向抗体的很有前景的药物递送载体。此前，我们证明静脉注射骨髓来源的肥大细胞EVs（BMMC-EVs）可通过与游离IgE相互作用减轻哮喘小鼠的过敏性气道炎症。本研究探讨经鼻给予负载粉尘螨提取物的BMMC-EVs诱导局部免疫耐受并更有效减轻小鼠过敏性哮喘的潜力。将BMMC与粉尘螨粗提物（DfE）共培养。获得BMMC-EVs-DfE并分析其中DfE的存在情况和浓度。通过在BALB/c小鼠腹腔注射DfE和氢氧化铝建立过敏性哮喘模型。小鼠经鼻用PBS、BMMC-EVs-DfE、BMMC-EVs和DfE进行免疫。然后，治疗后用DfE对小鼠进行激发。基于肺组织学、支气管肺泡灌洗细胞计数、肺细胞因子水平和血浆抗体水平分析免疫效果。与接受BMMC-EVs-DfE、BMMC-EVs和DfE免疫的小鼠相关，未观察到死亡或全身毒性迹象。BMMC-EVs-DfE免疫可减少支气管肺泡灌洗液（BALF）中的总细胞、巨噬细胞和嗜酸性粒细胞数量，并减轻肺组织中杯状细胞增生和MUC5AC表达。BMMC-EVs-DfE免疫显著抑制DfE特异性IgE和IgG3抗体以及组胺水平，同时提高DfE特异性IgG1和IgG2a水平。此外，BMMC-EVs-DfE可通过增加IFN-γ水平和降低IL-4水平将Th1/Th2平衡调节至Th1方向。我们在此证明BMMC-EVs-DfE可有效预防过敏性哮喘炎症，重建Th1/Th2平衡，减少杯状细胞增生和黏液产生。BMMC-EVs-DfE作为一种变应原递送平台可有效抑制哮喘气道炎症。
