Targeted delivery of antigen to intestinal dendritic cells induces oral tolerance and prevents autoimmune diabetes in NOD mice
Targeted delivery of antigen to intestinal dendritic cells induces oral tolerance and prevents autoimmune diabetes in NOD mice
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DOI：
10.1007/s00125-018-4593-3
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发表时间：
2018-06-01
期刊：
影响因子：
8.2
通讯作者：
Zong, Li
中科院分区：
文献类型：
--
作者：
Chen, Yulin;Wu, Jie;Zong, Li
目的/假设肠道免疫系统是生理诱导免疫耐受的理想靶点。然而，口服蛋白抗原递送的效率受到胃肠道中抗原降解和抗原提呈细胞摄取不良的限制。肠道树突状细胞（dc）是一种专业的抗原呈递细胞，易于诱导抗原特异性免疫耐受。本研究通过口服负载H6P的靶向纳米颗粒（NPs），将抗原热休克蛋白65-6xP277 （H6P）直接递送至NOD小鼠的肠道dc，并研究该抗原诱导免疫耐受以预防NOD小鼠自身免疫性糖尿病的能力。方法研制靶向NP给药系统，包封H6P，评估该系统保护和促进H6P递送至肠道dc的能力。将携带h6p的靶向NPs免疫NOD小鼠，每周口服1次，持续7周，并通过监测血糖水平来评估糖尿病的发生。结果负载H6P的靶向NPs保护了包封的H6P在胃肠道环境中的降解，并显著增加了肠道Peyer's补丁中dc对H6P的摄取（比对照H6P溶液组高4.1倍）。口服h6p靶向NPs疫苗可诱导抗原特异性T细胞耐受，并在100%的NOD小鼠中预防糖尿病。免疫偏差（T辅助[Th]1 to Th2）和CD4(+)CD25(+)FOXP3（+）调节性T细胞参与了免疫耐受的诱导。在这项研究中，我们成功地诱导了NOD小鼠的抗原特异性T细胞耐受，并阻止了糖尿病的发生。据我们所知，这是首次尝试将抗原递送到肠道dc，利用靶向NPs诱导T细胞耐受。
Aims/hypothesis The intestinal immune system is an ideal target to induce immune tolerance physiologically. However, the efficiency of oral protein antigen delivery is limited by degradation of the antigen in the gastrointestinal tract and poor uptake by antigen-presenting cells. Gut dendritic cells (DCs) are professional antigen-presenting cells that are prone to inducing antigen-specific immune tolerance. In this study, we delivered the antigen heat shock protein 65-6xP277 (H6P) directly to the gut DCs of NOD mice through oral vaccination with H6P-loaded targeting nanoparticles (NPs), and investigated the ability of this antigen to induce immune tolerance to prevent autoimmune diabetes in NOD mice.Methods A targeting NP delivery system was developed to encapsulate H6P, and the ability of this system to protect and facilitate H6P delivery to gut DCs was assessed. NOD mice were immunised with H6P-loaded targeting NPs orally once a week for 7 weeks and the onset of diabetes was assessed by monitoring blood glucose levels.Results H6P-loaded targeting NPs protected the encapsulated H6P from degradation in the gastrointestinal tract environment and significantly increased the uptake of H6P by DCs in the gut Peyer's patches (4.1 times higher uptake compared with the control H6P solution group). Oral vaccination with H6P-loaded targeting NPs induced antigen-specific T cell tolerance and prevented diabetes in 100% of NOD mice. Immune deviation (T helper [Th]1 to Th2) and CD4(+)CD25(+)FOXP3(+) regulatory T cells were found to participate in the induction of immune tolerance.Conclusions/interpretation In this study, we successfully induced antigen-specific T cell tolerance and prevented the onset of diabetes in NOD mice. To our knowledge, this is the first attempt at delivering antigen to gut DCs using targeting NPs to induce T cell tolerance.