Abstract：
The scavenging ability of cerium oxide nanoparticles (CeNPs) for reactive oxygen species has been intensively studied in the field of catalysis. However, the immunological impact of these particles has not yet been thoroughly investigated, despite intensive research indicating that modulation of the reactive oxygen species could potentially regulate cell fate and adaptive immune responses. In this study, we examined the intrinsic capability of CeNPs to induce tolerogenic dendritic cells via their reactive oxygen species-scavenging effect when the autoantigenic peptides were simply mixed with CeNPs. CeNPs effectively reduced the intracellular reactive oxygen species levels in dendritic cells in vitro, leading to the suppression of costimulatory molecules as well as NLRP3 inflammasome activation, even in the presence of pro-inflammatory stimuli. Subcutaneously administrated PEGylated CeNPs were predominantly taken up by antigen-presenting cells in lymph nodes and to suppress cell maturation in vivo. The administration of a mixture of PEGylated CeNPs and myelin oligodendrocyte glycoprotein peptides, a well-identified autoantigen associated with antimyelin autoimmunity, resulted in the generation of antigen-specific Foxp3+ regulatory T cells in mouse spleens. The induced peripheral regulatory T cells actively inhibited the infiltration of autoreactive T cells and antigen-presenting cells into the central nervous system, ultimately protecting animals from experimental autoimmune encephalomyelitis when tested using a mouse model mimicking human multiple sclerosis. Overall, our findings reveal the potential of CeNPs for generating antigen-specific immune tolerance to prevent multiple sclerosis, opening an avenue to restore immune tolerance against specific antigens by simply mixing the well-identified autoantigens with the immunosuppressive CeNPs.
摘要：
氧化铈纳米颗粒(CeNPs)对活性氧的清除能力在催化领域得到了广泛的研究。然而,这些颗粒的免疫学影响尚未得到彻底研究，尽管大量研究表明，活性氧的调节可能潜在地调节细胞命运和适应性免疫反应。在这项研究中,我们检查了当自身抗原肽与CeNP简单混合时，CeNP通过其活性氧清除作用诱导耐受性树突状细胞的内在能力。CeNPs有效降低体外树突状细胞的细胞内活性氧水平,导致共刺激分子的抑制以及NLRP3炎性体的激活，即使在促炎刺激的存在。皮下施用的PEG化的CeNP主要被淋巴结中的抗原呈递细胞摄取,并在体内抑制细胞成熟。聚乙二醇化CeNP和髓鞘少突胶质细胞糖蛋白肽的混合物的给药，一种与抗髓鞘素自身免疫相关的公认的自身抗原，导致小鼠脾脏中产生抗原特异性Foxp3+调节性T细胞。诱导的外周调节性T细胞积极抑制自身反应性T细胞和抗原呈递细胞向中枢神经系统的浸润，当使用模拟人类多发性硬化症的小鼠模型进行测试时，最终保护动物免受实验性自身免疫性脑脊髓炎的影响。总的来说,我们的发现揭示了CeNPs产生抗原特异性免疫耐受以预防多发性硬化症的潜力，通过简单地将已明确鉴定的自身抗原与免疫抑制CeNP混合，为恢复针对特定抗原的免疫耐受开辟了一条途径。
