Tolerogenic nanoparticles suppress central nervous system inflammation
Tolerogenic nanoparticles suppress central nervous system inflammation
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DOI：
10.1073/pnas.2016451117
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发表时间：
2020-12-15
影响因子：
11.1
通讯作者：
Quintana, Francisco J.
中科院分区：
文献类型：
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作者：
Kenison, Jessica E.;Jhaveri, Aditi;Quintana, Francisco J.
诱导免疫耐受的治疗方法仍然是治疗包括多发性硬化症（MS）在内的自身免疫性疾病的未满足的临床需求。基于其在控制免疫反应中的作用，配体激活转录因子芳基烃受体（AhR）是新型免疫疗法的候选靶点。在这里，我们报告了开发 AhR 激活纳米脂质体 (NLP) 以诱导抗原特异性耐受。在预防和治疗设置中，装载有 AhR 激动剂 ITE 和髓磷脂少突胶质细胞糖蛋白 (MOG)(35-55) 的 T 细胞表位的 NLP 可诱导耐受性树突状细胞，并抑制实验性自身免疫性脑脊髓炎 (EAE)（多发性硬化症的临床前模型）的发展。 EAE 抑制与 MOG(35-55) 特异性 FoxP3(+) 调节性 T 细胞（Treg 细胞）和 1 型调节性 T 细胞（Tr1 细胞）的扩增有关，同时伴有中枢神经系统浸润效应 T 细胞（Teff 细胞）的减少。值得注意的是，NLP 在 C57BL/6 x SJL F1 小鼠建立的 EAE 模型中诱导旁观者抑制。此外，NLP 可改善非肥胖糖尿病小鼠的慢性进行性 EAE，该模型在某些方面类似于继发性进行性 MS。总之，这些研究描述了在自身免疫性疾病中治疗诱导抗原特异性耐受的平台。
Therapeutic approaches for the induction of immune tolerance remain an unmet clinical need for the treatment of autoimmune diseases, including multiple sclerosis (MS). Based on its role in the control of the immune response, the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) is a candidate target for novel immunotherapies. Here, we report the development of AhR-activating nanoliposomes (NLPs) to induce antigen-specific tolerance. NLPs loaded with the AhR agonist ITE and a T cell epitope from myelin oligodendrocyte glycoprotein (MOG)(35-55) induced tolerogenic dendritic cells and suppressed the development of experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS, in preventive and therapeutic setups. EAE suppression was associated with the expansion of MOG(35-55)-specific FoxP3(+) regulatory T cells (Treg cells) and type 1 regulatory T cells (Tr1 cells), concomitant with a reduction in central nervous system-infiltrating effector T cells (Teff cells). Notably, NLPs induced bystander suppression in the EAE model established in C57BL/6 x SJL F1 mice. Moreover, NLPs ameliorated chronic progressive EAE in nonobese diabetic mice, a model which resembles some aspects of secondary progressive MS. In summary, these studies describe a platform for the therapeutic induction of antigen-specific tolerance in autoimmune diseases.