McCarthy Derrick P, Yap Jonathan Woon-Teck, Harp Christopher T, Song W Kelsey, Chen Jeane, Pearson Ryan M, Miller Stephen D, Shea Lonnie D
Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Department of Biomedical Engineering, Evanston, IL, USA.
Nanomedicine. 2017 Jan;13(1):191-200. doi: 10.1016/j.nano.2016.09.007. Epub 2016 Oct 6.
Tolerogenic nanoparticles (NPs) are rapidly being developed as specific immunotherapies to treat autoimmune disease. However, many NP-based therapies conjugate antigen (Ag) directly to the NP posing safety concerns due to antibody binding or require the co-delivery of immunosuppressants to induce tolerance. Here, we developed Ag encapsulated NPs comprised of poly(lactide-co-glycolide) [PLG(Ag)] and investigated the mechanism of action for Ag-specific tolerance induction in an autoimmune model of T helper type 1/17 dysfunction - relapse-remitting experimental autoimmune encephalomyelitis (R-EAE). PLG(Ag) completely abrogated disease induction in an organ specific manner, where the spleen was dispensable for tolerance induction. PLG(Ag) delivered intravenously distributed to the liver, associated with macrophages, and recruited Ag-specific T cells. Furthermore, programmed death ligand 1 (PD-L1) was increased on Ag presenting cells and PD-1 blockade lessened tolerance induction. The robust promotion of tolerance by PLG(Ag) without co-delivery of immunosuppressive drugs, suggests that these NPs effectively deliver antigen to endogenous tolerogenic pathways.
耐受性纳米颗粒（NPs）正迅速发展成为治疗自身免疫性疾病的特异性免疫疗法。然而，许多基于NP的疗法将抗原（Ag）直接偶联到NP上，由于抗体结合而引发安全问题，或者需要共同递送免疫抑制剂来诱导耐受性。在此，我们开发了由聚（丙交酯-共-乙交酯）[PLG(Ag)]组成的包封抗原的纳米颗粒，并在1型/17型辅助性T细胞功能障碍的自身免疫模型——复发缓解型实验性自身免疫性脑脊髓炎（R-EAE）中研究了诱导Ag特异性耐受性的作用机制。PLG(Ag)以器官特异性方式完全消除了疾病诱导，其中脾脏对于耐受性诱导并非必需。静脉注射的PLG(Ag)分布到肝脏，与巨噬细胞相关联，并募集Ag特异性T细胞。此外，抗原呈递细胞上的程序性死亡配体1（PD-L1）增加，而PD-1阻断减弱了耐受性诱导。PLG(Ag)在不共同递送免疫抑制药物的情况下强力促进耐受性，这表明这些纳米颗粒有效地将抗原递送至内源性耐受性途径。
