The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, People's Republic of China.
Int J Nanomedicine. 2022 Apr 13;17:1711-1724. doi: 10.2147/IJN.S349360. eCollection 2022.
Effector T cells, especially T helper 1 (Th1) cells and T helper 17 (Th17) cells, are involved in the pathogenesis of many autoimmune diseases such as uveitis. Under hyperactive immune conditions, these effector T cells pathologically maintain a high expression level of programmed cell death protein 1 (PD-1) receptors and distinctively engage aerobic glycolysis via cellular energy metabolism mediated by pyruvate kinase M2 (PKM2). Therefore, we proposed that the synergy of metabolic inhibition and receptor guidance might target and down-regulate these hyperactive effector T cells to achieve anti-immune effects.
PD-1 antibody and TEPP-46 were integrated by polyethylene glycol (PEG) modified poly (lactic-co-glycolic acid) (PLGA) as a nanoplatform (TPP). Characteristics of TPP were basically detected. The biosafety of TPP was evaluated in vitro and in vivo. The targeting effect of TPP was detected by laser scanning confocal microscopy and flow cytometry (FCM). Interleukin-2 (IL-2)/interleukin-17A (IL-17A)/interferon-gamma (IFN-γ) producing cells were detected by FCM. Experimental autoimmune uveoretinitis (EAU) was induced in C57BL/6J mice as the inflammatory model.
TPP had homogeneous distribution, good stability in vitro, and high biosafety in vitro and in vivo. Encapsulated TEPP-46 showed a sustained release profile with burst, steady and slow release periods. Early activation and proliferation of effector T cells was inhibited by TPP treatment in vitro. Th1 and Th17 cells were suppressed by TPP in vitro and in vivo. EAU was alleviated in mice by systemic administration of TPP.
The novel nanoplatform TPP could suppress Th1 and Th17 cells and exhibited an anti-inflammatory effect on EAU, providing an alternative approach to ameliorate autoimmune diseases mediated by these cells.
效应 T 细胞，特别是辅助性 T 细胞 1（Th1）和辅助性 T 细胞 17（Th17），参与了许多自身免疫性疾病的发病机制，如葡萄膜炎。在过度活跃的免疫条件下，这些效应 T 细胞病理性地保持高水平的程序性细胞死亡蛋白 1（PD-1）受体表达，并通过丙酮酸激酶 M2（PKM2）介导的细胞能量代谢明显参与有氧糖酵解。因此，我们提出代谢抑制和受体导向的协同作用可能靶向并下调这些过度活跃的效应 T 细胞，以实现免疫抑制作用。
PD-1 抗体和 TEPP-46 通过聚乙二醇（PEG）修饰的聚（乳酸-共-羟基乙酸）（PLGA）作为纳米平台（TPP）整合。基本检测了 TPP 的特征。通过激光扫描共聚焦显微镜和流式细胞术（FCM）评估 TPP 的生物安全性。通过激光扫描共聚焦显微镜和流式细胞术（FCM）检测 TPP 的靶向效果。通过流式细胞术（FCM）检测白细胞介素-2（IL-2）/白细胞介素-17A（IL-17A）/干扰素-γ（IFN-γ）产生细胞。在 C57BL/6J 小鼠中诱导实验性自身免疫性葡萄膜炎（EAU）作为炎症模型。
TPP 分布均匀，具有良好的体外稳定性，具有较高的体外和体内生物安全性。包封的 TEPP-46 表现出具有爆发、稳定和缓慢释放期的持续释放曲线。TPP 处理可抑制体外效应 T 细胞的早期激活和增殖。TPP 在体外和体内均抑制 Th1 和 Th17 细胞。TPP 全身给药可缓解小鼠 EAU。
新型纳米平台 TPP 可抑制 Th1 和 Th17 细胞，并对 EAU 具有抗炎作用，为改善这些细胞介导的自身免疫性疾病提供了一种替代方法。
