PD-1 Targeted Nanoparticles Inhibit Activated T Cells and Alleviate Autoimmunity via Suppression of Cellular Energy Metabolism Mediated by PKM2

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.