College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China.
State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042, China.
Neurotherapeutics. 2019 Apr;16(2):381-393. doi: 10.1007/s13311-019-00718-3.
Nogo-66 receptor (NgR) and paired immunoglobulin-like receptor B (PirB) are two common receptors of various myelin-associated inhibitors (MAIs) and, thus, play an important role in MAIs-induced inhibitory signalling of regeneration following spinal cord injury (SCI). Based on the concept of protective autoimmunity, vaccine approaches could induce the production of antibodies against inhibitors in myelin, such as using purified myelin, spinal cord homogenates, or MAIs receptor NgR, in order to block the inhibitory effects and promote functional recovery in SCI models. However, due to the complication of the molecules and the mechanisms involved in MAIs-mediated inhibitory signalling, these immunotherapy strategies have yielded inconsistent outcomes. Therefore, we hypothesized that the choice and modification of self-antigens, and co-regulating multiple targets, may be more effective in repairing the injured spinal cord and improving functional recovery. In this study, NgR and PirB were selected to construct a double-targeted granulocyte-macrophage colony stimulating factor-NgR-PirB (GMCSF-NgR-PirB) nucleic acid vaccine, and investigate the efficacy of this immunotherapy in a spinal cord injury model in rats. The results showed that this vaccination could stimulate the production of antibodies against NgR and PirB, block the inhibitory effects mediated by various MAIs, and promote nerve regeneration and functional recovery after spinal cord injury. These findings suggest that nucleic acid vaccination against NgR and PirB can be a promising therapeutic strategy for SCI and other central nervous system diseases and injuries.
神经生长抑制因子-66 受体（NgR）和配对免疫球蛋白样受体 B（PirB）是多种髓鞘相关抑制因子（MAIs）的共同受体，因此在脊髓损伤（SCI）后再生过程中 MAIs 诱导的抑制信号中发挥重要作用。基于保护性自身免疫的概念，疫苗方法可以诱导针对髓鞘中抑制剂的抗体产生，例如使用纯化的髓鞘、脊髓匀浆或 MAIs 受体 NgR，以阻断抑制作用并促进 SCI 模型中的功能恢复。然而，由于涉及 MAIs 介导的抑制信号的分子和机制的复杂性，这些免疫治疗策略的结果并不一致。因此，我们假设选择和修饰自身抗原以及共同调节多个靶点可能更有效地修复受损的脊髓并改善功能恢复。在这项研究中，选择 NgR 和 PirB 构建了双靶向粒细胞-巨噬细胞集落刺激因子-NgR-PirB（GMCSF-NgR-PirB）核酸疫苗，并在大鼠脊髓损伤模型中研究了这种免疫疗法的疗效。结果表明，这种疫苗接种可以刺激针对 NgR 和 PirB 的抗体产生，阻断各种 MAIs 介导的抑制作用，并促进脊髓损伤后的神经再生和功能恢复。这些发现表明，针对 NgR 和 PirB 的核酸疫苗接种可能成为 SCI 和其他中枢神经系统疾病和损伤的有前途的治疗策略。
