State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Biomaterials. 2011 Nov;32(31):7988-98. doi: 10.1016/j.biomaterials.2011.07.009. Epub 2011 Jul 23.
As a common receptor for three myelin associated inhibitors, Nogo-66 receptor (NgR) mediates their inhibitory activities on neurite outgrowth in the adult mammalian central nervous system (CNS). Therapeutic vaccination protocol targeting NgR emulsified with Freund's adjuvant (FA) has been used in spinal cord injury (SCI) models. However, the vaccine emulsified with FA may induce some side effects, which are not suitable for further clinical application. As an adjuvant, gold nanoparticles (GNPs) could stimulate a stronger immune response without producing detectable toxicity and physiological damage than FA. There is, however, uncertainty regarding the efficacy of axon regeneration and neuroprotection in vaccines with GNPs as an adjuvant. In this investigation, a recombinant protein vaccine targeting NgR, human NgR-Fc (hNgR-Fc) fusion protein conjugated with 15 nm GNPs was prepared and its effects on axonal regeneration and functional recovery in spinal cord-injured rats were investigated. The results showed that adult rats immunized with the protein vaccine produced higher titers of anti-NgR antibody than that with FA, and the antisera promoted neurite outgrowth in presence of MAG in vitro. In a spinal cord dorsal hemisection model, vaccine immunized with GNPs promoted axonal regeneration more effectively than FA, resulted in significant protection from neuronal loss, and improved functional recovery. Thus, as an adjuvant, 15 nm GNPs can effectively boost the immunogenicity of hNgR-Fc protein vaccine, and promote the repair of spinal cord-injured rats. The utilization of GNPs, for clinical considerations, may be a more beneficial supplement than FA to the promising therapeutic vaccination strategy for promoting SCI repair.
作为三种髓鞘相关抑制剂的共同受体，Nogo-66 受体（NgR）介导它们在成年哺乳动物中枢神经系统（CNS）中的抑制性神经突生长活性。针对 NgR 用弗氏佐剂（FA）乳化的治疗性疫苗方案已用于脊髓损伤（SCI）模型。然而，用 FA 乳化的疫苗可能会引起一些副作用，这不适合进一步的临床应用。作为佐剂，金纳米颗粒（GNPs）可以刺激更强的免疫反应，而不会产生可检测的毒性和生理损伤，比 FA 更有效。然而，对于用 GNPs 作为佐剂的疫苗，在轴突再生和神经保护方面的疗效存在不确定性。在这项研究中，制备了一种针对 NgR 的重组蛋白疫苗，即与人 NgR-Fc（hNgR-Fc）融合蛋白偶联的 15nm GNPs，并研究了其对脊髓损伤大鼠轴突再生和功能恢复的影响。结果表明，用蛋白疫苗免疫的成年大鼠产生的抗 NgR 抗体滴度高于 FA 组，并且抗血清在存在 MAG 的情况下促进神经突生长。在脊髓背侧半切模型中，用 GNPs 免疫的疫苗比 FA 更有效地促进轴突再生，导致神经元丢失的显著保护，并改善功能恢复。因此，作为佐剂，15nm GNPs 可以有效地增强 hNgR-Fc 蛋白疫苗的免疫原性，并促进脊髓损伤大鼠的修复。从临床考虑，GNPs 的使用可能比 FA 更有利于促进 SCI 修复的有前途的治疗性疫苗策略。
