Immunology Laboratory, INSERM U563, Toulouse University Medical School, Toulouse, France.
J Neurol Sci. 2009 Dec;287 Suppl 1:S17-23. doi: 10.1016/S0022-510X(09)71296-1.
Although it was originally synthesised to induce experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, glatiramer acetate (GA) is actually used in the treatment of this human disease. Serendipity thus was responsible for the discovery of the therapeutic properties of what has become one of the only two first-line therapies currently approved for relapsing-remitting multiple sclerosis. Despite being discovered over forty years ago, novel aspects of the mechanism of action of GA are still being uncovered today. Initially, the immunomodulatory effects of GA were believed to involve high-affinity binding of the polypeptide to MHC Class II molecules on antigen-presenting cells. Subsequently, it was demonstrated that GA activated a specific population of GA-reactive T cells of a type-2 helper (Th2) phenotype, promoting an antiinflammatory environment and the preferential migration of GA-specific Th2 cells into the central nervous system, leading to decreased local inflammation through 'bystander suppression'. More recently, it has been shown that GA-reactive Th2 cells will secrete neurotrophins, important factors for neuronal survival and for axonal protection, in the central nervous system. Moreover, perhaps by this mechanism, GA increases proliferation, differentiation and survival of oligodendrocyte precursor cells; potentially enhancing myelin repair processes in situ. In parallel to this work, light has been shed on immunomodulatory effects of GA on other immune cell types. These findings were stimulated by the observation that adoptive transfer of GA-specific T cells alone had a limited capacity to suppress experimental autoimmune encephalomyelitis compared to injection of GA itself, suggesting that other cell types such as monocytes also played a role. It has now been documented that GA treatment can also modulate antigen-presenting cells such as monocytes, dendritic cells, and also additional adaptive immune system cell types such as CD8+ T cells and Treg cells. In this respect, it is important to note that the interplay between such antigen-presenting cells and T cells is fundamental given the coordinated and bidirectional interactions between these two cell types in the immune network.
虽然最初合成它是为了诱导实验性自身免疫性脑脊髓炎，即多发性硬化症的动物模型，但醋酸格拉替雷（GA）实际上被用于治疗这种人类疾病。因此，正是这种偶然发现揭示了这种药物的治疗特性，它已经成为目前批准用于缓解-复发型多发性硬化症的两种一线治疗药物之一。尽管 GA 是在 40 多年前被发现的，但它的作用机制的新方面至今仍在不断被揭示。最初，GA 的免疫调节作用被认为涉及多肽与抗原呈递细胞上 MHC Ⅱ类分子的高亲和力结合。随后，研究表明 GA 激活了一种特定的 GA 反应性 T 细胞群，即 2 型辅助（Th2）表型，促进抗炎环境和 GA 特异性 Th2 细胞优先迁移到中枢神经系统，通过“旁观者抑制”减少局部炎症。最近，研究表明 GA 反应性 Th2 细胞将在中枢神经系统中分泌神经营养因子，这是神经元存活和轴突保护的重要因素。此外，GA 可能通过这种机制增加少突胶质细胞前体细胞的增殖、分化和存活；潜在地增强原位髓鞘修复过程。与此同时，GA 对其他免疫细胞类型的免疫调节作用也得到了阐明。这些发现是受到以下观察结果的启发：与单独注射 GA 相比，过继转移 GA 特异性 T 细胞抑制实验性自身免疫性脑脊髓炎的能力有限，这表明其他细胞类型（如单核细胞）也发挥了作用。现在已经证明，GA 治疗还可以调节抗原呈递细胞，如单核细胞、树突状细胞，以及其他适应性免疫系统细胞类型，如 CD8+T 细胞和 Treg 细胞。在这方面，需要注意的是，鉴于这两种细胞类型在免疫网络中相互协调和双向相互作用，抗原呈递细胞和 T 细胞之间的相互作用非常重要。
