Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications
Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications
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DOI：
10.1073/pnas.0404887101
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发表时间：
2004-10-05
影响因子：
11.1
通讯作者：
Aharoni, R
中科院分区：
文献类型：
--
作者：
Arnon, R;Aharoni, R
醋酸格拉替默（Glatiramer acetate， GA, Copaxone，共聚物1）是一种被批准用于治疗多发性硬化症的药物，在抑制各种物种的实验性自身免疫性脑脊髓炎方面非常有效。GA的作用模式是通过最初与MHC分子的强混杂结合，随后与各种髓磷脂抗原竞争以将其呈递到T细胞。其作用的另一个方面是有效诱导特异性T辅助2 （Th2）型抑制细胞迁移到大脑并导致原位旁观者抑制。此外，大脑中的ga特异性细胞除了表达脑源性神经营养因子外，还表达抗炎细胞因子IL-10和转化生长因子β，而不表达ifn - γ。基于这种免疫调节作用模式，我们探索了GA在其他两个应用方面的潜力：预防移植物排斥反应和改善炎症性肠病。GA通过延长皮肤移植物的存活时间和抑制甲状腺移植物的功能恶化，有效地改善了两种系统的移植物排斥反应，跨越了次要和主要的组织相容性障碍。在所有移植系统中，GA处理抑制了Th1炎症因子的有害分泌，并诱导了有益的Th2/3抗炎反应。GA与低剂量免疫抑制药物合用也有效。炎症性肠病的特点是肠道中有害的不平衡的促炎免疫反应。GA可显著抑制三硝基苯磺酸所致结肠炎的各种表现，包括死亡、体重减轻、宏观和微观结肠损伤。GA抑制了局部淋巴细胞增殖和肿瘤坏死因子α的有害分泌，但诱导了转化生长因子β，从而证实了GA的作用方式参与了Th1向Th2的转移。
Glatiramer acetate (GA, Copaxone, Copolymer 1) is an approved drug for the treatment of multiple sclerosis and is highly effective in the suppression of experimental autoimmune encephalomyelitis in various species. The mode of action of GA is by initial strong promiscuous binding to MHC molecules and consequent competition with various myelin antigens for their presentation to T cells. A further aspect of its action is potent induction of specific suppressor cells of the T helper 2 (Th2) type that migrate to the brain and lead to in situ bystander suppression. Furthermore, the GA-specific cells in the brain express the antiinflammatory cytokines IL-10 and transforming growth factor beta, in addition to brain-derived neurotrophic factor, whereas they do not express IFN-gamma. Based on this immunomodulatory mode of action, we explored the potential of GA for two other applications: prevention of graft rejection and amelioration of inflammatory bowel diseases. GA was effective in amelioration of graft rejection in two systems by prolongation of skin graft survival and inhibition of functional deterioration of thyroid grafts, across minor and major histocompatibility barriers. in all transplantation systems GA treatment inhibited the detrimental secretion of Th1 inflammatory cytokines and induced beneficial Th2/3 antiinflammatory response. GA was effective also in combination with low-dose immunosuppressive drugs. Inflammatory bowel diseases are characterized by detrimental imbalanced proinflammatory immune reactivity in the gut. GA significantly suppressed the various manifestations of trinitrobenzene sulfonic acid-induced colitis, including mortality, weight loss, and macroscopic and microscopic colonic damage. GA suppressed local lymphocyte proliferations and tumor necrosis factor alpha detrimental secretion but induced transforming growth factor beta, thus confirming the involvement of Th1 to Th2 shift in GA mode of action.