The relevance of animal models in multiple sclerosis research.
The relevance of animal models in multiple sclerosis research.
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DOI：
10.1016/j.pathophys.2010.04.004
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发表时间：
2011-02
期刊：
影响因子：
--
通讯作者：
Pirko I
中科院分区：
文献类型：
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作者：
Denic A;Johnson AJ;Bieber AJ;Warrington AE;Rodriguez M;Pirko I
多发性硬化症（MS）是一种病因不明的复杂疾病，没有有效的治疗方法，尽管几十年的广泛研究导致了几种部分有效的治疗方法的发展。研究人员只能有限地获得早期和免疫活性的MS组织样本，并且与动物模型研究相比，在人类研究中对实验环境的修改更受限制。由于这些原因，需要动物模型来阐明潜在的免疫病理机制，并测试新的治疗和修复方法。单一小鼠模型不可能捕获并充分纳入多发性硬化症的所有临床、放射学、病理和遗传特征。多发性硬化症最常研究的三大类动物模型包括：(1)纯自身免疫性实验性自身免疫性/过敏性脑脊髓炎（EAE）；(2)病毒诱导的慢性脱髓鞘病模型，主要模型为Theiler 's小鼠脑脊髓炎病毒（TMEV）感染；(3)毒素诱导的脱髓鞘模型，包括铜酮模型和溶磷脂酰胆碱（lyso-卵磷脂）诱导的局灶性脱髓鞘。在过去的几十年里，EAE在我们对中枢神经系统炎症、免疫监视和免疫介导的组织损伤的整体理解方面有很大的帮助。此外，EAE还直接推动了三种获批治疗多发性硬化症的药物的开发，分别是醋酸格拉替雷默、米托蒽醌和那他珠单抗。另一方面，许多在EAE中显示出良好效果的治疗方法在ms中要么无效，要么在某些情况下有害。TMEV模型的特点是慢性进行性疾病病程，在易感小鼠中持续整个生命周期。MS的几个特征，包括轴突损伤和修复的作用和意义，脱髓鞘残疾的部分独立性，表位从病毒扩散到髓磷脂表位，髓鞘再生的意义，都在这个模型中得到了证明。基于TMEV的MS模型也具有人类疾病的几个MRI发现。毒素诱导脱髓鞘模型主要用于局灶性脱髓鞘和再脱髓鞘的研究。这篇综述中描述的三种主要动物模型都不能被认为是优越的；相反，它们最好被视为相互补充。尽管存在局限性，但合理利用和应用这些模型来解决具体的研究问题仍将是人类脱髓鞘疾病研究中最有用的工具之一。
Multiple Sclerosis (MS) is a complex disease with an unknown etiology and no effective cure, despite decades of extensive research that led to the development of several partially effective treatments. Researchers have only limited access to early and immunologically active MS tissue samples, and the modification of experimental circumstances is much more restricted in human studies compared to studies in animal models. For these reasons, animal models are needed to clarify the underlying immune-pathological mechanisms and test novel therapeutic and reparative approaches. It is not possible for a single mouse model to capture and adequately incorporate all clinical, radiological, pathological and genetic features of MS. The three most commonly studied major categories of animal models of MS include: (1) the purely autoimmune experimental autoimmune/allergic encephalomyelitis (EAE); (2) the virally induced chronic demyelinating disease models, with the main model of Theiler’s Murine Encephalomyelitis Virus (TMEV) infection and (3) toxin-induced models of demyelination, including the cuprizone model and focal demyelination induced by lyso-phosphatidyl choline (lyso-lecithine). EAE has been enormously helpful over the past several decades in our overall understanding of CNS inflammation, immune surveillance and immune-mediated tissue injury. Furthermore, EAE has directly led to the development of three approved medications for treatment in multiple sclerosis, glatiramer acetate, mitoxantrone and natalizumab. On the other hand, numerous therapeutical approaches that showed promising results in EAE turned out to be either ineffective or in some cases harmful in MS. The TMEV model features a chronic progressive disease course that lasts for the entire lifespan in susceptible mice. Several features of MS, including the role and significance of axonal injury and repair, the partial independence of disability from demyelination, epitope spread from viral to myelin epitopes, the significance of remyelination have all been demonstrated in this model. TMEV based MS models also feature several MRI findings of the human disease. Toxin induced demyelination models have been mainly used to study focal demyelination and remyelination. None of the three main animal models described in this review can be considered superior; rather, they are best viewed as complementary to one another. Despite their limitations, the rational utilization and application of these models to address specific research questions will remain one of the most useful tools in studies of human demyelinating diseases.