Friese Manuel A, Montalban Xavier, Willcox Nick, Bell John I, Martin Roland, Fugger Lars
MRC Human Immunology Unit and Department of Clinical Neurology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom.
Brain. 2006 Aug;129(Pt 8):1940-52. doi: 10.1093/brain/awl083. Epub 2006 Apr 24.
The rodent model for multiple sclerosis, experimental allergic (autoimmune) encephalomyelitis (EAE), has been used to dissect molecular mechanisms of the autoimmune inflammatory response, and hence to devise and test new therapies for multiple sclerosis. Clearly, artificial immunization against myelin may not necessarily reproduce all the pathogenetic mechanisms operating in the human disease, but most therapies tested in multiple sclerosis patients are nevertheless based on concepts derived from studies in EAE. Unfortunately, several treatments, though successful in pre-clinical EAE trials, were either less effective in patients, worsened disease or caused unexpected, severe adverse events, as we review here. These discrepancies must, at least in part, be due to genetic and environmental differences, but the precise underlying reasons are not yet clear. Our understanding of EAE pathogenesis is still incomplete and so, therefore, are any implications for drug development in these models. Here, we suggest some potential explanations based on new thinking about key pathogenic concepts and differences that may limit extrapolation from EAE to multiple sclerosis. To try to circumvent these rodent-human dissimilarities more systematically, we propose that pre-clinical trials should be started in humanized mouse models.
用于研究多发性硬化症的啮齿动物模型，即实验性变应性（自身免疫性）脑脊髓炎（EAE），已被用于剖析自身免疫性炎症反应的分子机制，从而设计和测试针对多发性硬化症的新疗法。显然，针对髓磷脂的人工免疫不一定能重现人类疾病中所有的致病机制，但在多发性硬化症患者中测试的大多数疗法仍然基于从EAE研究中得出的概念。不幸的是，正如我们在此回顾的那样，几种治疗方法虽然在临床前EAE试验中取得了成功，但在患者中要么效果较差，要么使疾病恶化，要么导致意想不到的严重不良事件。这些差异至少部分归因于遗传和环境差异，但其确切的潜在原因尚不清楚。我们对EAE发病机制的理解仍然不完整，因此这些模型对药物开发的任何启示也不完整。在此，我们基于对关键致病概念和差异的新思考提出一些潜在的解释，这些差异可能会限制从EAE推断到多发性硬化症。为了更系统地规避这些啮齿动物与人类的差异，我们建议在人源化小鼠模型中开展临床前试验。
