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Brain Advance Access originally published online on April 24, 2006
Brain 2006 129(8):1940-1952; doi:10.1093/brain/awl083
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© The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Review Articles

The value of animal models for drug development in multiple sclerosis

Manuel A. Friese1, Xavier Montalban4, Nick Willcox2, John I. Bell1,3, Roland Martin4 and Lars Fugger1,5

1 MRC Human Immunology Unit and Department of Clinical Neurology, John Radcliffe Hospital, University of Oxford Oxford, UK 2 Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford Oxford, UK 3 Office of the Regius Professor, John Radcliffe Hospital, University of Oxford Oxford, UK 4 Edifici Escola D'infermeria, 2a Planta, Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d'Hebron Barcelona, Spain 5 Department of Clinical Immunology, Aarhus University Hospital Skejby Sygehus, Denmark

Correspondence to: Lars Fugger, 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 or Roland Martin, Edifici Escola D'infermeria, 2a Planta, Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain E-mail: lars.fugger{at}molecular-medicine.oxford.ac.uk

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.

Key Words: animal models; experimental allergic encephalomyelitis; immunomodulation; multiple sclerosis; treatments

Abbreviations: CFA, complete Freund's adjuvant; EAE, experimental allergic (autoimmune) encephalomyelitis; HSCT, haematopoietic stem cell transplantation; MBP, myelin basic protein; PDEs, phosphodiesterases; PML, progressive multifocal leukoencephalopathy; PPARs, peroxisome proliferator-activated receptors; TCR, T-cell receptor; TH1, T helper 1; TNF, tumour necrosis factor

Received November 30, 2005. Revised March 5, 2006. Accepted March 14, 2006.


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