Brain Advance Access originally published online on April 24, 2006
Brain 2006 129(8):1940-1952; doi:10.1093/brain/awl083
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Review Articles |
The value of animal models for drug development in multiple sclerosis
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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. S. Tzartos, M. A. Friese, M. J. Craner, J. Palace, J. Newcombe, M. M. Esiri, and L. Fugger Interleukin-17 Production in Central Nervous System-Infiltrating T Cells and Glial Cells Is Associated with Active Disease in Multiple Sclerosis Am. J. Pathol., January 1, 2008; 172(1): 146 - 155. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Forte, B. G. Gold, G. Marracci, P. Chaudhary, E. Basso, D. Johnsen, X. Yu, J. Fowlkes, M. Rahder, K. Stem, et al. Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis PNAS, May 1, 2007; 104(18): 7558 - 7563. [Abstract] [Full Text] [PDF]
|
|