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* Human Disease Immunogenetics Group, Department of Infectious Diseases and Transplantation Biology Group, Medical Research Council Clinical Sciences Centre, Imperial College, Hammersmith Hospital, London, United Kingdom;
Department of Neuroinflammation, Division of Neuroscience, Imperial College and Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands;
Biological Imaging Centre, Medical Research Council Clinical Sciences Centre, Imperial College, London, United Kingdom;
Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115;
¶ Department of Clinical Neurosciences, Royal Free and University College Medical School, London, United Kingdom;
|| Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom; and
# Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
Multiple sclerosis (MS) is thought to involve CD4 T cell recognition of self myelin, many studies focusing on a pathogenic role for anti-myelin, HLA-DR15-restricted T cells. In experimental allergic encephalomyelitis, it is known which epitopes trigger disease and that disease is associated with determinant spread of T cell reactivity. Characterization of these events in human MS is critical for the development of peptide immunotherapies, but it has been difficult to define the role of determinant spread or define which epitopes might be involved. In this study, we report humanized transgenic mice, strongly expressing HLA-DR15 with an MS-derived TCR; even on a RAG-2 wild-type background, mice spontaneously develop paralysis. Disease, involving demyelination and axonal degeneration, correlates with inter- and intramolecular spread of the T cell response to HLA-DR15-restricted epitopes of myelin basic protein, myelin oligodendrocyte glycoprotein, and 
B-crystallin. Spread is reproducible and progressive, with two of the epitopes commonly described in responses of HLA-DR15 patients. The fact that this pattern is reiterated as a consequence of CNS tissue damage in mice demonstrates the value of the transgenic model in supplying an in vivo disease context for the human responses. This model, encompassing pathologically relevant, spontaneous disease with the presentation of myelin epitopes in the context of HLA-DR15, should offer new insights and predictions about T cell responses during MS as well as a more stringent test bed for immunotherapies.
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