The Journal of Experimental Medicine
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Published 19 July 2004. doi:10.1084/jem.20030994
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 2, 223-234
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Unique Clinical and Pathological Features in HLA-DRB1*0401–restricted MBP 111–129–specific Humanized TCR Transgenic Mice

Jacqueline A. Quandt1, Mirza Baig1, Karen Yao1, Kazuyuki Kawamura1, Jaebong Huh1, Samuel K. Ludwin3, Hong-Jin Bian4, Mark Bryant2, Laura Quigley1, Zoltan A. Nagy5, Henry F. McFarland1, Paolo A. Muraro1, Roland Martin1, and Kouichi Ito1

1 National Institute of Neurological Disorders and Stroke, 2 Veterinary Resources Program/Office of the Director, National Institutes of Health, Bethesda, MD 20892
3 Queen's University, Ontario, Canada K7L 4V1
4 Hoffmann-LaRoche, Nutley, NJ 07110
5 GPC-Biotech AG, D-82152 Martinsried/Munich, Germany

Address correspondence to Kouichi Ito, Dept. of Neurology, Robert Wood Johnson Medical School, UMDNJ, 683 Hoes Ln., Piscataway, NJ 08854. Phone: (732) 235-5482; Fax: (732) 235-4773; email: itoko{at}umdnj.edu

Amino acid residues 111–129 represent an immunodominant epitope of myelin basic protein (MBP) in humans with human leukocyte antigen (HLA)-DRB1*0401 allele(s). The MBP 111–129–specific T cell clone MS2-3C8 was repeatedly isolated from a patient with multiple sclerosis (MS), suggesting an involvement of MS2-3C8 T cells in the pathogenesis. To address the pathogenic potential of the MS2-3C8 T cell clone, we generated transgenic (Tg) mice expressing its T cell receptor and restriction element, HLA-DRB1*0401, to examine the pathogenic characteristics of MS2-3C8 Tg T cells by adoptive transfer into HLA-DRB1*0401 Tg mice. In addition to the ascending paralysis typical of experimental autoimmune encephalomyelitis, mice displayed dysphagia due to restriction in jaw and tongue movements and abnormal gait. In accordance with the clinical phenotype, infiltrates of MS2-3C8 Tg T cells and inflammatory lesions were predominantly located in the brainstem and the cranial nerve roots in addition to the spinal cord and spinal nerve roots. Together, these data suggest a pathogenic role of MBP-specific T cells in inflammatory demyelination within the brainstem and cranial nerve roots during the progression of MS. This notion may help to explain the clinical and pathological heterogeneity of MS.

Key Words: HLA-DRB1*0401 • myelin basic protein • transgenic mouse • experimental autoimmune encephalomyelitis • multiple sclerosis

J. Quandt and M. Baig contributed equally to this work.

Abbreviations used in this paper: CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; HLA, human leukocyte antigen; MBP, myelin basic protein; MS, multiple sclerosis; PNS, peripheral nervous system; TCC, T cell clone; Tg, transgenic.


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