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Letter
Nature Genetics  23, 343 - 347 (1999)
doi:10.1038/15525

A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor

Lars S. Madsen1, 9, Ellen Christina Andersson1, 9, Liselotte Jansson6, 9, Michelle Krogsgaard8, Claus B. Andersen2, Jan Engberg3, Jack L. Strominger4, Arne Svejgaard1, Jens Peter Hjorth5, Rikard Holmdahl6, Kai W. Wucherpfennig7 & Lars Fugger8

1  Department of Clinical Immunology, The Royal Danish School of Pharmacy, Copenhagen, Denmark.

2  Department of Pathology, Rigshospitalet, The Royal Danish School of Pharmacy, Copenhagen, Denmark.

3  Department of Pharmacology, The Royal Danish School of Pharmacy, Copenhagen, Denmark.

4  Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.

5  Institute of Molecular and Structural Biology, Aarhus University, Aarhus, Denmark.

6  Section for Medical Inflammation Research, Lund University , Lund, Sweden.

7  Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA .

8  Department of Clinical Immunology, Aarhus University Hospital, Skejby Sygehus, Aarhus, Denmark.

9  These authors contributed equally to this work.

Correspondence should be addressed to Lars Fugger fugger@inet.uni2.dk
Multiple sclerosis (MS) is a complex chronic neurologic disease with a suspected autoimmune pathogenesis1, 2. Although there is evidence that the development of MS is determined by both environmental influences and genes, these factors are largely undefined3, 4, except for major histocompatibility (MHC) genes. Linkage analyses and association studies have shown that susceptibility to MS is associated with genes in the human histocompatibility leukocyte antigens (HLA) class II region, but the contribution of these genes to MS disease development is less compared with their contribution to disorders such as insulin-dependent diabetes mellitus5, 6, 7, 8, 9, 10, 11. Due to the strong linkage disequilibrium in the MHC class II region, it has not been possible to determine which gene(s) is responsible for the genetic predisposition12. In transgenic mice, we have expressed three human components involved in T-cell recognition of an MS-relevant autoantigen presented by the HLA-DR2 molecule: DRA*0101/DRB1*1501 (HLA-DR2), an MHC class II candidate MS susceptibility genes found in individuals of European descent; a T-cell receptor (TCR) from an MS-patient-derived T-cell clone specific for the HLA-DR2 bound immunodominant myelin basic protein (MBP) 84−102 peptide13, 14; and the human CD4 coreceptor. The amino acid sequence of the MBP 84−102 peptide is the same in both human and mouse MBP. Following administration of the MBP peptide, together with adjuvant and pertussis toxin, transgenic mice developed focal CNS inflammation and demyelination that led to clinical manifestations and disease courses resembling those seen in MS. Spontaneous disease was observed in 4% of mice. When DR2 and TCR double-transgenic mice were backcrossed twice to Rag2 (for recombination-activating gene 2)-deficient mice, the incidence of spontaneous disease increased, demonstrating that T cells specific for the HLA-DR2 bound MBP peptide are sufficient and necessary for development of disease. Our study provides evidence that HLA-DR2 can mediate both induced and spontaneous disease resembling MS by presenting an MBP self-peptide to T cells.

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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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