Nature Genetics
23, 343 - 347 (1999)
doi:10.1038/15525
A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell
receptorLars 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 Fugger81
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.dkMultiple 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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