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

Nature Genetics volume 23, pages 343–347 (1999)Cite this article

Abstract

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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Figure 1: The TCR is specific for the HLA-DR2:MBP peptide complex.
Figure 2: T cells from mice transgenic for both HLA-DR2 and the TCR respond to the MBP peptide in vitro.
Figure 3: CNS lesions account for the neurological symptoms observed in HLA-DR2/TCR transgenic mice.
Figure 4: Perivascular cuffs in the spinal cord from the mouse described in Fig. 3a–c.

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Acknowledgements

We thank D. Mathis and C. Benoist for providing vectors, discussions and for reading the manuscript; D. Littman for providing human CD4 transgenic mice; and M. Clark and M. Svejme for expertise and assistance in animal caretaking and immunohistopathology. This work was supported by grants from the Karen Elise Jensen Foundation of Denmark, the Swedish Medical Research Council, the European Union (BMH4-CT97-2522 and ERBBIO4CT960562), the National Multiple Sclerosis Society (USA), the NIH, the Danish Medical Research Council, the Novo Nordisk Foundation and the Danish Multiple Sclerosis Society.

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  1. Lars S. Madsen, Ellen Christina Andersson and Liselotte Jansson: These authors contributed equally to this work.

Authors and Affiliations

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

    Lars S. Madsen, Ellen Christina Andersson & Arne Svejgaard

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

    Claus B. Andersen

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

    Jan Engberg

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

    Jack L. Strominger

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

    Jens Peter Hjorth

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

    Liselotte Jansson & Rikard Holmdahl

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

    Kai W. Wucherpfennig

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

    Michelle Krogsgaard & Lars Fugger

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Correspondence to Lars Fugger.

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Madsen, L., Andersson, E., Jansson, L. et al. A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor. Nat Genet 23, 343–347 (1999). https://doi.org/10.1038/15525

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