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Abstract

The diversity of autoimmune responses poses a formidable challenge to the development of antigen-specific tolerizing therapy. We developed 'myelin proteome' microarrays to profile the evolution of autoantibody responses in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS). Increased diversity of autoantibody responses in acute EAE predicted a more severe clinical course. Chronic EAE was associated with previously undescribed extensive intra- and intermolecular epitope spreading of autoreactive B-cell responses. Array analysis of autoantigens targeted in acute EAE was used to guide the choice of autoantigen cDNAs to be incorporated into expression plasmids so as to generate tolerizing vaccines. Tolerizing DNA vaccines encoding a greater number of array-determined myelin targets proved superior in treating established EAE and reduced epitope spreading of autoreactive B-cell responses. Proteomic monitoring of autoantibody responses provides a useful approach to monitor autoimmune disease and to develop and tailor disease- and patient-specific tolerizing DNA vaccines.

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Acknowledgements

The authors thank members of the Steinman and Utz laboratories for scientific input. This work was supported by National Institutes of Health (NIH) K08 AR02133, an Arthritis Foundation Chapter Grant and Investigator Award and NIH NHLBI contract N01 HV 28183 to W.H.R; an Arthritis Foundation Investigator Award and Chapter Grant, a Baxter Foundation Career Development Award, a Program in Molecular and Genetic Medicine Grant, NIH grants DK61934, AI50864, AI50865, AI51614, AR49328, and NIH NHLBI contract N01-HV-28183 to P.J.U.; and NIH NINDS 5R01NS18235, NIH U19 DK61934 and NIH NHLBI contract N01-HV-28183 to L.S.

Author information

Author notes

  1. Paul J Utz, Hideki Garren and Lawrence Steinman: These authors contributed equally to this work.

Affiliations

  1. Department of Neurology and Neurological Sciences Stanford University School of Medicine, Stanford University School of Medicine, Stanford University School of Medicine, Stanford, 94305, California, USA

    • William H Robinson
    • , Paulo Fontoura
    • , Byung J Lee
    • , Henry E Neuman de Vegvar
    • , Jennifer Tom
    • , Rosetta Pedotti
    • , Carla D DiGennaro
    • , Dennis J Mitchell
    • , Derek Fong
    • , Peggy P-K Ho
    • , Pedro J Ruiz
    •  & Lawrence Steinman
  2. Division of Immunology and Rheumatology Department of Medicine, Stanford University School of Medicine, Stanford, 94305, California, USA

    • William H Robinson
    • , Byung J Lee
    • , Jennifer Tom
    • , Carla D DiGennaro
    • , Derek Fong
    •  & Paul J Utz
  3. GRECC, VA Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, 94304, California, USA

    • William H Robinson
    •  & Henry E Neuman de Vegvar
  4. Bayhill Therapeutics, Inc., 3430 West Bayshore Road, Palo Alto, 94303, California, USA

    • William H Robinson
    • , Paul J Utz
    • , Hideki Garren
    •  & Lawrence Steinman
  5. Department of Pathology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    • Emanual Maverakis
  6. Neuroimmunology Research, Veterans Affairs Medical Center, Portland, 97239, Oregon, USA

    • David B Stevens
  7. Neuroimmunology Laboratory, La Trobe University, Victoria, 3083, Australia

    • Claude C A Bernard
  8. Neuroimmunology Branch, NINDS, National Institutes of Health, Bethesda, 20892, Maryland, USA

    • Roland Martin
  9. Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, Massachusetts, USA

    • Vijay K Kuchroo
  10. Division of Immunological and Infectious Diseases, TNO Prevention and Health, Leiden, 2301, CE, The Netherlands

    • Johannes M van Noort
  11. Department of Neurology, University of California, San Francisco, 94143, California, USA

    • Claude P Genain
  12. Biomedical Primate Research Centre, Rijswijk, 2280, GH, The Netherlands

    • Sandra Amor
  13. Neuroimmunology Unit, Center for Molecular Medicine, Karolinska Hospital, S-171 76, Stockholm, Sweden

    • Tomas Olsson

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Competing interests

H.G. is an employee of, and owns shares of stock in, Bayhill Therapeutics. W.H.R., P.J.U and L.S. receive financial compensation for consulting for, and own shares of stock in, Bayhill Therapeutics.

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Correspondence to William H Robinson.

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https://doi.org/10.1038/nbt859

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