Nat Biotechnol. 2003 Aug 10
Robinson WH, Fontoura P, Lee BJ, De Vegvar HE, Tom J, Pedotti R, DiGennaro CD, Mitchell DJ, Fong D, Ho PP, Ruiz PJ, Maverakis E, Stevens DB, Bernard CC, Martin R, Kuchroo VK, Van Noort JM, Genain CP, Amor S, Olsson T, Utz PJ, Garren H, Steinman L.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA; Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA; GRECC, VA Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, California 94304, USA; Bayhill Therapeutics, Inc., 3430 West Bayshore Road, Palo Alto, California 94303, USA.
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.