Protein microarrays guide tolerizing DNA vaccine treatment of autoimmune encephalomyelitis.
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.
Robinson
William H
WH
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. wrobins@stanford.edu
Fontoura
Paulo
P
Lee
Byung J
BJ
de Vegvar
Henry E Neuman
HE
Tom
Jennifer
J
Pedotti
Rosetta
R
DiGennaro
Carla D
CD
Mitchell
Dennis J
DJ
Fong
Derek
D
Ho
Peggy P-K
PP
Ruiz
Pedro J
PJ
Maverakis
Emanual
E
Stevens
David B
DB
Bernard
Claude C A
CC
Martin
Roland
R
Kuchroo
Vijay K
VK
van Noort
Johannes M
JM
Genain
Claude P
CP
Amor
Sandra
S
Olsson
Tomas
T
Utz
Paul J
PJ
Garren
Hideki
H
Steinman
Lawrence
L
D000818:Animals; D004361:Drug Tolerance; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology*; D007118:Immunoassay / Q000379:methods*; D051379:Mice; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology; D009186:Myelin Sheath / Q000276:immunology*; D040081:Protein Array Analysis / Q000379:methods*; D025941:Protein Interaction Mapping / Q000379:methods; D016896:Treatment Outcome; D019444:Vaccines, DNA / Q000276:immunology* / Q000627:therapeutic use*
D019444:Vaccines, DNA