title: Tolerizing DNA vaccines for autoimmune arthritis.
abstract: Current therapies for rheumatoid arthritis (RA) and other autoimmune diseases non-specifically suppress immune function, and there is great need for fundamental approaches such as antigen-specific tolerizing therapy. In this paper we describe development of antigen-specific tolerizing DNA vaccines to treat collagen-induced arthritis (CIA) in mice, and use of protein microarrays to monitor response to therapy and to identify potential additional autoimmune targets for next generation vaccines. We demonstrate that tolerizing DNA vaccines encoding type II collagen (CII) reduced the incidence and severity of CIA. Atorvastatin, a statin drug found to reduce the severity of autoimmunity, potentiated the effect of DNA vaccines encoding CII. Analysis of cytokines produced by collagen-reactive T cells derived from mice receiving tolerizing DNA encoding CII, as compared to control vaccines, revealed reduced production of the pro-inflammatory cytokines IFN-gamma and TNF-alpha. Arthritis microarray analysis demonstrated reduced spreading of autoantibody responses in mice treated with DNA encoding CII. The development of tolerizing DNA vaccines, and the use of antibody profiling to guide design of and to monitor therapeutic responses to such vaccines, represents a promising approach for the treatment of RA and other autoimmune diseases.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Peggy P
authors.initials: PP
authors.lastname: Ho
authors.forename: John P
authors.initials: JP
authors.lastname: Higgins
authors.forename: Brian A
authors.initials: BA
authors.lastname: Kidd
authors.forename: Beren
authors.initials: B
authors.lastname: Tomooka
authors.forename: Carla
authors.initials: C
authors.lastname: Digennaro
authors.forename: Lowen Y
authors.initials: LY
authors.lastname: Lee
authors.forename: Henry E Neuman
authors.initials: HE
authors.lastname: de Vegvar
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.forename: William H
authors.initials: WH
authors.lastname: Robinson
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000069059:Atorvastatin; D001323:Autoantibodies / Q000097:blood; D003094:Collagen / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D006538:Heptanoic Acids / Q000627:therapeutic use; D006614:Hindlimb / Q000276:immunology / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D015847:Interleukin-4 / Q000276:immunology; D007596:Joints / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D040081:Protein Array Analysis; D011758:Pyrroles / Q000627:therapeutic use; D049490:Systems Biology; D019444:Vaccines, DNA / Q000627:therapeutic use*
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D019444:Vaccines, DNA; D015847:Interleukin-4; D003094:Collagen; D000069059:Atorvastatin