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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-γ and TNF-α. 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.
Acknowledgements
The authors would like to thank Dr G. Hermans, B. J. Lee, and members of the Robinson and Steinman laboratories for insightful scientific discussions. This work was supported by NIH K08 AR02133, an Arthritis Foundation Arthritis Investigator Award, NIH NHLBI contract N01 HV 28183, a Baxter Foundation Award, and a Department of Veterans Affairs funding to W.H.R.; and a Northern California Chapter Grant to P.P.H.