A Novel Dna Vaccine Targeting Macrophage Migration Inhibitory Factor Protects Joints from Inflammation and Destruction in Murine Models of Arthritis

Onodera, Shin
Ohshima, Shigeki
Tohyama, Harukazu
Yasuda, Kazunori
Nishihira, Jun
Iwakura, Yoichiro
Matsuda, Ikkei
Minami, Akio
Koyama, Yoshikazu

¹Hokkaido University Graduate School of Medicine, Sapporo, Japan
²GeneticLab Co., Sapporo, Japan
³Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan
⁴Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan

Address correspondence and reprint requests to Yoshikazu Koyama, Department of Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo 060–8638, Japan. E-mail: [email protected]

Supported in part by grants-in-aid from the Ministry of Science and Education (no. 15591560), the Hip Joint Foundation of Japan, and the Uehara Memorial Foundation.

Submitted for publication June 30, 2006; accepted in revised form November 09, 2006

Arthritis & Rheumatism 56(2):p 521-530, February 2007.

Objective

Previous studies have demonstrated that neutralization of macrophage migration inhibitory factor (MIF) by anti-MIF antibodies decreases joint inflammation and destruction in a type II collagen–induced arthritis model in mice. The aim of this study was to develop and describe a simple and effective method of active immunization that induces anti-MIF autoantibodies, which may neutralize MIF bioactivity.

Methods

We developed a MIF DNA vaccine by introducing oligonucleotides encoding a tetanus toxoid (TTX) Th cell epitope into the complementary DNA sequence of murine MIF. Mice were injected with this construct in conjunction with electroporation. The ability of this immunization to inhibit the development of collagen antibody–induced arthritis (CAIA) in BALB/c mice and spontaneous autoimmune arthritis in interleukin-1 receptor antagonist (IL-1Ra)–deficient mice was then evaluated.

Results

Mice that received the MIF/TTX DNA vaccine developed high titers of autoantibodies that reacted to native MIF. Compared with unvaccinated mice, vaccinated mice also produced less serum tumor necrosis factor α after receiving an intravenous injection of lipopolysaccharide. In addition, vaccination with MIF/TTX DNA resulted in significant amelioration of both CAIA in BALB/c mice and symptoms of autoimmune arthritis in IL-1Ra–knockout mice.

Conclusion

These results suggest that MIF/TTX DNA vaccination may be useful for ameliorating the symptoms of rheumatoid arthritis.