A novel DNA vaccine targeting macrophage migration inhibitory factor protects joints from inflammation and destruction in murine models of arthritis.
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 alpha 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.


CONCLUSIONS
These results suggest that MIF/TTX DNA vaccination may be useful for ameliorating the symptoms of rheumatoid arthritis.
Onodera
Shin
S
Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Ohshima
Shigeki
S
Tohyama
Harukazu
H
Yasuda
Kazunori
K
Nishihira
Jun
J
Iwakura
Yoichiro
Y
Matsuda
Ikkei
I
Minami
Akio
A
Koyama
Yoshikazu
Y
D000595:Amino Acid Sequence; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D003094:Collagen; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D007596:Joints / Q000473:pathology / Q000503:physiopathology*; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D013745:Tetanus Toxoid / Q000032:analysis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D019444:Vaccines, DNA / Q000494:pharmacology* / Q000627:therapeutic use*
D001323:Autoantibodies; D053590:Interleukin 1 Receptor Antagonist Protein; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; D013745:Tetanus Toxoid; D014409:Tumor Necrosis Factor-alpha; D019444:Vaccines, DNA; D003094:Collagen; D004247:DNA; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse