A novel DNA vaccine-targeting macrophage migration inhibitory factor improves the survival of mice with sepsis.
Sepsis is a common and frequently fatal condition and there is an urgent need for new therapies that will further reduce sepsis-induced mortality. Macrophage migration inhibitory (MIF) factor is important in the regulation of innate and adaptive immunity and is believed to play a key regulatory role in sepsis and autoimmune disease. As MIF deficiency or immunoneutralization protects mice or rats from fatal endotoxic shock or other inflammatory diseases, we examined whether DNA vaccination against this molecule would also be protective. DNA vaccines can stimulate both humoral and cellular immunity simultaneously and have been shown to be effective against a variety of pathogens or cytokine-driven pathologies. Mice were immunized with a MIF/tetanus toxin (TTX) DNA vaccine and sepsis was then induced by lipopolysaccharide or cecal ligation and puncture. The MIF/TTX DNA-vaccinated mice were protected from the lethal effect of sepsis compared with control-vaccinated mice in both models. Compared with the control-vaccinated mice, the MIF/TTX DNA-vaccinated mice also showed significantly lower serum tumor necrosis factor (TNF)-alpha protein levels and reduced mRNA expression of TNF-alpha, interleukin (IL)-1beta, IL-6, macrophage inflammatory protein-2 and Toll-like receptor-4 in the lungs. Thus, the MIF/TTX DNA vaccine may be useful for the prophylaxis of septic shock.
Tohyama
S
S
Department of Sports Medicine and Joint Reconstruction Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Onodera
S
S
Tohyama
H
H
Yasuda
K
K
Nishihira
J
J
Mizue
Y
Y
Hamasaka
A
A
Abe
R
R
Koyama
Y
Y
D000818:Animals; D000906:Antibodies / Q000032:analysis; D015415:Biomarkers / Q000097:blood; D002432:Cecum / Q000293:injuries; D054426:Chemokine CXCL2 / Q000097:blood; D015316:Genetic Therapy / Q000379:methods*; D015850:Interleukin-6 / Q000097:blood; D008026:Ligation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000276:immunology; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics* / Q000276:immunology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D012772:Shock, Septic / Q000276:immunology / Q000628:therapy*; D012867:Skin / Q000293:injuries; D051197:Toll-Like Receptor 4 / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D019444:Vaccines, DNA / Q000008:administration & dosage*; D014945:Wound Healing
D000906:Antibodies; D015415:Biomarkers; D054426:Chemokine CXCL2; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D019444:Vaccines, DNA