ABSTRACT
Vaccination is one of the most powerful health tools available owing to its ability to confer protection against various diseases. The long-term impact of such protection in terms of public-health savings is nearly incalculable and becomes even more evident when considering if the vaccination concept is extended to the therapeutic potential of a given molecule. In this sense, DNA vaccines are especially important tools with enormous potential owing to the molecular precision that they offer. The properties of the plasmid DNA molecule in terms of stability, cost-effectiveness and lack of cold-chain requirement are additional advantages over traditional vaccines and therapeutics. We focus on the current knowledge of autoimmune mechanisms, engineering of DNA vaccines and attempts that have already been made in order to intervene in autoimmune processes. Our experience with a genetic vaccine containing the heat-shock protein gene (hsp65) from mycobacteria is also described.
Subject(s)
Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , Vaccines, DNA/immunology , Vaccines, DNA/therapeutic use , Bacterial Proteins/genetics , Bacterial Proteins/immunology , Chaperonin 60 , Chaperonins/genetics , Chaperonins/immunology , HumansABSTRACT
We described a prophylactic and therapeutic effect of a DNA vaccine encoding the Mycobacterium leprae 65-kDa heat shock protein (DNA-hsp65) in experimental murine tuberculosis. However, high homology of the vaccine to the corresponding mammalian hsp60, together with the CpG motifs in the plasmidial vector, could trigger or exacerbate an autoimmune disease. In the present study, we evaluate the potential of DNA-hsp65 vaccination to induce or modulate arthritis in mice genetically selected for acute inflammatory reaction (AIR), either maximal (AIRmax) or minimal (AIRmin). Mice immunized with DNA-hsp65 or injected with the corresponding DNA vector (DNAv) developed no arthritis, whereas pristane injection resulted in arthritis in 62% of AIRmax mice and 7.3% of AIRmin mice. Administered after pristane, DNA-hsp65 downregulated arthritis induction in AIRmax animals. Levels of interleukin (IL)-12 were significantly lower in mice receiving pristane plus DNA-hsp65 or DNAv than in mice receiving pristane alone. However, when mice previously injected with pristane were inoculated with DNA-hsp65 or DNAv, the protective effect was significantly correlated with lower IL-6 and IL-12 levels and higher IL-10 levels. Our results strongly suggest that DNA-hsp65 has no arthritogenic potential and is actually protective against experimentally induced arthritis in mice.
Subject(s)
Arthritis/prevention & control , Bacterial Proteins/administration & dosage , Chaperonins/administration & dosage , DNA/administration & dosage , Disease Models, Animal , Animals , Chaperonin 60 , Enzyme-Linked Immunosorbent Assay , Interleukin-12/metabolism , MiceABSTRACT
Nucleic acid vaccines are an attractive alternative to conventional protein vaccines because of their ability to induce de novo production of antigens in a given tissue after DNA delivery. Although DNA vaccines are highly effective in inducing both cell-mediated and humoral immunity, little is known about the many cell types involved in plasmid DNA uptake in vivo. Here we demonstrate, for the first time, that plasmid DNA can be taken up by both bone marrow and lymph node B cells after intramuscular immunization. Plasmid DNA was also detected in CD11b+ and CD11c+ cells. This phenomenon was not restricted to plasmid DNA encoding mycobacterial 65-kd heat shock protein (pcDNA3-hsp65) because we observed similar results with plasmid-encoding green fluorescent protein (GFP-pEGFP-2C). In addition to plasmid DNA uptake, B cells also express the encoded protein, suggesting that B cells play a role in the immune response after DNA immunization. The biodistribution of plasmid DNA in B cells opens a new perspective in B-cell gene therapy for the in vivo use of plasmid DNA.
