Perhaps the most straightforward way to facilitate T-cell stimulation during DNA vaccination is to deliver genes encoding for the known costimulatory and secreted cytokine signals. The numerous types and variations of these signals are too many to discuss here, but are reviewed thoroughly elsewhere (78). Examples of secreted
cytokines signals are the Th1 cytokines such as IL-2, and IL-12, Th2 cytokines such as IL-4 and IL-10, and the seemingly nonpolarized GM-CSF, the most commonly used genetic adjuvant. The timing and administration with respect to antigen plasmid administration can significantly affect the outcome of a genetic cytokine vaccination. Also, combinations of two or more of these cytokine signals can have a more pronounced effect than either of the two alone. There are indications that modifications can be made to certain known immunostimulatory cytokines which can alter their systemic toxicity profile while still retaining their antitumor effects (79). Genes encoding for the T-cell activating costimulatory molecules such as B7.1 and B7.2 are promising candidates for increasing potency, but results have been conflicting (78,80).
Some fusion partners have an inherent immunogenicity to which they can impart upon an antigen. Examples of this are tetanus toxoid (81), plant viral proteins (82), and HSP70
(83). Addition of these fusion constructs is associated with large increases in potency. Mechanisms of this increased immunogenicity are thought to involve induction of helper T-cell responses through processing of the fusion proteins by the MHC class II pathway.
A range of traditional adjuvants have also been explored by coadministration with the genetic vaccine formulation. As previously discussed, the delivery systems themselves can have adjuvant properties. Even the gold beads used in gene gun immunization have adjuvant properties. A recent study has shown gold beads in tandem with in vivo electroporation led to an increase in observed immune responses (84). Importantly, this did not enhance gene expression, but may have acted as a recruiting factor for DCs
(84). Other examples include alum (aluminum salts) and Freund's oil-in-water adjuvant (a powerful, yet toxic adjuvant containing mycobacterial materials). It is doubtful that the latter will ever be used in humans despite the fact that modifications have been made to decrease toxicity of this system. A cationic emulsion, called MF59, has been used to adsorb and increase the persistence of plasmid DNA encoding HIV p55 gag at the injection site, which resulted in increased serum IgG titers when compared with naked plasmid in mice and rabbits (85).
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