Th1-biased immune responses induced by DNA-based immunizations are mediated via action on professional antigen-presenting cells to up-regulate IL-12 production

The efficacy of DNA-based immunization in conferring protective immunity ag ainst certain microbial pathogens including human immunodeficiency virus ty pe 1 (HIV-1) has been described. The potential advantage of DNA-based immun ization over the traditional vaccines largely results from its capacity to efficiently induce Th1-biased immune responses against an encoded antigen. We describe how Th1-biased immune responses are induced by DNA-based immuni zation, using a DNA vaccine construct encoding HIV-1 gp160 cDNA and an euka ryotic expression plasmid carrying murine IFN-gamma cDNA. Transfection of a n eukaryotic expression plasmid carrying immunostimulatory sequences (ISS) as well as a gene of interest (DNA vaccine) into professional antigen prese nting cells (APC) induced transactivation of IL-12 mRNA, which resulted in antigen-specific Th1-biased immune responses against the encoded antigen. T h1-biased immune responses induced by DNA-based immunization were substanti ally upregulated by a codelivery of an ectopic IFN-gamma expression system, and this augmentation was mediated via action on professional antigen pres enting cells to upregulate IL-12 production. Taken together, it appears lik ely that Th1-biased immune responses induced by DNA-based immunization are mediated via action on professional antigen-presenting cells to produce IL- 12. Interestingly, the model provided strikingly resembles that previously described in infection with Listeria monocytogenes, an intracellular Gram-p ositive bacterium that induces strong Th1-biased immune responses. The resu lt suggests that DNA-based immunization mimics certain aspects of natural i nfection with microbial organisms like attenuated vaccines, which in turn p rovides a rationale to the question of why DNA-based immunization so effici ently induces protective immunity against these microbial pathogens.