Gene Vaccination: Theory and Practice

nomenon [26]. Indeed, Krieg et al. [21] showed that the elimination of the CpG in a particular ODN invariably abolished immune stimulation, but changes in the ODN sequences that did not affect the CpG or the flanking bases did not alter the immuno stimulatory (IS) effect. Furthermore, they extended the initial observations of the IS effects to non-palindromic CpG-enriched ODN [21]. Subsequent studies showed that CpG-enriched ODN also induce the secretion of IL-6 and IL-12 [19] and IFN-a [6, 27]. By adding or deleting various IS sequences (ISS)-ODN to or from different pDNAs, it was demonstrated that the ISS have a pivotal role in the induction of the subsequent immune response to the gene product in gene-vaccinated animals. The enhanced Thl immune response induced by gene vaccination is the consequence of the activation of the innate immune response by the ISS in the pDNA backbone [30, 31], rather than the low dose of intracellularly produced antigen. The cell activation products induced by the ISS, i. e. , IFN-a [3], IFN-~ [43], IL-12 [37], and IL-18 [25], are established inducers of IFN-y synthesis and promote the differentiation of naive T helper cells to Thl lym phocytes. Thus, the ISS activate the precise innate cytokine network required to pro mote Thl differentiation (see Fig. 1). In a recent study it was demonstrated that this ap proach is also applicable to a protein antigen.