Leading researchers review the activation of the mammalian immune system by bacterial DNA and its immunostimulatory sequences (ISS), and consider the applications of ISS in clinical medicine. The authors survey the latest findings concerning the receptor-recognition and signaling pathways triggered by ISS , the process of cell activation, and the potential vaccination strategies using ISS. Specific pharmaceutical applications discussed include infectious disease (Hepatitis B, HIV, and mycobacterial infections), allergy (asthma and conjunctivitis), cancer (lymphoma), and inflammation and autoimmunity (arthritis and colitis).

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.

Leading researchers review the activation of the mammalian immune system by bacterial DNA and its immunostimulatory sequences (ISS), and consider the applications of ISS in clinical medicine. The authors survey the latest findings concerning the receptor-recognition and signaling pathways triggered by ISS , the process of cell activation, and the potential vaccination strategies using ISS. Specific pharmaceutical applications discussed include infectious disease (Hepatitis B, HIV, and mycobacterial infections), allergy (asthma and conjunctivitis), cancer (lymphoma), and inflammation and autoimmunity (arthritis and colitis).