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As a result of early studies on mycobacteria (Tokunaga et al. 1992; Yamamoto et al. 1992), it is now well established that DNA from nonvertebrates, as well as certain synthetic oligodeoxynucleotides (ODNs), can cause strong activation of lymphoid cells, especially B cells, natural killer (NK) cells and antigen-presenting cells (APCs) (Messina et al. 1991; Krieg et al. 1995; Ballas et al. 1996; Stacey et al. 1996; Sparwasser et al. 1998); such activation leads to B-cell proliferation and enhanced production of cytokines by APCs and NK cells. The immunostimulatory properties of DNA/ODNs are controlled by unmethylated CpG dinucleotide motifs with optimal flanking sequences (Krieg et al. 1995). Reflecting the paucity of these motifs in vertebrate DNA — which is generally heavily methylated — purified DNA from humans, mice, frogs and fish (and also plants) are nonstimulatory for lymphoid cells, at least in terms of eliciting B-cell proliferation (Sun et al. 1997). By contrast, DNA from nonvertebrates, which is largely unmethylated, is strongly stimulatory for B cells (Sun et al. 1997); this applies to DNA from bacteria, insects, nematodes, yeasts and mollusks. For bacteria, insect and yeast DNA, selective methylation of CpG motifs abolished immunostimulatory activity (Krieg et al. 1995; Sun et al. 1996, 1997). |
