We established that oligodeoxynucleotides expressing """"""""CpG"""""""" motifs (CpG ODN)mediate a variety of immunological functions, including the activation of B lymphocytes and the induction of Th1 cytokine production by NK, T and dendritic cells. We have been exploring the mechanism(s) underlying this immune activation, and found that a 6 base pair DNA motif (containing an unmethylated CpG dinucleotide flanked by two 5' purines and two 3' pyrimidines) that is common to bacterial but not mammalian DNA caused this stimulation in mice. We found that synthetic oligonucleotides expressing CpG motifs can act as anti-allergens (by deviating the immune response towards Th1 and away from Th2 driven IgE secretion), and can be used to prevent and/or treat bacterial, parasitic and viral infections by up-regulating the innate immune system. We are particularly interested in the ability of CpG ODN to prevent/treat diseases caused by potential biowarfare agents, including Ebola virus and anthrax. We are therefore examining methods of increasing and prolonging the protective effects of CpG ODN. We are examining the in vitro activity of CpG ODN on human cells and exploring their activity in vivo in monkeys. We find that the motif that is optimally active in primates differs from that most active in mice. Indeed, two different motifs active on two different human cell types have been identified. These stimulate different types of immune response, and may prove useful in optimizing the human response specific pathogens. Most recently, we demonstrated that CpG ODN were able to provide some protection against infection by anthrax and Ebola virus in murine models. We also showed that we could significantly reduce the level of Leishmania infection in rhesus monkeys treated with CpG ODN expected to be active in humans. By analyzing the response of >50 normal donors to a large panel of ODN, we found that individuals varied in their response to specific ODN, such that optimal stimulation of a diverse population will require combinations of different ODN motifs. Finally, a series of studies identified those regions of the IL-6 and IL-12 promoter that are involved in CpG ODN induced cell triggering at the molecular level.
