Phosphorotioate oligonucleotides: looking for the motif(s) possessing immunostimulatory activities in humans

DNA vaccination is an effective approach in inducing the switch of murine immune responses from a Th2 to a Th1 profile of cytokine production. This activity has been related to the presence of particular immunostimulatory sequences (ISS), represented by an unmethylated hexamer 5’-pur-pur-CpG-pyr-pyr-3’, the so called `CpG motif’. In mouse, CpG motif-containing oligonucleotides (ODNs), probably through the binding to TLR9 receptor2are able to induce a Th1 response towards allergens, by the stimulation of IL-12, IFNs and IL-18 production by APC, which in turn activate NK cells. They are also able to induce significant B cell proliferation and differentiation3. Despite a large body of evidences suggesting the efficacy of CpG motif-containing ODNs in animals, the activities of these compounds in humans have been less clarified. Moreover, no clear results concerning the sequence(s) actually important in humans have been obtained so far, but it has been postulated that ISS active in mouse and humans are, at least partially, different.