Phosphorothioate oligodeoxynucleotides promote the in vitro development ofhuman allergen-specific CD4(+) T cells into Th1 effectors

wDNA vaccination is an effective approach in inducing the switch of murine immune responses from a Th2 to a Th1 profile of cytokine production that ha s been related to the activity of unmethylated CPG motifs present in bacter ial, but not mammalian, DNA, We report here that some synthetic phosphoroth ioate, but not phosphodiester, oligo;deoxynucleotides (ODNs) were able to i nduce B cell proliferation and to shift the in vitro differentiation of Der matophagoides pteronyssinus group 1-specific human CD4(+) T cells from atop ic donors into Th cell effecters showing a prevalent Th1, instead of Th2, c ytokine profile. This latter effect was completely blocked by the neutraliz ation of IL-12 and IFN (alpha and gamma) in bulk culture, suggesting that t he Th1-inducing activity of phosphorothioate ODNs was mediated by their abi lity to stimulate the production of these cytokines by monocytes, dendritic , and MC cells. Cytosine methylation abolished the Th1-inducing activity of ODNs; however, CpG dinucleotide-containing ODNs exhibited the Th1-shifting effect independently of the presence or the absence of CpG motifs (5'-pur- pur-CpG-pyr-pyr-3'). Moreover, the inversion of CpG to GpC resulted only in a partial reduction of this activity, suggesting that the motif responsibl e for the Th1-skewing effect in humans is at least partially different from that previously defined in mice, These results support the concept that th e injection of allergens mixed to,or conjugated with, appropriate ODNs may provide a novel allergen-specific immunotherapeutic regimen fur the treatme nt of allergic disorders.