CpG oligodeoxynucleotide induction of antiviral effector molecules in sheep

Immunostimulatory CpG oligodeoxynucleotide (ODN) can protect mice against infection by many pathogens but the mechanisms mediating disease protection are not well defined. Furthermore, the mechanisms of CpG ODN induced disease protection in vivo have not been investigated in other species. We investigated the induction of antiviral effector molecules in sheep treated with a class B CpG ODN (2007). Subcutaneous injection of ODN 2007 induced a dose-dependent increase in serum levels of the antiviral effector molecule, 2′5′-A synthetase. Peak levels of enzyme were observed 4 days following ODN injection and enzyme levels remained elevated for the following 3–5 days. Repeated ODN injections induced a more sustained elevation of serum 2′5′-A synthetase activity. Finally, formulation of ODN 2007 in emulsigen increased the level of serum 2′5′-A synthetase activity and this response was CpG-specific. Elevated serum 2′5′-A synthetase activity suggested that CpG ODN acted through the induction of either interferon (IFN)-α or IFN-γ. ODN 2007 did not induce detectable levels of IFN-α or IFN-γ when incubated with peripheral blood mononuclear cells, but both IFN-α and IFN-γ were detected following stimulation of lymph node cells with ODN 2007. CpG ODN induction of 2′5′-A synthetase in vitro correlated with the secretion of both IFN-α and IFN-γ. Furthermore, immunohistochemical staining of skin revealed a marked cellular infiltration at the site of ODN 2007 injection. This cellular infiltration was CpG-specific and consisted of primarily CD172+ myeloid cells. Many of the cells recruited to the site of ODN 2007 injection expressed IFN-α and some IFN-γ. These observations support the conclusion that localized cell recruitment and activation contribute to CpG ODN induction of antiviral effector molecules, such as interferon and 2′5′-A synthetase.