Repeated peripheral administrations of CpG oligodeoxynucleotides lead to sustained CNS immune activation

Bacterial DNA containing CpG motifs activates cells of the innate immune system. In this study, we examined the effects of multiple peripheral bacterial DNA-mediated CNS innate immune stimulation. To study this issue, we repeatedly peripherally administered synthetic CpG-oligodeoxynucleotides (CpG-ODN) and assayed effects on CNS-associated TNF-alpha (TNFalpha) and C1q mRNA levels. We for the first time accounted for frequency of CpG-ODN administration and time kinetics of mRNA expression. We were able show that multiple intraperitoneal CpG-ODN administrations have a sustainable effect on immune effectors of the brain and stimulate TNFalpha mRNA secretion even up to 7 days after the last CpG-ODN application. This could on the one hand indicate a depot effect after multiple peripheral CpG-ODN administrations, however, it could also indicate that the cell producing TNFalpha mRNA remains activated for the indicated time period. Furthermore, elevated mRNA levels of C1q were observed, possibly indicating microglial activation after multiple peripheral bacterial DNA administrations. In this study, we have correlated frequency of CpG-ODN administrations with CNS-associated TNFalpha mRNA levels and show that multiple peripheral administrations of CpG-ODN lead to a sustained level of a Th1-associated cytokine in the brain. These findings indicate that the repeated peripherial administration of CpG oligodeoxynucleotides offer a therapeutical possibility for CNS-associated infections and tumors.