BAYERISCHER FORSCHUNGSVERBUND PRIONEN
Therapeutical potential of stimulating innate immunity in prion disease
Arbeitsfeld:Therapie der Prionkrankheiten
The aim of this project was to investigate the potential of stimulating innate immunity with regard to prion infection. Based on prelimary work we were able to show that administration of CpG-ODN lead to distinct prolongation of survival time in a mouse model of prion infection(1). The mechanisms underlying this effect however were unclear. To investigate this question in more detail studies were instigated to access possible mechanisms which might explain the effect of CpG-ODN on prion disease. As we knew that CpG-ODN activates B cells(2), and we were aware of studies which suggested a suppression of B cell activation in prion infected mice(3) we speculated that CpG-ODN prevents prion induced B cell suppression hereby protecting the host against infection. To test this hypothesis we first had to investigate whether prion infection induces B cell suppression in our mouse model of prion infection. To this end we examined immunoglobulin concentrations in prion infected mice. We were able to show that prion infection leads to distinct changes in immunoglobulin levels during prion infection, with lower immunoglobulin concentrations at time of clinical prion disease and in the incubation period of prion disease in C57BL/6 mice (Sethi et al. submitted for publication). However as an increase in immunoglobulin concentrations could be observed in SV129 mice without significantly effecting incubation times compared to C57BL/6 mice, we conclude that the observed changes in B cell activity do not effect prion pathogenesis, therefore it seems unlikely that the effect of CpG-ODN on prion disease is based on the prevention of prion induced B cell suppression. Another possible mechanism behind CpG-ODN mediated effects on prion infection could be structural changes in splenic microarchitecture which could, regarding the vital role of the spleen in prion pathogenesis, could effect prion pathogenesis. To examine this we evaluated splenic structure after repeated CpG-ODN administration, we did not observe destruction of splenic microarchitecture however we observed a distinct hyperplasia of white pulp follicles and follicular dendritic cells (FDC), and furthermore an in increase in the macrophage population was observed. We can therefore disclude the possibility that the effects of CpG-ODN on prion disease are based on destruction of spleen microarchitecture however it may very well be that the hyperplasia observed effects prion pathogenesis or that alternatively an increase in macrophages leads to increase in phagocytosis of prions thereby mediating an anti-prion effect. We then conducted experiments to investigate whether CpG-ODN administration leads to a sustained increase in Ig antibodies which could conceptually effect prion pathogenesis, indeed we were able to show that multiple CpG-ODN administrations lead to a distinct stimulation of Th-1 Ig isotype producing B cells, further studies would now have to verify if these antibodies effect prion pathogenesis, for instance through invitro experiments where the administration of these immunoglobulins could prevent the conversion of PrPc to PrPSc. With regard to prion infection we have been able to show that various effects of multiple CpG-ODN administration may very well underlie the effect of CpG-ODN on prion infection. In this context the most likely scenario is an addition of multiple effects which lead to abrogation of prion pathogenesis, our results are complemented by a study which shows that possibly to the mechanism which we suggest an effect of oligonucleotides could also effect prion pathogenesis(5). However further studies are needed as mentioned above to clarify which mechanisms mainly underlies the effect of CpG-ODN on prion pathogenesis. Additionally to the information we have obtained on the effect of multiple CpG-ODN administration on prion diesese, we have been able to show that multiple CpG-ODN administration leads to organ specific immune activation, regarding the CNS (Wagner, Sethi et al. submitted) and liver (manuscript in preparation). These results offer the possibility to advance further immunotherapeutic strategies against infection, including prions and tumors. Therefore this project has not only yielded valuable information regarding possible mechanisms underlying the effect of CpG-ODN on prion disease it has also opened new avenues fort he therapeutic administration of CpG-ODN against infection and tumor.