Abstract
(Englisch)
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In prion infections, the first phase of prion replication takes place primarily in the Iymphoreticular system. The identification of the immune cell actively involved in this phase is essential for deciphering the mechanisms of peripheral prion pathogenesis.
By understanding these mechanisms, it might be possible to develop post-exposure prophylaxis.
Follicular dendritic cells (FOGs) are a likely candidate for prion replication and/or accumulation within the Iymphoreticular system. In our recent work (Montrasio et al. 2000) we showed that selective depletion of FOGs by interfering with Iymphotoxin f) (L Tf)) signalling abolished splenic accumulation of PrPSc, independently of whether FOGs were 'switched off' before or after prion inoculation. Infectivity replication and/or accumulation was also impaired in the spleen of treated animals. We have observed that FOGs depletion during the first phase (8 weeks) of prion infection led to a delay in neuroinvasion. Mice receiving L Tf)R-lg starting one week after inoculation developed clinical disease with a delay of approximately 25 days delay as compared to control mice. If FOG depletion was initiated one week before inoculation, the effect on incubation time even more pronounced: two out of three mice developed scrapie symptoms days later than controls treated with human IgG; and one mouse survived more than 435 days.
Because nvGJO affects the Iymphoreticular systems before the appearance of clinical symptoms, early diagnosis and long-term treatment with L Tf)R-lg may conceivable retard progression of disease.
Publications in this project:
1. Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. F.Montrasio, R.Frigg, M.Glatzel, M.A.Klein, F.Mackay, A.Aguzzi, G.Weissmann (2000). Science, 288:1257-1259.
2. Prions: health scare and biological challenge. Aguzzi A, Montrasio F, Kaeser PS Nat Rev Mol Cell Bioi 200 1 ;2(2): 118-26.
3. Interventional strategies against prion diseases.Aguzzi A, Aguzzi A, Glatzel M, Montrasio F, Prinz M, Heppner FL. Nat Rev Neurosci 2001 ;2(10):745-9.
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