NR AOQT
AU Bruce,M.E.; Ierna,M.X.; Mabbott,N.A.
TI Insights into TSE pathogenesis based on follicular dendritic cell manipulation
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Oral sessions OS-20
PT Konferenz-Vortrag
AB Previous studies in mouse models have shown that follicular dendritic cells (FDCs) are critical for accumulation of TSE infectivity in lymphoid tissues. Furthermore, neuroinvasion after peripheral challenge is impaired in mice in which the integrity or function of FDCs has been compromised. This may explain the relative resistance of newborn mice to peripheral scrapie challenge, as an increase in susceptibility about 10 days after birth correlates with the development of PrP-expressing FDCs in lymphoid tissues. This suggests that the maturation state of the host immune system may influence susceptibility to natural TSEs. In adult mice, treatment with a lymphotoxin beta receptor (LTBR) fusion protein temporarily de-differentiates FDCs, by blocking maturation signals from B cells, providing a tool for investigating the timing of FDC involvement in pathogenesis. We found that a single LTBR treatment shortly before intraperitoneal (ip) ME7 scrapie challenge blocks accumulation of infectivity in spleen and reduces susceptibility about a hundredfold. However, treated mice challenged with high scrapie doses still develop disease, implying either an alternative FDC-independent route of neuroinvasion or sequestration of infectivity in a non-FDC compartment until FDCs reappear about a month after treatment. Single treatments up to 6 weeks after challenge result in progressively smaller but still significant delays in neuroinvasion. In contrast, LTBR treatment shortly before high dose oral scrapie challenge completely prevents transmission, while treatment two weeks after oral challenge has no effect on susceptibility or disease progression. These results suggest that FDCs are critical following oral challenge but that the interval between infection of lymphoid tissues and neuroinvasion is very short. Therefore, following accidental TSE infection, the time window in which FDC-targeted treatments may be effective is likely to vary according to the route of exposure.
AD
M.E. Bruce, N.A. Mabbott, IAH Neuropathogenesis Unit, UK;
M.X. Ierna, University of Strathclyde, UK
SP englisch
PO Deutschland