NR AOWD
AU Mabbott,N.A.; Bruce,M.E.
TI Follicular dendritic cell de-differentiation dramatically reduces scrapie susceptibility
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - PG-18
PT Konferenz-Poster
AB Transmissible spongiform encephalopathies (TSEs) may be acquired peripherally, in which case infectivity usually accumulates in lymphoid tissues before dissemination to the nervous system. Studies of mouse scrapie models have shown that mature follicular dendritic cells (FDCs), expressing the host prion protein (PrPc), are critical for replication of infection in lymphoid tissues and subsequent neuroinvasion. As FDCs require lymphotoxin signals from B lymphocytes to maintain their differentiated state, blockade of this stimulation with a lymphotoxin-beta-receptor/Ig fusion protein (LTBR-Ig) leads to their temporary de-differentiation. Here, a single treatment with LTBR-Ig before intraperitoneal scrapie inoculation blocked the early accumulation of scrapie within the spleen and substantially reduced disease susceptibility. These effects coincided with an absence of FDCs in the spleen for approximately 28 days following treatment. Although the period of FDC de-differentiation was extended to at least 49 days by consecutive LTBR-Ig treatments, this had little added protective benefit following injection with a moderate dose of scrapie. We also demonstrate that mature FDCs are critical for the transmission of scrapie from the gastrointestinal tract. Treatment with LTBR-Ig before oral scrapie inoculation blocked disease-specific PrP (PrPsc) accumulation in Peyer's patches and mesenteric lymph nodes and prevented neuroinvasion. However, treatment 14 days after oral inoculation did not affect survival time or susceptibility suggesting infectivity may have already spread to the peripheral nervous system. Thus the duration of FDC involvement in scrapie pathogenesis may vary widely depending on the route of exposure. While FDC manipulation may offer a potential approach for early intervention in peripherally acquired TSEs, these data suggest the duration of the treatment window will likewise vary according to the route of inoculation.
AD Neil A. Mabbott, Moira E. Bruce, Institute for Animal Health, Edinburgh, UK
SP englisch
PO Deutschland