title: Follicular dendritic cell dedifferentiation by treatment with an inhibitor of the lymphotoxin pathway dramatically reduces scrapie susceptibility.
abstract: 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 (PrP(c)), are critical for replication of infection in lymphoid tissues and subsequent neuroinvasion. Since FDCs require lymphotoxin signals from B lymphocytes to maintain their differentiated state, blockade of this stimulation with a lymphotoxin beta receptor-immunoglobulin fusion protein (LT beta R-Ig) leads to their temporary dedifferentiation. Here, a single treatment with LT beta R-Ig before intraperitoneal scrapie inoculation blocked the early accumulation of infectivity and disease-specific PrP (PrP(Sc)) within the spleen and substantially reduced disease susceptibility. These effects coincided with an absence of FDCs in the spleen for ca. 28 days after treatment. Although the period of FDC dedifferentiation was extended to at least 49 days by consecutive LT beta R-Ig treatments, this had little added protective benefit after 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 LT beta R-Ig before oral scrapie inoculation blocked PrP(Sc) 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 that infectivity may have already spread to the peripheral nervous system. Although manipulation of FDCs may offer a potential approach for early intervention in peripherally acquired TSEs, these data suggest that the duration of the treatment window may vary widely depending on the route of exposure.
authors.affiliation: Neuropathogenesis Unit, Institute for Animal Health, Edinburgh EH9 3JF, Scotland, United Kingdom. neil.mabbott@bbrsc.ac.uk
authors.forename: Neil A
authors.initials: NA
authors.lastname: Mabbott
authors.forename: Janice
authors.initials: J
authors.lastname: Young
authors.forename: Irene
authors.initials: I
authors.lastname: McConnell
authors.forename: Moira E
authors.initials: ME
authors.lastname: Bruce
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D020566:Dendritic Cells, Follicular / Q000166:cytology* / Q000187:drug effects*; D004198:Disease Susceptibility; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D007150:Immunohistochemistry; D008221:Lymphoid Tissue / Q000378:metabolism; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha / Q000037:antagonists & inhibitors*; D053308:Lymphotoxin-beta; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D010581:Peyer's Patches / Q000378:metabolism; D018620:PrPSc Proteins / Q000096:biosynthesis / Q000472:pathogenicity*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D012608:Scrapie / Q000188:drug therapy* / Q000503:physiopathology; D013154:Spleen / Q000378:metabolism
chemical_list: D007074:Immunoglobulin G; C505887:Ltb protein, mouse; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D018620:PrPSc Proteins; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins