Temporary blockade of the tumor necrosis factor receptor signaling pathway impedes the spread of scrapie to the brain.
Although the transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases, their agents usually replicate and accumulate in lymphoid tissues long before infection spreads to the central nervous system (CNS). Studies of a mouse scrapie model have shown that mature follicular dendritic cells (FDCs), which express the host prion protein (PrP(c)), are critical for replication of infection in lymphoid tissues. In the absence of mature FDCs, the spread of infection to the CNS is significantly impaired. Tumor necrosis factor alpha (TNF-alpha) secretion by lymphocytes is important for maintaining FDC networks, and signaling is mediated through TNF receptor 1 (TNFR-1) expressed on FDCs and/or their precursors. A treatment that blocks TNFR signaling leads to the temporary dedifferentiation of mature FDCs, raising the hypothesis that a similar treatment would significantly delay the peripheral pathogenesis of scrapie. Here, specific neutralization of the TNFR signaling pathway was achieved through treatment with a fusion protein consisting of two soluble human TNFR (huTNFR) (p80) domains linked to the Fc portion of human immunoglobulin G1 (huTNFR:Fc). A single treatment of mice with huTNFR:Fc before or shortly after intraperitoneal injection with the ME7 scrapie strain significantly delayed the onset of disease in the CNS and reduced the early accumulation of disease-specific PrP in the spleen. These effects coincided with a temporary dedifferentiation of mature FDCs within 5 days of huTNFR:Fc treatment. We conclude that treatments that specifically inhibit the TNFR signaling pathway may present an opportunity for early intervention in peripherally transmitted TSEs.
Mabbott
Neil A
NA
Neuropathogenesis Unit, Institute for Animal Health, Edinburgh EH9 3JF, Scotland, United Kingdom. neil.mabbott@bbsrc.ac.uk
McGovern
Gillian
G
Jeffrey
Martin
M
Bruce
Moira E
ME
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000378:metabolism; D004195:Disease Models, Animal; D000068800:Etanercept; D015151:Immunoblotting; D007074:Immunoglobulin G / Q000494:pharmacology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018620:PrPSc Proteins / Q000302:isolation & purification / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D012608:Scrapie / Q000503:physiopathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000276:immunology / Q000378:metabolism
D007074:Immunoglobulin G; D018620:PrPSc Proteins; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D000068800:Etanercept