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Follicular Dendritic Cell Dedifferentiation by Treatment with an Inhibitor of the Lymphotoxin Pathway Dramatically Reduces Scrapie Susceptibility

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Název: Follicular Dendritic Cell Dedifferentiation by Treatment with an Inhibitor of the Lymphotoxin Pathway Dramatically Reduces Scrapie Susceptibility
Autoři: Mabbott, Neil, Young, J., McConnell, I., Bruce, Moira
Zdroj: Mabbott, N, Young, J, McConnell, I & Bruce, M 2003, ' Follicular dendritic cell dedifferentiation by treatment with an inhibitor of the lymphotoxin pathway dramatically reduces scrapie susceptibility ', Journal of Virology, vol. 77, no. 12, pp. 6845-54 .
Informace o vydavateli: American Society for Microbiology, 2003.
Rok vydání: 2003
Témata: Lymphotoxin-beta, 0301 basic medicine, Scrapie/drug therapy, PrPSc Proteins, Lymphoid Tissue, Recombinant Fusion Proteins, PrPSc Proteins/pathogenicity, Dendritic Cells, Follicular/cytology, Spleen/metabolism, Receptors, Tumor Necrosis Factor, Dendritic Cells, Follicular/drug effects, Mice, Peyer's Patches, 03 medical and health sciences, 0302 clinical medicine, Lymphotoxin beta Receptor, Membrane Proteins/antagonists & inhibitors, Lymphoid Tissue/metabolism, Animals, Lymphotoxin-alpha/antagonists & inhibitors, Peyer's Patches/metabolism, Lymphotoxin-alpha, Scrapie/physiopathology, PrPSc Proteins/biosynthesis, Membrane Proteins, Cell Differentiation, Immunohistochemistry, 3. Good health, Mice, Inbred C57BL, Cell Differentiation/drug effects, Immunoglobulin G, Disease Susceptibility, Dendritic Cells, Follicular, Spleen, Scrapie
Popis: 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. Since FDCs require lymphotoxin signals from B lymphocytes to maintain their differentiated state, blockade of this stimulation with a lymphotoxin β receptor-immunoglobulin fusion protein (LTβR-Ig) leads to their temporary dedifferentiation. Here, a single treatment with LTβR-Ig before intraperitoneal scrapie inoculation blocked the early accumulation of infectivity and disease-specific PrP (PrPSc) 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 LTβR-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 LTβR-Ig before oral scrapie inoculation blocked PrPScaccumulation 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.
Druh dokumentu: Article
Popis souboru: application/pdf
Jazyk: English
ISSN: 1098-5514
0022-538X
DOI: 10.1128/jvi.77.12.6845-6854.2003
Přístupová URL adresa: https://jvi.asm.org/content/77/12/6845.full.pdf
https://pubmed.ncbi.nlm.nih.gov/12768004
https://www.research.ed.ac.uk/portal/files/11456671/Follicular_dendritic_cell_dedifferentiation_by_treatment_with_an_inhibitor_of_the_lymphotoxin.pdf
https://pubmed.ncbi.nlm.nih.gov/12768004/
https://europepmc.org/article/MED/12768004
https://www.research.ed.ac.uk/portal/en/publications/follicular-dendritic-cell-dedifferentiation-by-treatment-with-an-inhibitor-of-the-lymphotoxin-pathway-dramatically-reduces-scrapie-susceptibility(4943a1ba-1bc5-46fd-b659-b577bd57eac2).html
https://journals.asm.org/doi/pdf/10.1128/JVI.77.12.6845-6854.2003
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC156207
https://hdl.handle.net/20.500.11820/4943a1ba-1bc5-46fd-b659-b577bd57eac2
https://www.pure.ed.ac.uk/ws/files/11456671/Follicular_dendritic_cell_dedifferentiation_by_treatment_with_an_inhibitor_of_the_lymphotoxin.pdf
Rights: ASM Journals Non-Commercial TDM
Přístupové číslo: edsair.doi.dedup.....e487fe9073ead26d72aac653a20829f3
Databáze: OpenAIRE
Popis
Abstrakt: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. Since FDCs require lymphotoxin signals from B lymphocytes to maintain their differentiated state, blockade of this stimulation with a lymphotoxin β receptor-immunoglobulin fusion protein (LTβR-Ig) leads to their temporary dedifferentiation. Here, a single treatment with LTβR-Ig before intraperitoneal scrapie inoculation blocked the early accumulation of infectivity and disease-specific PrP (PrPSc) 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 LTβR-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 LTβR-Ig before oral scrapie inoculation blocked PrPScaccumulation 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.
ISSN:10985514
0022538X
DOI:10.1128/jvi.77.12.6845-6854.2003