NR ARCP
AU Klein,M.A.; Remer,K.; Flechsig,E.
TI Neuro-immune interaction in peripheral prion pathogenesis
QU TSE-Forum, 4. Kongress - Nationale TSE-Forschungsplattform, Düsseldorf 28.10.-29.10.2004, Vortrag V-06
PT Konferenz-Vortrag
AB
The pathophysiological sequences which lead from the uptake of prions to the clinical disease in the nervous system are not understood in detail. Accumulating evidence indicates that the peripheral nervous system and the immune system are involved in the transfer of the infectious agent. In most TSE diseases the gastro-intestinal tract represents the natural entry site for the infectious agent. Various cells including dendritic cells (DC) and M cells have been suggested as candidates for the up-take of prions from the gut lumen and for a role in the transport to the underlying gut associated lymphoid tissue (GALT). After oral infection prions accumulate in the follicular dendritic network of the GALT and are very rapidly detectable in associated nerve fibers. The mechanisms how prions infiltrate the GALT, other secondary lymphoid organs and finally the nervous tissue are still unclear. DC are possible candidates for an initial up-take and dissemination of prions since these cells are motile and specialized in antigen presentation and up-take of pathogens. We started to further clarify the role of DC in the transport of prions from the periphery to the spleen and the ability of DC to transmit the disease.
Immature DC were generated from bone marrow of Prnp+/+ and Prnpo/o mice by differentiation with murine GM-CSF in vitro and transferred to Prnp+/+-recipient mice by subcutaneous injection. First results show that bone-marrow DC take up recombinant PrP, PrPc and PrPsc in vitro and transmit the disease independent of their own PrP-expression. Possible mechanisms for this up-take could involve active phagocytosis or accumulation of PrP on the cell surface of DC. To investigate the role of DC after acquisition of PrPsc in vivo splenic DC (sDC) were isolated from spleens of RML-infected EGFP transgenic mice. Fractions of sDC, T-/B-/NK-cells and macrophages, a residual cell fraction, and 1% splenic stroma were transferred to Prnp+/+-recipient mice intraperitoneally. Preliminary results indicate that the stromal fraction (containing FDC, and nerve fibers) and the cellular fraction containing T, B, NK and macrophages lead to the development of scrapie in recipient mice after >200 days. Further analyses will clarify, whether the purified splenic DC are harboring prions and would represent a cellular component to transport the agent within infected animals.
AD Michael A. Klein, Katharina Remer and Eckhard Flechsig, Prion Research Group, Institute of Virology and Immunobiology, University of Würzburg
SP englisch
PO Deutschland
OR Tagungsband