NR ATNY
AU Koenig,M.; Kalinke,U.
TI Generation of a new transgenic mouse model to study PrP-specific B cell tolerance
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Poster Session: Human prions, risk of blood products, and therapy HUMAN-22
PT Konferenz-Poster
AB Transmissible spongiform enzephalopathies (TSEs) including BSE, scrapie or nvCJD are neurodegenerative disorders affecting humans and other species. TSEs are most probably caused by misfolded isoforms (PrPsc) of the cellular prion-protein (PrPc). Due to immunologic tolerance against host PrPc, in PrPsc infected individuals pathogen-specific immunity is not induced. So far there is no effective prophylactic or therapeutic approach available. To study the basis of B cell tolerance in greater detail, we set out to develop a new transgenic mouse model. The targeting strategy is based on replacing the four JH elements of the endogenous immunoglobulin heavy chain locus by a cassette containing two inversed rearranged variable heavy chain regions (VH) flanked by opposed loxP sites. The one VH located next to the intron enhancer was derived from the LCM-virus specific antibody KL25, whereas the inversed VH was cloned form a PrP-specific antibody. Mice derived form the targeted embryonic stem cells presumably will express an anti-LCMV-antibody heavy chain, whereas upon induction of Cre expression, the loxP flanked cassette is expected to be inverted, thus moving the anti-PrP-specificity in a position where it can be transcribed. This model would allow the induction of the development of a limited number of PrP-specific B cells, i.e. self-reactive B cells, in a host primarily carrying B cells with specificities against foreign antigens. In conclusion, the new mouse model will allow studying the fate of potentially auto-aggressive B cells in vivo. Furthermore we plan to characterize conditions leading to autoimmunity and to get insights whether immunotherapy against self-epitopes is applicable.
AD Martin Koenig, Ulrich Kalinke, Paul-Ehrlich-Institut, Division of Immunology, Langen
SP englisch
PO Deutschland