Humanised mice for the study of chronic viral infections Flashcards
Why are HBV; HCV and HIV difficult to study?
narrow species tropism- only humans and chimpanzees
What is a surrogate model for HBV infection?
woodchuck hep B virus
What is the problem with cell culture systems?
limited to highly adapted viral genomes and don’t fully recapitulate viral pathogenesis
What is the success of xenografting dependent on ?
the inability for the host to reject the foreign cells
What is the immunodeficiency in Nude mice?
athymic- no T cells
What is the immunodeficiency with IL2gR-deficiency?
NK cell and DC deficiency
Which cells express CD47?
majority of health cells
what is the function of CD47?
interacts with SIRPa on macrophages triggering a don’t eat me signal
Why are NOD mice very useful xenorecipients?
have a SIRPa allele very similar to human SIRPa therefore mouse macrophages recognise human cells as self
What happens when the IL2 gamma chain is knocked out?
results in deficiencies in multiple subsets of cell and inability to respond to lots of cytokines– unable to mount an immune reposnse
What are human peripheral blood lymphocyte mice?
mice where PBMCs have been intraperitoneally injected into the mouse- allowing you to test human immune cell responses for a short period
What is the problem with human peripheral blood lymphocyte mice?
will get host vs graft as human T cells will attack mouse
How do you create human immune system mice?
take haematopoietic stem cells from the foetal liver and inject them into an irradiated mouse, which then develops a human immune system educated by mouse antigens
What is a human bone marrow/liver/thymus mice?
a mouse that develops multi-lineage haematpoiesis as well as organised lymphoid tissues of human origin
What happens to HIV in HIS mice?
accumulate mutations in CD8 T cell epitopes Env and Nef to evade T cells
What is a problem with HIS mice?
have a suboptimal humoral rresponse
How can humoral immunity in HIS mie be improved?
cytokines and growth factors
what happens when cytokine are supplemented to HIS mice?
get a change in Th1/Th2 balance- increased Th2 cells
What are MISTRG mice?
Rag2 deficient, IL2gR deficient mice with human versions of IL3; GM-CSF and thrombopoietin that have completely functional NK cells
What is the probem with injecting human IL-12 into a mouse?
the immune response kills the mouse after around 4 weeks
How is a human liver-chimeric mouse created?
a highly immunodeficient mouse lacking T, B and NK cells with liver injury is injected into the spleen with human hepatocytes creating a model for HBV and HCV
Why does there need to be liver injury in the immunodeficient mouse?
to give the human hepatocytes a survival advantage
What can be used as a marker of engraftment with human liver-chimeric mice?
albumin
What has to be given to enable engraftment in the mouse with fetal liver?
oncostatin M
What can the pathogenesis; adaptive immunity adn vaccinations be testing on mice with HBV/HCV?
create a human immune system mouse first then reconstitute the liver
What is the result of HBV infection on human NK cell infiltration into the liver?
HBV doubles the numbers of NK cells infiltrating hte liver
What is the new frontier in humanised mouse models?
replacing the use of primary cells in creating humanised models with induced pluripotent SCs
Which cytokines is the common gamma chain part of hte receptors for?
IL2; IL4; IL7: IL9; IL15 nad IL21
What is the problem with the HIS model?
cells are educated on the murine thymus- lacks some human-specific factors needed to fully mimic all aspects of human T cell development and are H2 restricted (mouse MHC)
What is a disadvantage of hte BLT model?
development of a wasting GVHD-like syndrome following long-term engraftment
Why is the BLT model mainly used for studying HIV?
BLT has a higher level of human mucosal engraftment allowing hte vaginal and rectal transmission of HIV to be studied
What mediates the entry of HCV into the cell?
claudin-1
