Human xenograft models Flashcards
What does the ability to xenograft cells or tissue depend on?
inability of the host to reject foreign cells- no host vs graft
What is compartmental xenografting?
engraftment of health cells/tissues of mice with human cells
What type of immunodeficiency do Nude mice have?
athymic- no T cell repsonses
What type of immunodeficiency do SCID and Rag1 deficient mice have?
no B and T cell maturation
What type of immunodeficiency do IL2gR deficient mice get?
NK cell and DC deficiency
How do macrophages recognise RBCs to phagocytose?
they slowly lose CD47 which is recognised by SIRPa on macrophages
Which cytokines does IL2 receptor common gamma chain deficiency result in deficiencies in?
IL-2; IL-4; IL-7; IL-9; IL15; IL-21 TSLP
What cell types does IL2 gamma chain defiency result in deficiencies of?
B cells; T cells; NK cells; DCs
What is the benefit of the BLT model?
human T cells are educated on human thymus; superior reconsitituion of GALT; rectal and vaginal tissues with human leucocytes
How is the engraftment of humanised mouse models determined?
FACS comapring the number of cells with human vs mouse CD45
How long can human PBL-SCID mice be used for?
4-6 weeks due to severe GvHD
What disease are BLT mice particularly used for?
HIV- pathogeneesis and treatments
What type of virus is dengue virus?
plus strand RNA virus of the flaviviridae family
What is the secondary infection of dengue virus associated with?
exacerbation of symptoms- haemorrhagic fever or shock syndrome
Why are humanised mice models useful in dengue virus?
other animal models have not been very useful, but humanised mice exhibit key dengue pathogenesis
What is the disease with yellow fever?
viral haemorrhagic fever- mortality 15-50%
How was the yellow fever vaccine developed?
live attenuated Asibi strain by passaging in different animal cells
Why are humanised mice models good for yellow fever?
there are no animal models of the diseease
What happened to the yellow fever virus as it was passaged to become attenuated?
it lost virulence but gained immunogenicity
What is responsible for the pathogenicity of ywllo fever?
envelope
How was the importance of hte envelope in yellow fever determined?
reverse genetics
What is the problem with HIS mice and yellow fever vaccination?
do not develop humoral repsonses properly and actually die faster than non-immunised mice exposed to yellow fever
Waht type of humanised mouse model does yellow fever vaccination work in?
PBL-SCID model: if mice are given PBMCs from an immunised human—lack of immune functionality in the mice is reponsible for lack of immune clearance
Waht are the antibody levels like in HIS mice compared with normal human?
massively redued
How can humoral immunity in huamnised mice models be improved?
supplementing non-corss reactive cytokines and growth factors
Waht cytokines are essential for B cell differentiation?
GM-CSF and IL-4
Which type of Th response is favoured in huamnised mice?
Th2
How cna humanised mice models be used to study T cell plasticity?
Th2 bias in humanised mice but if supply IL-12, cells switch to Th1
What is seen in NK cells in conventional humanised micemodels?
IL2gR deficiency combined with limited cross-reactivity with human factors–impaired nk cells
What mouse model displays completely functional NK cells?
expression of human IL3; GM-CSf and thrombopoeitin —-MISTRG mice
What is important about MISTRG mice?
normal myeloid development
What mutations are see in FNRG KO-NOD mice?
FAH-/-: metabolic liver disease; NOD background- optimal xenograft maintenance; Rag-/-: T and B cell deficiency; IL2gR-/-: NK cell deficiency
How much of the mouse liver can be repopulated with human hepatocytes?
upto 90%
How can the repopulation of hte mouse liver with human cells be measured?
human albumin levels
What is the function of human liver-chimeric mice?
study of human-specific hepatotropic infections
What is given to facilitate the engraftment of foetal hepatoblasts in FNRG mice?
recombinant human oncostatin M
what happens with NK cells upon infection with HBV?
NK cells infiltrate the human liver
What are some of the laternative approaches to animal models?
bio-engineering artificial organs using primary cells and microfluidics
