Comparison of animal model to human data Flashcards
Mice vs. Man (similarities and differences)
- mice are mainstay of in vivo immunological experimentation
- ~300 genes are unique to a species
- significant differences in:
- immune system development
- immune system activation
- immune response to challenge
- lifespan and size
- pathological challenges
=> not everything can be translated -> interpret findings with caution
Explain the differences in PBMC composition
mouse:
- 70-80 % T cells; 2/3 CD4+ and 1/3 CD8+
- 10-15 % B cells
- < 5% NK cells
- < 2,3% monocytes
- < 1% Other
human:
70–90 % lymphocytes
- 10-20 % monocytes
- 1–2 % dendritic cells
Nitric oxide formation and innate immunity
- macrophages are activated by INF-γ
- play an essential part in innate immunity for mice
Antimicrobial role of vitamine D3
- synthesis is UV-B dependent
- induces hCAP18/Cathelicidin expression in monocytes cells
- induction of CAMP by VitD3 is not evolutionary conserved
Itaconic acid expression and host defence
Itaconitate is sugar, synthesis between Citrate and Isocitrate (TCA-cycle)
- Itaconic acid formation correlates with LPS induced immune responsive gene (IRG) 1induction and also inhibits growth of Mtb and Salmonella enterica
- murine macrophages produce 100 fold higher itaconic acid levels compared to human
TLR/NF-kB dependent formation of Wnt
- Wnt plays role in embryogenesis, differentiation and carcinogenesis
- seems to play also a role in inflammation and infection regulation
- Wnt5a -> pro-inflammatory
- Wnt3a/Wnt/ß-Catenin -> anti-inflammatory
- Wnt6 expression in lung of Mtb-infected mice and man (macrophages)
induction is TLR dependent in human and zebrafish but not in mice; the function is similar in human and mice
TLR 13 (function and evolution)
- only active in mice not in human
- TLR signalling in general:
- dimers
- proinflammatory cytokine formation when adaptor TIRAP/MAL, MyD88 => surface TLRs
- Type I interferon formation when adaptor TRAM/TICAM2, TRIF/TICAM1 => endosome TLRs
Chemokine expression in mice and human
- > 50 known
- many species exclusive chemokines -> redundant signalling
- ligand (chemokine) binds to 7TMR (GPR) and induces activating signalling by G-protein and ß-arrestin + desensitisation and internalisation by ß-arrestin
- also ligand dependent -> biased to one or the other side
models for MS
- multifunctional disease with large autoimmune component -> allergic encephalomyelitis is used model
- in mice INF-γ appears to help in a protective manner
- in human INF-γ makes it worse
- ant-α4 integrity on the other hand is an example of successful translation from mice to human
TB granuloma formation
- granuloma necrosis in Mtb infection can be seen in human, guinea pig and rabbit but not in mice
- IL-13tg mice however develope granulomas
TB vaccination MVA85
BCG vaccination protects newborns from meningitis; no protection against pulmonary TB
improved TB vaccine was successful in cattle, rhesus macaques, mice and guinea pigs but not in human
Mouse models in human inflammatory diseases
hard to generalise
mice are probably not a good model (don‘t mimic up to 90% of genes) but are the best we have
TGN1412: cytokine storm in phase 1
- recombinantly expressed, humanized superagonist for anti-CD28 -> stimulates and expands T cell independently of ligation of T cell receptor
- intended for treatment of rheumatoid arthritis and B cell lymphoma
- very good in mice (not toxic, not proinflammatory)
- severe side effects in phase 1 study -> hospitalisation of all 6 patients
Summary for comparison
- species differences (mice ≠ man, C57BL6 ≠ Balb/C)
- sex difference
- a model is a model
- cell specific expression of receptors, molecules and genes
