Caput Animal models for RA
13 important questions on Caput Animal models for RA
What therapies are used for treatment of RA?
- Nonsteroidal anti-inflammatory drugs (NSAIDs): first-line therapy, provide relief from the symptoms of RA
- Glucocorticoids: intra-articular steroids
- Disease modifying anti-rheumatic drugs (DMARDs): limit long-term morbidity by achieving disease control before irreversible damage occurs
- Biologicals: targeting of specific critical mediators of inflammation
Why are animal models needed?
• A fraction of the patients responds poorly to treatment or not at all
• Side effects (infections, malignancies)
• No permanent cure and long term (expensive) treatment
Clinical trials are only allowed when ijn vivo data from animal models show the potential of the drugs.
What are the similarities and differences between the human model and the animal model of RA?
Human RA is progresive and spontaneous.
Animal model: Genetics, disease antigen and age are now and can be similarized. In animal models of RA, lymphoid structures are found in the synovium which is not the case in human, but pathology is the same. The disease model in animals is induced and sometimes self remitting.
This influences the predictive value.
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Explain why no arthritis model consistently predicts the effect of therapeutic agents in patients.
No model is truly RA.
What specific characteristics are important for an animal model specific for RA?
- The model needs to be useful for novel immunotherapy development (so, regulation of disease is investigated; not the cause of disease).
- The model has to be T cell dependent, since T cells are crucial in RA pathogenesis.
What are the pro's and cons of using specific mice and monkeys as animal models?
Mice are a good representative model for human RA and best for development of therapy.
Which aspects need to be taken in consideration when you decide which model is most convenient?
Why are mice often most convenient?
- Animal species, strains
- Experimental design
- Disease incidence
- Reproductibility
- Laborious
- Costs
Mice are small, less expensive, easy to handle, inbred and KO strains are available, intensively used (knowledge, tools).
Which mice models for RA do you know and in how do they differ?
- Antigen induced arthritis: chronic disease, antigen is irrelevant (is not seen in human RA).
- Collagen or proteoglycan induced arthritis: chronic disease, antigen is relevant (human RA; collage/proteoglycnn is attacked by immune system.
- K/BxN mice, SKG, IRAP and PG-TCR mice: transgene, spontaneous development of RA
- Adjuvant arthritis: self-remitting.
What are the differences in mice models of collagen induced arthritis and proteoglycan induced arthritis?
Proteoglycan induced arthritis: less used, old females, laborious to make disease inducing antigen, resembles human RA (but: development of spondylitis = different disease).
"RA is associated with the development of autoimmunity to type I1 cartilage collagen and to cartilage proteoglycan. The immunity expresses itself through both the production of autoantibodies and the development of T cell-mediated cellular immunity. "
Explain the mechanism of the proteoglycan induced arthritis mouse model
...
It causes chronic (relapsing), t cell mediated arthritis due to a cross-reactive immune respons between immunizing (human) and self (mouse) proteoglycan.
How can targeting T cells be used as a therapy for RA?
Therapy: activate Tregs and transfer them to patient to supress disease.
What markers can be used to isolate/identify T regulatory cells?
How can Tregs be examined in research; how are Tregs characterized (which markers)?
"Only CD25+ LAG3+ Tcells supress".
APC expresses Hsp, Tcell binds, upregulates LAG3 and then supresses (so, transfer of only LAG3+ cells is not necessary).
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