Models of Rheumatoid Arthritis (RA)
Rheumatoid arthritis (RA), is a systmic chronic autoimmune inflammatory disease of the joints resulting in cartilage and joint destruction. RA affects 0,5-1% of the population with a onset typically between ages 25-50 and a predominance in women. Disease pathogenesis is highly heterogenous and influenced of both environmental and genetic factors. Also disease devleopment and disease course is hetergenous. The clinical phase of disease when symphtoms appear and also treatment is initiated is proceeded by a preclinical where the immune system build up a response towards the target organ. RA is characterized by inflammation in the synovial membrane, leucocyte infiltration, joint swelling and pain. Although joints are the main target of the disase progress in RA, patients may present with extra-articular features including sub-cutaneous nodules, vasculitis and pulmonary fibrosis. In addition, there is a systemic inflammatory response with eleveated levels of autoantibodies and acute phase proteins.
Due to this complexity of the disease, a singe in vivo model cannot mimic RA there are a number of valid models reflecting different aspects of the human disease. Redoxis offers passively and actively induced models of RA in both rats and mice. All have their own chararcteristics and cellular mechansims and carefull model selection is therefor crucial for sucsessfull experiments.
Rat and mouse models mimicking different aspects of the pathogenesis in human disease are invaluable tools to understand the basic biological mechansms, to identify and validate novel disease mediating pathways and targets and to screen and evaluate efficacy fo potential preventive and therapeutic agents. All models exhibit classical features fo RA including joint swelling, synovitis, pannus formation and bone erosion but differ in onset, chronicity, severity, resolution and histopathology.
Mouse Collagen Induced arthritis
Collagen-Induced Arthritis (CIA) in mice is one of the most commonly used animal models of autoimmune arthritis. Disease is induced in susceptible strains by immunization with heterologous collagen type II (CII) in adjuvant. CIA in mice carries both the pathology driven by T cells and the antibody production against collagen. Disease is induced with one injection of CII in complete Freund´s adjuvant (CFA). A booster injection containing collagen in Incomplete Freund´s adjuvant (IFA) is given day 21 to enhance disease development. CIA is dependent on genetic factors but also environmental factors determine the severity of the disease.
Onset of arthritis is observed shortly after boost day 21. The mice develop an acute nonsymmetrical erosive polyarthritis. Both Th1 and Th17 cells play important roles in the disease but Th17 cells appear to play the dominant pathological role. Both B and T cell immunity to autologous CII is requried for disease manifestation.
Mouse Collagen antibody induced arthritis (CAIA)
Collagen antibody induced arthritis (CAIA) in mice is an arthritis model independent of both B and T cells. Disease is induced with antibodies to collagen type II. The antibodies bind to cartilage, thereby activating the immune system and recruiting macrophages and granulocytes to the joints. CAIA is an acute model of arthritis. CAIA can also be used to investigate timing of the effect of a potential therapy by administrating the drug at different days after disease induction. CAIA in the susceptible strains DBA/1 or BALB/c has a disease course that is highly predictable with an onset after LPS boost day 5. The disease reaches maximum severity around day 15 and is thereafter healing out.
Mouse Glucose-6-phosphate Isomerase induced arthritis (GPIA)
Glucose-6-phosphate isomerase-induced arthritis (GPIA) is a CD4+ T cell dependent autoimmune disease causing symmetric polyarthritis of the small distal joint. In this model, arthritis is induced by immunization with an injection of a single short peptide or whole recombinant protein of a ubiquitously expressed protein, glucose-6-phosphate isomerase [GPI] emulsified with adjuvant, in genetically unaltered mice. The immunization leads to an acute disease with a highly reproducible onset about 9 days after induction. The most severe phase of the disease is between 10-15 days after induction and is thereafter decreasing in severity until eventually healing out and the experiment can be terminated between days 20-25.
Rat Collagen induced arthritis
Collagen-induced arthritis (CIA) in rat is an animal model that to a large extent mimics the criteria used for diagnosis of rheumatoid arthritis (RA). CIA in rat is a model that is characterized by both the T cell dependent inflammatory response and the collagen antibody dependent B cell response. CIA can be induced in susceptible rat strains (e.g. DA, Wistar, PVG, Lewis) with one single injection of homologous collagen type II in IFA, subcutaneously at the base of the tail. Disease onset is approximately two weeks after induction, most severe phase of arthritis is observed between 20-30 days after induction and the experiment can be terminated after 30-40 days.
Rat Pristane Induced Arthritis
Pristane-induced arthritis (PIA) in rats is an animal model that mimics the criteria used for diagnosis of rheumatoid arthritis (RA). PIA is one of the most reproducible models of RA with high incidence and little variation in severity. Disease is characterized by a pronounced T cell dependent inflammatory response resulting in inflammation of peripheral joints. Disease is induced with a single injection of pristane and has a highly reproducible onset of arthritis between day 8-12. The most severe phase of arthritis is often between day 15-25 after induction and experiment can be terminated after 25-30 days.
Rat Adoptive transfer model
Arthritis in rats can be transferred to naïve recipients with Ex Vivo activated arthritogenic CD4+ T cells. In this model, autoreactive cells are transferred to naïve recipient rats following activation in presence of the test item ex vivo. We know from earlier studies that it is CD4+ T cells that transfer the disease and this model provides an opportunity to study the effect of novel drug candidates ex vivo in a controlled manner requiring low amount of test item. Splenocytes are collected from donor rats day 10-14 after induction of Pristane Induced Arthritis (PIA). Cells are stimulated ex vivo for 48 hours with Concanavalin A. After 48 hours of T cell activation in the presence of drug candidate, the cells can be transferred to naïve recipient rats that develop arthritis with onset estimated to 5-8 days after transfer. Cells can be analysed for used as a tool to study the direct or indirect effect of novel candidate drugs on the immune cells in an Ex Vivo assay providing a controlled environment where concentration of compounds and cellular phenotypes can be closely examined, i.e. without concern of formulation, bioavailability and first pass metabolism.