Abstract
BackgroundTo facilitate the development of therapies for rheumatoid arthritis (RA), the Innovative Medicines Initiative BTCure has combined the experience from several laboratories worldwide to establish a series of protocols for different animal models of arthritis that reflect the pathogenesis of RA. Here, we describe chronic pristane-induced arthritis (PIA) model in DA rats, and provide detailed instructions to set up and evaluate the model and for reporting data.MethodsWe optimized dose of pristane and immunization procedures and determined the effect of age, gender, and housing conditions. We further assessed cage-effects, reproducibility, and frequency of chronic arthritis, disease markers, and efficacy of standard and novel therapies.ResultsOut of 271 rats, 99.6% developed arthritis after pristane-administration. Mean values for day of onset, day of maximum arthritis severity and maximum clinical scores were 11.8±2.0 days, 20.3±5.1 days and 34.2±11 points on a 60-point scale, respectively. The mean frequency of chronic arthritis was 86% but approached 100% in long-term experiments over 110 days. Pristane was arthritogenic even at 5 microliters dose but needed to be administrated intradermally to induce robust disease with minimal variation. The development of arthritis was age-dependent but independent of gender and whether the rats were housed in conventional or barrier facilities. PIA correlated well with weight loss and acute phase reactants, and was ameliorated by etanercept, dexamethasone, cyclosporine A and fingolimod treatment.ConclusionsPIA has high incidence and excellent reproducibility. The chronic relapsing-remitting disease and limited systemic manifestations make it more suitable than adjuvant arthritis for long-term studies of joint-inflammation and screening and validation of new therapeutics.
Highlights
There is a critical need for better and well-defined animal models for rheumatoid arthritis (RA) that display the specific aspects of the human disease and can serve as platforms for research on the underlying pathology, as well as for drug discovery and validation [1,2]
The onset of overt pristane-induced arthritis (PIA) is characterized by an increased acute phase response, which together with the symmetrical disease manifestations, presence of IgG rheumatoid factors, and the chronic disease course establishes PIA as one of the few models that fulfils the American College of Rheumatology (ACR) classification criteria for RA [16,19,20,21]
To best illustrate the various clinical aspects of PIA, we compared the disease course between rats immunized with pristane (PIA), IFA (OIA), IFA supplemented with Mycobacterium butyricum (AA), and rat collagen type II (CII) emulsified in IFA (CIA)
Summary
There is a critical need for better and well-defined animal models for rheumatoid arthritis (RA) that display the specific aspects of the human disease and can serve as platforms for research on the underlying pathology, as well as for drug discovery and validation [1,2]. Administration of paraffin oils and mannide monooleate can elicit arthritis in the absence of Mb (i.e. incomplete Freund's adjuvant, IFA). This so-called oil-induced arthritis (OIA) model is acute and relatively mild compared to AA [11,12]. Similar to other rat adjuvant-models, initiation and perpetuation of pristane-induced arthritis (PIA) is dependent on CD4+ T cells [14,15]. In contrast to AA, self, rather than foreign, MHC class II-restricted antigens initiate the immune response in PIA The specificities of these antigens remain largely unknown, T cell recall responses have been demonstrated to both ubiquitous and joint-specific antigens in acute and chronic PIA [16,17]. We describe chronic pristane-induced arthritis (PIA) model in DA rats, and provide detailed instructions to set up and evaluate the model and for reporting data
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