UBC Theses and Dissertations
Investigation of an adjuvant-enhanced model of murine arthritis and its therapeutic application Ratkay, Leslie Gabriel
A major difficulty in understanding the etiology and pathogenic mechanisms of rheumatoid arthritis has been the lack of a suitable animal model. Based on the MRL-lpr spontaneous arthritis model, a new murine arthritis model was developed, that is reliable and practical for therapeutic evaluations. The MRL-lpr mouse strain develops an early autoimmune disease. After the characterization of our colony, it was concluded that while the strain did not exhibit differences in the lupus-like syndromes, the spontaneous arthritis became less severe than originally described. To enhance the spontaneous arthritis of MRL-lpr mice, the effect of complete Freund’s adjuvant (CFA) was investigated. In contrast to the low percentage observed in control animals, 67-82% of mice showed clinical evidence of arthritis. Similarly, the histopathological and immunohistological analyses of the CFA injected mice indicated a significantly higher frequency of inflammation, cartilage erosion and pannus formation, with marked infiltration of activated inflammatory cells, including lymphocytes. The requirement of the lpr gene and background MRL genes was then examined. It was found that while both 7 month old MRL-+ and 3 month old MRL-lpr mice developed arthritis, B6, B6-lpr, and 3 month old MRL-+ did not display the condition after CFA-treatment. These observations suggest that while the lpr gene causes a more severe early effect, background genes other than the lpr are also involved in the disease. The effect of pregnancy, as another possible enhancing factor, was also investigated. Sixty-eight percent of female MRL-lpr mice developed a post partum exacerbation of their mild spontaneous arthritis. Post-partum or post adjuvant-injection administration of estradiol prevented the enhancement of arthritis. The effectiveness of a recently developed photodynamic therapy (PDT) was also assessed and compared with conventional experimental therapies in the treatment of adjuvant arthritis. PDT inhibited the development of adjuvant enhanced arthritis with similar effectiveness as the conventional treatments, but without their negative side effects. These results illustrate that CFA-enhancement results in a reproducible model of murine arthritis, which is useful in evaluating experimental therapeutic regimes, and demonstrating effectiveness of PDT arthritis therapy.
Item Citations and Data