The Tellurium-based Immunomodulator, AS101 Ameliorates Adjuvant-Induced Arthritis in Rats.

BACKGROUND Despite undeniable improvement in the management of rheumatoid arthritis (RA), the discovery of more effective, less toxic and, ideally, less immune suppressive drugs are much needed. In the current study, we set to explore the potential anti-rheumatic activity of the non-toxic, tellurium-based immunomodulator, AS101 in an experimental animal model of RA. METHODS The effect of AS101 was assessed on Adjuvant-induced arthritis (AIA) rats. Clinical signs of arthritis were assessed. Histopathological examination was used to assess inflammation, synovial changes and tissue lesions. Very late antigen-4 (VLA4)+ cellular infiltration was detected using immunohistochemical staining. Enzyme-linked immunosorbent assay (ELISA) was used to measure circulating anti-cyclic-citrullinated-peptide autoantibody (ACPA) and real time PCR was used to measure the in vitro effect of AS101 on interleukin-6 (IL-6) and interleukin-1beta (IL-1β) expression in activated primary human fibroblasts. RESULTS Prophylactic treatment with intraperitoneal AS101 reduced clinical arthritis scores in AIA rats (p<0.01). AS101 abrogated the migration of active chronic inflammatory immune cells, particularly VLA4+ cells, into joint cartilage and synovium, reduced the extent of joint damage, and preserved joint architecture. As compared to PBS-treated AIA rats, histopathological inflammatory scores were significantly reduced (p<0.05). Furthermore, AS101 resulted in a marked reduction of circulating ACPA in comparison to PBS-treated rats (p<0.05). Importantly, AS101 significantly reduced mRNA levels of pro-inflammatory mediators such as IL-6 (p<0.05) and IL-1β (p<0.01) in activated primary human fibroblasts. CONCLUSION Taken together, we report the first demonstration of the anti-rheumatic/inflammatory activity of AS101 in experimental RA model thereby supporting an alternative early therapeutic intervention and identifying a promising agent for therapeutic intervention.