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JAK2-STAT3 Blockade by AG490 Suppresses Autoimmune Arthritis in Mice via Reciprocal Regulation of Regulatory T cells and Th17 cells

Park JS, Lee J, Lim MA et al. - J Immunol 2014; 192:4417-4424

In this study, Park et al sought to investigate the effects of the JAK2 inhibitor, AG490 in RA. Using murine CIA models, both preventative and therapeutic models were investigated. In the preventative model, CIA mice treated with AG490 showed a significantly lower incidence rate of arthritis and arthritic scores when compared to mice injected with vehicle. In the therapeutic model, as in the preventative, AG490 treated mice exhibited less severe arthritis.
Through further experiments, it was demonstrated that the clinical improvements shown in the mCIA models were due to the inhibition of Th17 differentiation and the upregulation of Treg cells. This lowered the amount of Th17-induced proinflammatory cytokine production. The reciprocal regulation between Th17 and Treg cells is driven by p-STAT3 and p-STAT5 competition. STAT3 is required for Th17 differentiation while STAT5 is needed for Treg. Though not statistically significant, there was a decrease in STAT3 cells and increase in STAT5 suggesting that AG490 specifically inhibits the JAK2-STAT3 pathway, leaving JAK2-STAT5 unaffected. Also, a direct inhibitory effect on osteoclastgenesis.
While JAK2 inhibition is normally avoided due to its essential role in hematopoiesis, in the doses used for arthritis inhibition within this murine model there is no effect on normal erythropoiesis. It is unclear how this would translate into humans. However, these results suggest that AG490 may be a promising treatment for rheumatoid arthritis.

Keywords: JAK, Preclinical, MOA

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Upload date: May 2014

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