AbstractObjectiveTo assess the therapeutic potential of a P2X purinergic receptor antagonist, namely, periodate oxidized ATP, in collagen‐induced arthritis (CIA).MethodsArthritis was induced in male DBA/1J mice by immunization with type II collagen (CII). Animals showing digit inflammation and paw swelling were treated intraperitoneally with 100 μl of 3 mM oxidized ATP daily for 10 days. At the end of the treatment period, animals were killed and paws were removed for histologic analysis and evaluation of T cell infiltration. Humoral response to CII was analyzed, and specific serum autoantibody levels were correlated with the clinical scores observed in the different treatment groups.ResultsTreatment with oxidized ATP resulted in a sustained reduction in disease activity, which was associated with a significant decrease in CD3+ T cell infiltration in arthritic lesions and a significant amelioration of cartilage erosion. Peripheral Treg cells were significantly increased upon P2X blockade in mouse lymph nodes. Moreover, a marked reduction in circulating autoantibodies directed against mouse CII was detected. There was a significant correlation between serum autoantibody levels and the clinical efficacy of oxidized ATP.ConclusionOur findings indicate that P2X receptor antagonism has important therapeutic potential in chronic inflammatory rheumatic disorders. Taken together, our results underscore the value of the P2X receptor signaling pathway as a potential pharmacologic target for the modulation of adaptive immunity in CIA.