reversal of acute and chronic synovial inflammation by anti-transforming growth factor β

Abstract

Transforming growth factor β (TGF-β) induces leukocyte recruitment and activation, events central to an inflammatory response. In this study, we demonstrate that antagonism of TGF-β with a neutralizing antibody not only blocks inflammatory cell accumulation, but also tissue pathology in an experimental model of chronic erosive polyarthritis. Intraarticular injection of monoclonal antibody 1D11.16, which inhibits both TGF-β1 and TGF-β2 bioactivity, into animals receiving an arthropathic dose of bacterial cell walls significantly inhibits arthritis. Inhibition was observed with a single injection of 50 μg antibody, and a 1-mg injection blocked acute inflammation >75% compared with the contralateral joints injected with an irrelevant isotype control antibody (MOPC21) as quantitated by an articular index (AI = 0.93 ± 0.23 for 1D11.16, and AI = 4.0 ± 0 on day 4; p <0.001). Moreover, suppression of the acute arthritis achieved with a single injection of antibody was sustained into the chronic, destructive phase of the disease (on day 18, AI = 0.93 ± 0.07 vs. AI = 2.6 ± 0.5; p <0.01). The decreased inflammatory index associated with anti-TGF-β treatment was consistent with histopathologic and radiologic evidence of a therapeutic response. These data implicate TGF-β as a profound agonist not only in the early events responsible for synovial inflammation, but also in the chronicity of streptococcal cell wall fragment-induced inflammation culminating in destructive pathology. Interrupting the cycle of leukocyte recruitment and activation with TGF-β antagonists may provide a mechanism for resolution of chronic destructive lesions.