Reversal of Acute and Chronic Synovial Inflammation by Anti - Transformlng Growth Factor

Transforming growth factor 3 (TGF-3) induces leukocyte recruitment and activation, events central to an inflammatory response. In this study, we demonstrate that antagonism of TGF-3 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 1Dll.16, which inhibits both TGF-B1 and TGF-32 bioactivity, into animals receiving an arthropathic dose of bacterial cell walls significantly inhibits arthritis. Inhibition was observed with a single injection of 50 #g antibody, and a 1-mg injection blocked acute inflammation >75% compared with the contralateraljoints injected with an irrelevant isotype control antibody (MOPC21) as quantitated by an articular index (AI = 0.93 _+ 0.23 for 1Dl1.16, and AI = 4.0 _+ 0 on day 4; iv <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-/~ treatment was consistent with histopathologic and radiologic evidence of a therapeutic response. These data implicate TGF-3 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-B antagonists may provide a mechanism for resolution of chronic destructive lesions.