Oral administration of autoantigens can influence the outcome of experimental autoimmune diseases, yet little is known about nonself Ag-induced tolerance. In this study, we administered group A streptococcal cell wall (SCW) peptidoglycan-polysaccharide complexes orally and monitored the impact on SCW-induced erosive polyarthritis. Oral administration of low dose SCW (3 microg/day), initiated 7 days before an arthritogenic dose of systemic SCW, virtually eliminated the joint swelling and destruction typically observed during both the acute and chronic phases of the arthritis. High (300 microg), but not intermediate (30 microg), dose regimens also profoundly inhibited the disease. Most previous studies have demonstrated that prior feeding is required for efficacy, yet oral feeding of low dose SCW suppressed the evolution of arthritis even when administration was begun 10-15 days after induction of the arthritis. While the synovial inflammatory cell infiltration and expression of proinflammatory cytokines were markedly suppressed, no local enhancement of the regulatory cytokines IL-4, IL-10, and TGF-beta was detected. Oral administration of low dose SCW, however, up-regulated circulating levels of TGF-beta, concomitant with decreased circulating TNF-alpha and suppression of chronic arthritis. Moreover, IL-10 was increased in tolerized spleen lymphocytes, and unexpectedly, this SCW-specific IL-10 production was TGF-beta dependent. These data support a pivotal role for TGF-beta, although not necessarily in the joint, in the regulation of specific immune tolerance responsible for suppressed synovial inflammation and matrix destruction. The distant induction and up-regulation of regulatory cytokines and/or cells may contribute to the inhibition of the immune response through blunted infiltration of inflammatory cells to the joint.