ORAL DELIVERY OF GROUP-A STREPTOCOCCAL CELL-WALLS AUGMENTS CIRCULATING TGF-BETA AND SUPPRESSES STREPTOCOCCAL CELL-WALL ARTHRITIS

Oral administration of autoantigens can influence the outcome of exper imental autoimmune diseases, yet little is known about nonself Ag-indu ced tolerance. In this study, we administered group A streptococcal ce ll wall (SCW) peptidoglycan-polysaccharide complexes orally and monito red the impact on SCW-induced erosive polyarthritis, Oral administrati on of low dose SCW (3 mu g/day), initiated 7 days before an arthritoge nic dose of systemic SCW, virtually eliminated the joint swelling and destruction typically observed during both the acute and chronic phase s of the arthritis. High (300 mu g), but not intermediate (30 mu g), d ose regimens also profoundly inhibited the disease. Most previous stud ies have demonstrated that prior feeding is required for efficacy, yet oral feeding of low dose SCW suppressed the evolution of arthritis ev en when administration was begun 10-15 days after induction of the art hritis. While the synovial inflammatory cell infiltration and expressi on of proinflammatory cytokines were markedly suppressed, no local enh ancement of the regulatory cytokines IL-4, IL-10, and TGF-beta was det ected. Oral administration of low dose SCW, however, up-regulated circ ulating levels of TGF-beta, concomitant with decreased circulating TNF -alpha and suppression of chronic arthritis. Moreover, IL-10 was incre ased in tolerized spleen lymphocytes, and unexpectedly, this SCW-speci fic IL-10 production was TGF-beta dependent. These data support a pivo tal role for TGF-beta, although not necessarily in the joint, in the r egulation of specific immune tolerance responsible for suppressed syno vial 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 inf lammatory cells to the joint.