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*
Oral Infection and Immunity Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892; and
Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
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 µg/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 µg), but not
intermediate (30 µg), 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-ß was detected. Oral administration of low dose SCW,
however, up-regulated circulating levels of TGF-ß, concomitant with
decreased circulating TNF-
and suppression of chronic arthritis.
Moreover, IL-10 was increased in tolerized spleen lymphocytes, and
unexpectedly, this SCW-specific IL-10 production was TGF-ß dependent.
These data support a pivotal role for TGF-ß, 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.
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