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*
Laboratory of Immunology, Istituto Superiore di Sanità, Rome, Italy; and
Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institutes of Health, Bethesda, MD 20892
Trinitrobenzene sulfonic acid (TNBS)-induced colitis is an
IL-12-driven, Th1 T cell-mediated colitis that resembles human Crohn’s
disease. In the present study, we showed initially that the oral
administration of recombinant subunit B of cholera toxin (rCT-B) at the
time of TNBS-induced colitis by intrarectal TNBS instillation inhibits
the development of colitis or, at later time when TNBS-induced colitis
is well established, brings about resolution of the colitis.
Dose-response studies showed that a majority of mice (68%) treated
with rCT-B at a dose of 100 µg (times four daily doses) exhibited
complete inhibition of the development of colitis, whereas a minority
(30%) treated with rCT-B at a dose of 10 µg (times four daily doses)
exhibited complete inhibition; in both cases, however, the remaining
mice exhibited some reduction in the severity of inflammation. In
further studies, we showed that rCT-B administration is accompanied by
prevention/reversal of increased IFN-
secretion (the hallmark of a
Th1 response) without at the same time causing an increase in IL-4
secretion. This decreased IFN- secretion was not associated with the
up-regulation of the secretion of counterregulatory cytokines (IL-10 or
TGF-
), but was associated with a marked inhibition of IL-12
secretion, i.e., the secretion of the cytokine driving the Th1
response. Finally, we showed that rCT-B administration results in
increased apoptosis of lamina propria cells, an effect previously shown
to be indicative of IL-12 deprivation. From these studies, rCT-B
emerges as a powerful inhibitor of Th1 T cell-driven inflammation that
can conceivably be applied to the treatment of Crohn’s
disease.
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