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Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115
Oral administration of Ag results in systemic hyporesponsiveness
termed oral tolerance. The regulatory cells induced by oral Ag are
effective in the suppression of Th1-type autoimmune diseases. We
examined the cytokine microenvironment in gut-associated lymphoid
tissue in response to orally administered OVA in OVA TCR-transgenic
mice. Mice were fed a low (0.5 mg) or high (500 mg) dose of OVA one
time or five times. Immunohistochemical analysis demonstrated increased
IL-4, IL-10, and TGF-ß in the gut within 6 h of a low-dose
feeding and after five low-dose or high-dose feedings. IFN-
and IL-2
either decreased or showed no change, with the exception of a small
transient increase in IL-2 at 6 h after a low dose. Increases in
IL-4 and IL-10 were found in the dome of the Peyer’s patch, and
increases in TGF-ß were observed in the interfollicular region and
the villi. IL-10 was also substantially increased in the villi. IL-4
and IL-10 were produced predominately by CD4+ T
cells. TGF-ß was found predominately in macrophages and
CD4+ T cells. Peyer’s patches had a marked up-regulation
of TGF-ß mRNA as measured by RT-PCR. These results demonstrate the
differential activation of cytokine production in discrete regions of
gut-associated lymphoid tissue. The induction of cytokines known to
inhibit autoimmune disease at the site of Ag absorption indicates an
important role for the mucosal immune system in the establishment of
oral tolerance.
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