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Department of Molecular Immunology, Immunex Corporation, Seattle WA 98101
Oral administration of soluble protein Ag induces tolerance, a
phenomenon that has hampered mucosal vaccine design. To provoke active
immunity, orally administered Ag must be fed together with a mucosal
adjuvant such as cholera toxin (CT). Unfortunately, CT is not suitable
for clinical use because of its associated toxicity. There is,
therefore, a need to develop alternative mucosal immunization regimens.
Here we have attempted to alter the intrinsically tolerogenic nature of
the intestine and improve immunization potential by expanding and
activating intestinal APC in vivo. Previous studies have indicated that
intestinal dendritic cells (DC) present oral Ag, but do so in a
tolerogenic manner. In the present study we investigated whether DC can
be converted from tolerogenic into immunogenic APC by treating mice
with Flt3 ligand (Flt3L), a DC growth factor, and then immunizing with
CT. We observed increased local and systemic responses to CT in the
presence of elevated numbers of intestinal DC. In parallel, CT induced
up-regulation of CD80 and CD86 on these Flt3L-expanded DC. In an
attempt to develop a toxin-free adjuvant system, we investigated
whether IL-1 could be used as an alternative DC-activating stimulus.
Using a combination of Flt3L and IL-1
, we observed a potent active
response to fed soluble Ag, rather than the tolerogenic response
normally observed. These data suggest that Flt3L-expanded DC are well
positioned to regulate intestinal responses depending on the presence
or the absence of inflammatory signals. Flt3L may therefore be a
reagent useful for the design of mucosal immunization
strategies.
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