Modulating dendritic cells to optimize mucosal immunization protocols.
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-1alpha, 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.
Williamson
E
E
Department of Molecular Immunology, Immunex Corporation, Seattle WA 98101, USA. williame@immunex.com
Westrich
G M
GM
Viney
J L
JL
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000284:Administration, Oral; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002772:Cholera Toxin / Q000008:administration & dosage / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D007108:Immune Tolerance; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D007114:Immunization / Q000379:methods*; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology; D007375:Interleukin-1 / Q000008:administration & dosage; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D008565:Membrane Proteins / Q000008:administration & dosage / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010581:Peyer's Patches / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000941:Antigens; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D018836:Inflammation Mediators; D007375:Interleukin-1; D008024:Ligands; D008565:Membrane Proteins; C084881:flt3 ligand protein; D010047:Ovalbumin; D002772:Cholera Toxin