title: Enterotoxin-based mucosal adjuvants alter antigen trafficking and induce inflammatory responses in the nasal tract.
abstract: The safety of nasal vaccines containing enterotoxin-based mucosal adjuvants has not been studied in detail. Previous studies have indicated that native cholera toxin (nCT) can alter antigen trafficking when applied nasally. In this study, we determined the enterotoxin-based variables that alter antigen trafficking. To measure the influence of enterotoxin-based mucosal adjuvants on antigen trafficking in the nasal tract, native and mutant enterotoxins were coadministered with radiolabeled tetanus toxoid (TT). The nCT and heat-labile enterotoxin type 1 (LTh-1) redirected TT into the olfactory neuroepithelium (ON/E). Antigen redirection occurred mainly across the nasal epithelium without subsequent transport along olfactory neurons into the olfactory bulbs (OB). Thus, no significant accumulation of the vaccine antigen TT was observed in the OB when coadministered with nCT. In contrast, neither mutant CT nor mutant LTh-1, which lack ADP-ribosyltransferase activity, redirected TT antigen into the ON/E. Thus, ADP-ribosyltransferase activity was essential for antigen trafficking across the olfactory epithelium. Accumulation of TT in the ON/E was also due to B-subunit binding to GM1 gangliosides, as was demonstrated (i) by redirection of TT by LTh-1 in a dose-dependent manner, (ii) by ganglioside inhibition of the antigen redirection by LTh-1 and nCT, and (iii) by the use of LT-IIb, a toxin that binds to gangliosides other than GM1. Redirection of TT into the ON/E coincided with elevated production of interleukin 6 (IL-6) but not IL-1beta or tumor necrosis factor alpha in the nasal mucosa. Thus, redirection of TT is dependent on ADP-ribosyltransferase activity and GM1 binding and is associated with production of the inflammatory cytokine IL-6.
authors.affiliation: Department of Pathobiology, College of Veterinary Medicine, Auburn University, AL 36849, USA. vangifw@vetmed.auburn.edu
authors.forename: Frederik W
authors.initials: FW
authors.lastname: van Ginkel
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Jackson
authors.forename: Naoto
authors.initials: N
authors.lastname: Yoshino
authors.forename: Yukari
authors.initials: Y
authors.lastname: Hagiwara
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Metzger
authors.forename: Terry D
authors.initials: TD
authors.lastname: Connell
authors.forename: Hong L
authors.initials: HL
authors.lastname: Vu
authors.forename: Michael
authors.initials: M
authors.lastname: Martin
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Fujihashi
authors.forename: Jerry R
authors.initials: JR
authors.lastname: McGhee
mesh_terms: D036002:ADP Ribose Transferases / Q000235:genetics / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002772:Cholera Toxin / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D005732:Gangliosides / Q000502:physiology; D018928:Immunity, Mucosal / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009297:Nasal Mucosa / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D013745:Tetanus Toxoid / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D005732:Gangliosides; D018836:Inflammation Mediators; D015850:Interleukin-6; D013745:Tetanus Toxoid; D002772:Cholera Toxin; D036002:ADP Ribose Transferases