title: Nasal Administration of Cholera Toxin as a Mucosal Adjuvant Damages the Olfactory System in Mice.
abstract: Cholera toxin (CT) induces severe diarrhea in humans but acts as an adjuvant to enhance immune responses to vaccines when administered orally. Nasally administered CT also acts as an adjuvant, but CT and CT derivatives, including the B subunit of CT (CTB), are taken up from the olfactory epithelium and transported to the olfactory bulbs and therefore may be toxic to the central nervous system. To assess the toxicity, we investigated whether nasally administered CT or CT derivatives impair the olfactory system. In mice, nasal administration of CT, but not CTB or a non-toxic CT derivative, reduced the expression of olfactory marker protein (OMP) in the olfactory epithelium and olfactory bulbs and impaired odor responses, as determined with behavioral tests and optical imaging. Thus, nasally administered CT, like orally administered CT, is toxic and damages the olfactory system in mice. However, CTB and a non-toxic CT derivative, do not damage the olfactory system. The optical imaging we used here will be useful for assessing the safety of nasal vaccines and adjuvants during their development for human use and CT can be used as a positive control in this test.
authors.affiliation: Division of Mucosal Immunology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Fukuyama
authors.affiliation: Division of Mucosal Immunology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Okada
authors.affiliation: Department of Physiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamaguchi
authors.affiliation: Division of Mucosal Immunology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; International Research and Development Center for Mucosal Vaccine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyono
authors.affiliation: Department of Physiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kensaku
authors.initials: K
authors.lastname: Mori
authors.affiliation: Division of Mucosal Immunology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; International Research and Development Center for Mucosal Vaccine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Yuki
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000281:Administration, Intranasal / Q000009:adverse effects*; D000818:Animals; D001428:Bacterial Vaccines / Q000378:metabolism / Q000494:pharmacology; D002772:Cholera Toxin / Q000008:administration & dosage* / Q000276:immunology; D008297:Male; D008807:Mice, Inbred BALB C; D051842:Olfactory Marker Protein / Q000378:metabolism; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000378:metabolism; D018034:Olfactory Receptor Neurons / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D001428:Bacterial Vaccines; D051842:Olfactory Marker Protein; C497598:Omp protein, mouse; D002772:Cholera Toxin