title: Polymyxins as novel and safe mucosal adjuvants to induce humoral immune responses in mice.
abstract: There is currently an urgent need to develop safe and effective adjuvants for enhancing vaccine-induced antigen-specific immune responses. We demonstrate here that intranasal immunization with clinically used polypeptide antibiotics, polymyxin B (PMB) and colistin (CL), along with ovalbumin (OVA), increases OVA-specific humoral immune responses in a dose-dependently manner at both mucosal and systemic compartments. Enhanced immunity by boosting was found to persist during 8 months of observation. Moreover, mice intranasally immunized with OVA plus various doses of PMB or CL showed neither inflammatory responses in the nasal cavity and olfactory bulbs nor renal damages, compared to those given OVA alone. These data suggest that polymyxins may serve as novel and safe mucosal adjuvants to induce humoral immune responses. The polymyxin adjuvanticity was found to be independent of endotoxins liberated by its bactericidal activity, as indicated by similar enhancing effects of PMB in lipopolysaccharide (LPS)-hyporesponsive and LPS-susceptible mice. However, despite the presence of preexisting anti-PMB antibodies, we observed no reduction in the adjuvant function of polymyxins when they were given intranasally. Furthermore, the titers of OVA-specific Abs in mice intranasally immunized with OVA plus PMB or CL were significantly higher than those in mice administered with polymyxin analogues, such as polymyxin B nonapeptide and colistin methanesulfonate. The levels of released β-hexosaminidase and histamine in mast cell culture supernatants stimulated by PMB or CL were also significantly higher than those stimulated by their analogues. These results suggest that both the hydrophobic carbon chain and hydrophilic cationic cyclic peptide contribute to the mucosal adjuvanticity of PMB and CL.
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Microbiology, School of Medicine, Iwate Medical University, Iwate, Japan. nyoshino@iwate-med.ac.jp
authors.forename: Naoto
authors.initials: N
authors.lastname: Yoshino
authors.forename: Masahiro
authors.initials: M
authors.lastname: Endo
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kanno
authors.forename: Naomi
authors.initials: N
authors.lastname: Matsukawa
authors.forename: Reiko
authors.initials: R
authors.lastname: Tsutsumi
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takeshita
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Sato
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000281:Administration, Intranasal; D000818:Animals; D003091:Colistin / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006632:Histamine / Q000378:metabolism; D056724:Immunity, Humoral / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000008:administration & dosage / Q000494:pharmacology*; D011112:Polymyxin B / Q000008:administration & dosage / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D006632:Histamine; D010047:Ovalbumin; D001619:beta-N-Acetylhexosaminidases; D011112:Polymyxin B; D003091:Colistin