title: Distinct pathways of humoral and cellular immunity induced with the mucosal administration of a nanoemulsion adjuvant.
abstract: Nasal administration of an oil-in-water nanoemulsion (NE) adjuvant W805EC produces potent systemic and mucosal, Th-1- and Th-17-balanced cellular responses. However, its molecular mechanism of action has not been fully characterized and is of particular interest because NE does not contain specific ligands for innate immune receptors. In these studies, we demonstrate that W805EC NE adjuvant activates innate immunity, induces specific gene transcription, and modulates NF-κB activity via TLR2 and TLR4 by a mechanism that appears to be distinct from typical TLR agonists. Nasal immunization with NE-based vaccine showed that the TLR2, TLR4, and MyD88 pathways and IL-12 and IL-12Rβ1 expression are not required for an Ab response, but they are essential for the induction of balanced Th-1 polarization and Th-17 cellular immunity. NE adjuvant induces MHC class II, CD80, and CD86 costimulatory molecule expression and dendritic cell maturation. Further, upon immunization with NE, adjuvant mice deficient in the CD86 receptor had normal Ab responses but significantly reduced Th-1 cellular responses, whereas animals deficient in both CD80 and CD86 or lacking CD40 failed to produce either humoral or cellular immunity. Overall, our data show that intranasal administration of Ag with NE induces TLR2 and TLR4 activation along with a MyD88-independent Ab response and a MyD88-dependent Th-1 and Th-17 cell-mediated immune response. These findings suggest that the unique properties of NE adjuvant may offer novel opportunities for understanding previously unrecognized mechanisms of immune activation important for generating effective mucosal and systemic immune responses.
authors.affiliation: Division of Allergy, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Anna U
authors.initials: AU
authors.lastname: Bielinska
authors.forename: Paul E
authors.initials: PE
authors.lastname: Makidon
authors.forename: Katarzyna W
authors.initials: KW
authors.lastname: Janczak
authors.forename: Luz P
authors.initials: LP
authors.lastname: Blanco
authors.forename: Benjamin
authors.initials: B
authors.lastname: Swanson
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Smith
authors.forename: Tiffany
authors.initials: T
authors.lastname: Pham
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Szabo
authors.forename: Jolanta F
authors.initials: JF
authors.lastname: Kukowska-Latallo
authors.forename: James R
authors.initials: JR
authors.lastname: Baker
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000281:Administration, Intranasal; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004655:Emulsions / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D056724:Immunity, Humoral / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053711:Interleukin-12 Receptor beta 1 Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D004655:Emulsions; D053711:Interleukin-12 Receptor beta 1 Subunit; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D051193:Toll-Like Receptors; D018664:Interleukin-12