title: Activation of invariant natural killer T cells in regional lymph nodes as new antigen-specific immunotherapy via induction of interleukin-21 and interferon-γ.
abstract: Invariant natural killer T (iNKT) cells play important immunoregulatory functions in allergen-induced airway hyperresponsiveness and inflammation. To clarify the role of iNKT cells in allergic rhinitis (AR), we generated bone marrow-derived dendritic cells (BMDCs), which were pulsed by ovalbumin (OVA) and α-galactosylceramide (OVA/α-GalCer-BMDCs) and administered into the oral submucosa of OVA-sensitized mice before nasal challenge. Nasal symptoms, level of OVA-specific immunoglobulin (IgE), and T helper type 2 (Th2) cytokine production in cervical lymph nodes (CLNs) were significantly ameliorated in wild-type (WT) mice treated with OVA/α-GalCer-BMDCs, but not in WT mice treated with OVA-BMDCs. These anti-allergic effects were not observed in Jα18(-/-) recipients that lack iNKT cells, even after similar treatment with OVA/α-GalCer-BMDCs in an adoptive transfer study with CD4(+) T cells and B cells from OVA-sensitized WT mice. In WT recipients of OVA/α-GalCer-BMDCs, the number of interleukin (IL)-21-producing iNKT cells increased significantly and the Th1/Th2 balance shifted towards the Th1 dominant state. Treatment with anti-IL-21 and anti-interferon (IFN)-γ antibodies abrogated these anti-allergic effects in mice treated with α-GalCer/OVA-BMDCs. These results suggest that activation of iNKT cells in regional lymph nodes induces anti-allergic effects through production of IL-21 or IFN-γ, and that these effects are enhanced by simultaneous stimulation with antigen. Thus, iNKT cells might be a useful target in development of new treatment strategies for AR.
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sakurai
authors.forename: A
authors.initials: A
authors.lastname: Inamine
authors.forename: T
authors.initials: T
authors.lastname: Iinuma
authors.forename: U
authors.initials: U
authors.lastname: Funakoshi
authors.forename: S
authors.initials: S
authors.lastname: Yonekura
authors.forename: D
authors.initials: D
authors.lastname: Sakurai
authors.forename: T
authors.initials: T
authors.lastname: Hanazawa
authors.forename: T
authors.initials: T
authors.lastname: Nakayama
authors.forename: Y
authors.initials: Y
authors.lastname: Ishii
authors.forename: Y
authors.initials: Y
authors.lastname: Okamoto
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D000939:Epitopes; D005260:Female; D005699:Galactosylceramides / Q000276:immunology; D006967:Hypersensitivity / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology*; D007378:Interleukins / Q000096:biosynthesis / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D055611:Natural Killer T-Cells / Q000276:immunology*; D010047:Ovalbumin / Q000276:immunology; D012220:Rhinitis / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D000939:Epitopes; D005699:Galactosylceramides; D007378:Interleukins; C493154:alpha-galactosylceramide; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010047:Ovalbumin; D000098546:Interleukin-21
keywords: IFN-γ; IL-21; bone marrow-derived dendritic cells; invariant natural killer T cell; α-galactosylceramide