title: An inhibitory role for Sema4A in antigen-specific allergic asthma.
abstract: OBJECTIVE
  The class IV semaphorin Sema4A is critical for efficient Th1 differentiation and Sema4a (-/-) mice exhibit impaired Th1 immune responses. However, the role of Sema4A in Th2 cell-mediated allergic diseases has not been fully studied. The aim of this study was to clarify the regulatory role possessed by Sema4A in mouse models of allergic diseases, particularly allergic asthma.
  
  
  METHODS
  Sema4a (-/-) mice on a BALB/c background were examined for the development of allergic diseases. To induce experimental asthma, mice were sensitized with ovalbumin (OVA) followed by intranasal challenges with OVA. After challenge, airway hyperreactivity (AHR) and airway inflammation were evaluated. The role of Sema4A in asthma was examined using Sema4a (-/-) mice and Sema4A-Fc fusion proteins. The direct effects of Sema4A-Fc on antigen-specific effector CD4(+) T cells were also examined.
  
  
  RESULTS
  A fraction of Sema4a (-/-) BALB/c mice spontaneously developed skin lesions that resembled atopic dermatitis (AD) in humans. Furthermore, AHR, airway inflammation, and Th2-type immune responses were enhanced in Sema4a (-/-) mice compared to wild type (WT) mice when immunized and challenged with OVA. In vivo systemic administration of Sema4A-Fc during the challenge period ameliorated AHR and lung inflammation and reduced the production of Th2-type cytokines in WT mice. The inhibitory effects of Sema4A on airway inflammation were also observed in mice deficient in Tim-2, a Sema4A receptor. Finally, we showed that Sema4A-Fc directly inhibited IL-4-producing OVA-specific CD4(+) T cells.
  
  
  CONCLUSIONS
  These results demonstrate that Sema4A plays an inhibitory role in Th2-type allergic diseases, such as allergic asthma.
authors.affiliation: Department of Molecular Immunology, Research Institute for Microbial Diseases, WPI Immunology Frontier Research Center (IFReC), Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Morihana
authors.forename: Sho
authors.initials: S
authors.lastname: Goya
authors.forename: Masayuki
authors.initials: M
authors.lastname: Mizui
authors.forename: Teruhito
authors.initials: T
authors.lastname: Yasui
authors.forename: Durubaka V R
authors.initials: DV
authors.lastname: Prasad
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
authors.forename: Manabu
authors.initials: M
authors.lastname: Tamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Shikina
authors.forename: Yohei
authors.initials: Y
authors.lastname: Maeda
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Hidenori
authors.initials: H
authors.lastname: Inohara
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kikutani
mesh_terms: D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D002478:Cells, Cultured; D003876:Dermatitis, Atopic / Q000276:immunology; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology*; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D039961:Semaphorins / Q000172:deficiency / Q000502:physiology*
chemical_list: D000485:Allergens; D000939:Epitopes; C534721:Sema4A protein, mouse; D039961:Semaphorins; D010047:Ovalbumin