title: Inhalation of a harmless antigen (ovalbumin) elicits immune activation but divergent immunoglobulin and cytokine activities in mice.
abstract: BACKGROUND
  Exposure to aerosolized harmless antigen such as ovalbumin (OVA) has previously been shown to induce inhalation tolerance, a state characterized by inhibition of IgE synthesis and airway inflammation, upon secondary immunogenic antigen encounter. Immune events associated with this phenomenon are still poorly understood.
  
  
  OBJECTIVE
  The aim of this study was to investigate cellular and molecular mechanisms underlying this state of 'unresponsiveness'.
  
  
  METHODS
  After initial repeated OVA exposure, mice were subjected to a protocol of antigen-induced airway inflammation, encompassing two intraperitoneal injections of OVA adsorbed to aluminium hydroxide followed by airway challenge. We assessed immune events in the draining lymph nodes after sensitization, and in the lungs after challenge.
  
  
  RESULTS
  In animals initially exposed to OVA, we observed, at the time of sensitization, considerable expansion of T cells, many of which expressed the activation markers CD69 and CD25, as well as increased numbers of antigen-presenting cells, particularly B cells. While these animals produced low levels of IgE, the observed elevated levels of IgG1 signified isotype switching. Splenocytes and lymph node cells from OVA-exposed mice produced low levels of IL-4, IL-5, IL-13 and IFN-gamma, indicating aborted effector function of both T helper (Th)2- and Th1-associated cytokines. Real time quantitative polymerase chain reaction (PCR) (TaqMan) analysis of costimulatory molecules in the lungs after in vivo challenge showed that B7.1, B7.2, CD28 and CTLA-4 mRNA expression was low in animals initially exposed to OVA. Ultimately, these events were associated with abrogated airway inflammation and attenuated airway hyper-responsiveness. The decreased inflammation was antigen-specific and independent of IL-10 or IFN-gamma.
  
  
  CONCLUSIONS
  Initial exposure to OVA establishes a programme that prevents the generation of intact, fully functional inflammatory responses upon secondary antigen encounter. The absence of inflammation, however, is not associated with categorical immune unresponsiveness.
authors.affiliation: Department of Pathology and Molecular Medicine, Division of Respiratory Diseases and Allergy and Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: F K
authors.initials: FK
authors.lastname: Swirski
authors.forename: B U
authors.initials: BU
authors.lastname: Gajewska
authors.forename: D
authors.initials: D
authors.lastname: Alvarez
authors.forename: S A
authors.initials: SA
authors.lastname: Ritz
authors.forename: M J
authors.initials: MJ
authors.lastname: Cundall
authors.forename: E C
authors.initials: EC
authors.lastname: Cates
authors.forename: A J
authors.initials: AJ
authors.lastname: Coyle
authors.forename: J-C
authors.initials: JC
authors.lastname: Gutierrez-Ramos
authors.forename: M D
authors.initials: MD
authors.lastname: Inman
authors.forename: M
authors.initials: M
authors.lastname: Jordana
authors.forename: M R
authors.initials: MR
authors.lastname: Stämpfli
mesh_terms: D000818:Animals; D000918:Antibody Specificity / Q000187:drug effects / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000187:drug effects* / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000187:drug effects / Q000276:immunology; D007136:Immunoglobulins / Q000097:blood / Q000187:drug effects* / Q000276:immunology*; D019570:Inhalation Exposure / Q000009:adverse effects*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C / Q000276:immunology*; D018345:Mice, Knockout; D023421:Models, Animal; D010047:Ovalbumin / Q000276:immunology* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D012965:Sodium Chloride / Q000494:pharmacology; D013997:Time Factors
chemical_list: D015415:Biomarkers; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D007136:Immunoglobulins; D012333:RNA, Messenger; D012965:Sodium Chloride; D010047:Ovalbumin