title: Role of cysteinyl leukotrienes in human allergen-specific Th2 responses induced by granulocyte macrophage-colony stimulating factor.
abstract: BACKGROUND
  The pro-inflammatory cytokine, granulocyte macrophage-colony stimulating factor (GM-CSF), which is elevated in the lungs of atopic asthmatic patients, has been shown to enhance major histocompatibility class II expression of alveolar macrophages (AM). We hypothesized that exposure of AM and monocytes from atopic asthmatic patients to GM-CSF would enhance their antigen presenting function, and investigated putative mechanisms for this effect.
  
  
  METHODS
  Alveolar macrophages were purified from bronchoalveolar lavage by plastic adherence. Monocytes and CD4(+) T cells were purified from peripheral blood by magnetic bead separation. Antigen-presenting cell (APC) were pretreated with GM-CSF, pulsed with allergen and cocultured with autologous T cells. T-cell proliferation was determined by tritiated thymidine incorporation and cytokine production by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Exposure of allergen-pulsed AM and peripheral blood monocytes to GM-CSF significantly increased allergen-specific T-cell proliferation and T helper 2 (Th2) cytokine production. The enhanced response was dependent on costimulation by CD86, but not CD80. Inhibition of the 5-lipoxygenase pathway abrogated GM-CSF-mediated upregulation by monocytes of allergen-specific interleukin-5 (IL-5) and IL-13 cytokine production. Blocking of the cysteinyl leukotriene receptor 1 (cysLT(1)) receptor by a specific receptor antagonist inhibited allergen-specific IL-5 production in response to GM-CSF pretreatment.
  
  
  CONCLUSIONS
  Exposure to GM-CSF enhanced the capacity of human APC from atopic asthmatic patients to induce allergen-specific Th2 responses by a mechanism involving cysLT. Novel immunotherapies, targeting production of GM-CSF or its actions on APC have the potential, therefore, to prove beneficial in treatment of patients with inflammatory airway disease.
authors.affiliation: Asthma UK and MRC, Centre in Allergic Mechanisms of Asthma, King's College London, and Department of Asthma, Allergy and Respiratory Science, Guy's Hospital, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Faith
authors.forename: M H
authors.initials: MH
authors.lastname: Fernandez
authors.forename: J
authors.initials: J
authors.lastname: Caulfield
authors.forename: T-K
authors.initials: TK
authors.lastname: Loke
authors.forename: C
authors.initials: C
authors.lastname: Corrigan
authors.forename: B
authors.initials: B
authors.lastname: O'Connor
authors.forename: T H
authors.initials: TH
authors.lastname: Lee
authors.forename: C M
authors.initials: CM
authors.lastname: Hawrylowicz
mesh_terms: D000485:Allergens / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000276:immunology; D001249:Asthma / Q000276:immunology; D003545:Cysteine / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000276:immunology; D007155:Immunologic Factors / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D015289:Leukotrienes / Q000378:metabolism*; D008213:Lymphocyte Activation; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000485:Allergens; D016207:Cytokines; D007155:Immunologic Factors; D018836:Inflammation Mediators; D015289:Leukotrienes; C112381:cysteinyl-leukotriene; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003545:Cysteine