title: Normally suppressing CD40 coregulatory signals delivered by airway macrophages to TH2 lymphocytes are defective in patients with atopic asthma.
abstract: BACKGROUND
  We have previously shown that airway macrophages (AMs) from atopic nonasthmatic subjects, but not atopic asthmatic subjects, inhibit T-cell IL-5 production during an allergen-dependent interaction. However, the mechanisms responsible for the IL-5-modulating effect of the AMs are less clear.
  
  
  OBJECTIVE
  The aim of the present study was to define the roles of B7 and CD40 costimulatory signals delivered by AMs in regulating T-cell IL-5 responses in an allergen-stimulated coculture system.
  
  
  METHODS
  Peripheral blood CD4(+) T cells and AMs were cocultured under different conditions.
  
  
  RESULTS
  Compared with those from well-matched atopic nonasthmatic subjects, AMs from atopic asthmatic subjects demonstrated a significantly lower expression of B7-1 and CD40, but not B7-2 and HLA-DR, after either fresh isolation or coculture with allergen-reactive CD4(+) T cells. Lower IL-12 production by the AMs from asthmatic subjects was also observed under the same conditions. Allergen-related T-cell IFN-gamma and IL-5 production was inhibited by the addition of either neutralizing B7-1 or B7-2 antibody to the cocultures in both atopic groups. In contrast, IL-5 production was significantly increased by the addition of blocking CD40 antibody, whereas IL-12 production by the AMs was inhibited. Anti-IL-12 mAb enhanced IL-5 production in the cocultures from atopic nonasthmatic subjects, whereas a dose-dependent suppressive effect of recombinant human IL-12 on IL-5 production was seen in atopic asthmatic subjects.
  
  
  CONCLUSIONS
  In this coculture model system, lower IL-12 production by AMs and higher IL-5 production by CD4(+) T cells in atopic asthmatic subjects compared with that found in atopic nonasthmatic subjects are related to the lower expression of CD40 rather than B7-1 signals on the AMs from these patients.
authors.affiliation: Department of Respiratory Medicine, Alfred Hospital, and Monash University, Melbourne, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Tang
authors.forename: C
authors.initials: C
authors.lastname: Ward
authors.forename: D
authors.initials: D
authors.lastname: Reid
authors.forename: R
authors.initials: R
authors.lastname: Bish
authors.forename: P M
authors.initials: PM
authors.lastname: O'byrne
authors.forename: E H
authors.initials: EH
authors.lastname: Walters
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology; D001249:Asthma / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen; D001985:Bronchial Provocation Tests; D001999:Bronchoscopy; D019013:CD40 Antigens / Q000276:immunology*; D018920:Coculture Techniques; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology; D015848:Interleukin-5 / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology; D016210:Methacholine Chloride; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; D006684:HLA-DR Antigens; D015848:Interleukin-5; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D016210:Methacholine Chloride; D018664:Interleukin-12; D007371:Interferon-gamma