title: CD137 ligand prevents the development of T-helper type 2 cell-mediated allergic asthma by interferon-gamma-producing CD8+ T cells.
abstract: BACKGROUND
  Allergic asthma is a T-helper type 2 (Th2) cell-mediated chronic disease that is characterized by airway hyperreactivity (AHR) and chronic eosinophilic airway inflammation. Several studies suggest co-stimulatory molecules like CD137 as potential targets for therapeutic interventions in allergic airway disease. Recently, we could show in a murine asthma model that administration of an agonistic antibody against the receptor of the co-stimulatory molecule CD137 prevented and even reversed an already-established asthma phenotype.
  
  
  OBJECTIVE
  The purpose of this study was to analyse the effect of stimulation of the CD137 ligand by a monoclonal antibody (CD137L mAb).
  
  
  METHODS
  To induce an asthma-like phenotype, BALB/c mice were sensitized to ovalbumin (OVA), followed by an intrapulmonary allergen challenge. Anti-CD137L or control mAb were applied 1 day before OVA immunization or after the asthma phenotype was already established.
  
  
  RESULTS
  Stimulation of the CD137L instead of the receptor by CD137L mAb prevents the development of an asthma-like phenotype but does not reverse established disease. While the receptor-mediated effect is partly mediated by anergy of CD4(+) T cells and partly by induction of IFN-gamma-producing CD8(+) T cells, the effect of the CD137L mAb is completely dependent on IFN-gamma-producing CD8(+) T cells: blockade of IFN-gamma and depletion of CD8(+) T cells fully abrogated the observed protective effect. In vitro experiments showed that the anti-CD137L mAb ligates directly to CD8(+) T cells and induces the generation of IFN-gamma by this cell population.
  
  
  CONCLUSIONS
  Our results demonstrate that anti-CD137L mAb prevents disease development via IFN-gamma-producing CD8(+) T cells but is inferior to stimulation of the receptor that reverses established disease by a mechanism including CD4(+) T cell anergy.
authors.affiliation: Department of Pediatrics, Division of Pulmonology and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Polte
authors.forename: A
authors.initials: A
authors.lastname: Jagemann
authors.forename: J
authors.initials: J
authors.lastname: Foell
authors.forename: R S
authors.initials: RS
authors.lastname: Mittler
authors.forename: G
authors.initials: G
authors.lastname: Hansen
mesh_terms: D053330:4-1BB Ligand / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001249:Asthma / Q000276:immunology* / Q000517:prevention & control; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D018418:Th2 Cells / Q000276:immunology
chemical_list: D053330:4-1BB Ligand; D000911:Antibodies, Monoclonal; D007371:Interferon-gamma