title: Requirements for allergen-induced airway hyperreactivity in T and B cell-deficient mice.
abstract: BACKGROUND
  The pathogenesis of asthma is believed to reflect antigen-induced airway inflammation leading to the recruitment of eosinophils and activation of mast cells through cell-associated IgE. Controversies persist however, regarding the relative importance of different pathogenic cells and effector molecules.
  
  
  METHODS
  A variety of gene-targeted mice were examined for the induction of cholinergic airway hyperresponsiveness (AH), allergic airway inflammation, mucus production, and serum IgE reactivity following intratracheal challenge with a potent allergen. AH was determined using whole-body plethysmography following acetylcholine challenge. Where possible, results were confirmed using neutralizing antibodies and cell-specific reconstitution of immune deficient mice.
  
  
  RESULTS
  T and B cell-deficient, recombinase-activating-gene-deficient mice (RAG -/-) failed to develop significant allergic inflammation and AH following allergen challenge. Reconstitution of RAG -/- mice with CD4+ T cells alone was sufficient to restore allergen-induced AH, allergic inflammation, and goblet cell hyperplasia, but not IgE reactivity. Sensitized B cell-deficient mice also developed airway hyperreactivity and lung inflammation comparable to that of wild-type animals, confirming that antibodies were dispensable. Treatment with neutralizing anti-IL-4 antibody or sensitization of IL-4-deficient mice resulted in loss of airway hyperreactivity, whereas treatment with anti-IL-5 antibody or sensitization of IL-5-deficient mice had no effect.
  
  
  CONCLUSIONS
  In mice, CD4+ T cells are alone sufficient to mediate many of the pathognomonic changes that occur in human asthma by a mechanism dependent upon IL-4, but independent of IL-5, IgE, or both. Clarification of the role played by CD4+ T cells is likely to stimulate important therapeutic advances in treatment of asthma.
authors.affiliation: Department of Medicine, University of California San Francisco, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Corry
authors.forename: G
authors.initials: G
authors.lastname: Grünig
authors.forename: H
authors.initials: H
authors.lastname: Hadeiba
authors.forename: V P
authors.initials: VP
authors.lastname: Kurup
authors.forename: M L
authors.initials: ML
authors.lastname: Warnock
authors.forename: D
authors.initials: D
authors.lastname: Sheppard
authors.forename: D M
authors.initials: DM
authors.lastname: Rennick
authors.forename: R M
authors.initials: RM
authors.lastname: Locksley
mesh_terms: D019264:Adoptive Transfer; D000485:Allergens / Q000276:immunology*; D000818:Animals; D000946:Antigens, Fungal / Q000276:immunology; D001232:Aspergillus fumigatus / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D015496:CD4-Positive T-Lymphocytes / Q000637:transplantation; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D015847:Interleukin-4 / Q000502:physiology; D015848:Interleukin-5 / Q000502:physiology; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D000485:Allergens; D000946:Antigens, Fungal; D018398:Homeodomain Proteins; D015848:Interleukin-5; C064658:RAG-1 protein; D015847:Interleukin-4