Requirements for Allergen-Induced Airway Hyperreactivity in T and B Cell-Deficient Mice

Mol Med. 1998 May;4(5):344-55.

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.

Materials and 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adoptive Transfer
  • Allergens / immunology*
  • Animals
  • Antigens, Fungal / immunology
  • Aspergillus fumigatus / immunology
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / pathology
  • Bronchial Hyperreactivity / immunology*
  • Bronchial Hyperreactivity / pathology
  • Bronchial Hyperreactivity / physiopathology
  • CD4-Positive T-Lymphocytes / transplantation
  • Female
  • Homeodomain Proteins / genetics
  • Immunologic Deficiency Syndromes / genetics
  • Immunologic Deficiency Syndromes / immunology*
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-4 / physiology
  • Interleukin-5 / physiology
  • Lung / pathology
  • Lung / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology

Substances

  • Allergens
  • Antigens, Fungal
  • Homeodomain Proteins
  • Interleukin-5
  • RAG-1 protein
  • Interleukin-4