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

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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.

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Acknowledgements

The authors gratefully acknowledge the assistance of M. Kopf for permission to use IL-5 deficient mice, D. J. Fowell (UCSF) for T cell reconstitutions, E. Weider (Gladstone Institute, UCSF) for cell sorting, F. Kheradmand for artwork, and D. Erle (UCSF) for critical comments.

This work was supported by NIH HL56385, HL03344, the American Lung Association, and a U. S. Veterans Affairs Medical Research grant. R. M. L. is a Burroughs Wellcome Fund Scholar in Molecular Parasitology. DNAX Research Institute of Molecular and Cellular Biology is supported by Schering Plough Corporation.

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Authors and Affiliations

  1. Department of Medicine, University of California San Francisco, San Francisco, California, USA

    Dean Sheppard &  Richard M. Locksley

  2. Department of Microbiology/Immunology, University of California San Francisco, San Francisco, California, USA

    Husein Hadeiba &  Richard M. Locksley

  3. Department of Pathology, University of California San Francisco, San Francisco, California, USA

    Martha L. Warnock

  4. Department of Lung Biology Center at the San Francisco General Hospital, University of California San Francisco, San Francisco, California, USA

    David B. Corry & Dean Sheppard

  5. Department of Medicine, Veterans Administration Medical Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

    Viswanath P. Kurup

  6. DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, California, USA

    Gabriele Grünig & Donna M. Rennick

  7. Division of Infectious Diseases, University of California at San Francisco, Box 0654, C-443, 521 Parnassus Avenue, San Francisco, CA, 94143-0654, USA

    Richard M. Locksley

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  1. David B. Corry
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Correspondence to Richard M. Locksley.

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Corry, D.B., Grünig, G., Hadeiba, H. et al. Requirements for Allergen-Induced Airway Hyperreactivity in T and B Cell-Deficient Mice. Mol Med 4, 344–355 (1998). https://doi.org/10.1007/BF03401741

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