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Am. J. Respir. Cell Mol. Biol., Volume 23, Number 5, November, 2000 646-651

CD40L, but Not CD40, Is Required for Allergen-Induced Bronchial Hyperresponsiveness in Mice

Paul D. Mehlhop, Matthijs van de Rijn, Joanne P. Brewer, Alison B. Kisselgof, Raif S. Geha, Hans C. Oettgen, and Thomas R. Martin

Divisions of Immunology and Pulmonary Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts; and Department of Pathology, Stanford University, Palo Alto, California

Asthma is characterized by immunoglobulin (Ig) E production, infiltration of the respiratory mucosa by eosinophils (EOSs) and mononuclear cells, and bronchial hyperresponsiveness (BHR). Interaction of CD40 on B cells and antigen presenting cells, with its ligand (CD40L) expressed transiently on activated T cells, is known to augment both T cell-driven inflammation and humoral immune responses, especially IgE production. Considering both the prominent role of inflammation in asthma and the association of the disease with IgE, we hypothesized that CD40-CD40L interactions would be important in pathogenesis. To test this hypothesis, we subjected wild-type (WT) mice and animals lacking either CD40 or CD40L to repeated inhalation of Aspergillus fumigatus (Af  ) antigen. Af-treated WT mice displayed elevated IgE levels, bronchoalveolar lavage and pulmonary tissue eosinophilic inflammation, and BHR. IgE production was markedly suppressed in both the CD40 -/- and CD40L -/- strains. However, pulmonary inflammation did not appear to be inhibited by either of these mutations. Paradoxically, development of BHR was prevented by the lack of CD40L but not by the absence of CD40. We conclude that CD40/CD40L interactions, although critical in the induction of IgE responses to inhaled allergen, are not required for the induction of EOS-predominant inflammation. CD40L, but not CD40, is necessary for the development of allergen-induced BHR.

Abbreviations: Aspergillus fumigatus, Af; analysis of variance, ANOVA; bronchoalveolar lavage, BAL; BAL fluid, BALF; bronchial hyperresponsiveness, BHR; lacking CD40, CD40 -/-; lacking CD40 ligand, CD40L -/-; enzyme-linked immunosorbent assay, ELISA; eosinophil, EOS; pulmonary conductance, GL; hematoxylin and eosin, H&E; immunoglobulin, Ig; interleukin, IL; knockout, KO; methacholine, MCh; normal saline, NS; ovalbumin, OVA; standard error of the mean, SEM; wild-type, WT.




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