Concomitant airway expression of granulocyte-macrophage colony-stimulating factor and decorin, a natural inhibitor of transforming growth factor-β, breaks established inhalation tolerance

Filip K. Swirski, Beata U. Gajewska, Clinton S. Robbins, Abigail D'Sa, Jill R. Johnson, Mahmoud A. Pouladi, Mark D. Inman, Martin R. Stämpfli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

We previously showed that granulocyte-macrophage colony-stimulating factor (GM-CSF) breaks tolerance induction. The objective of this study was to determine whether GM-CSF breaks established inhalation tolerance. To induce tolerance, BALB/c mice were exposed to aerosolized ovalbumin (OVA) for 10 consecutive days. A control group was exposed to saline. Subsequently, tolerant and control animals were exposed to OVA in a GM-CSF-enriched airway microenvironment. Tolerant animals, unlike control animals, did not develop airway and peripheral blood eosinophilia, had diminished levels of OVA-specific IgE, and reduced airway hyper-responsiveness. While tolerant animals did not express IL-4, IL-5 and IL-13, levels of the regulatory cytokines IL-10, IFN-γ and transfoming growth factor (TGF)-β were similar between tolerant and non-tolerant animals. Lung CD4+ T cells were activated according to CD69, CD25 and T1/ST2 expression, but systemic responses characterized by splenocyte proliferation and Th2 effector function were dramatically reduced. Concurrent expression of GM-CSF and decorin, a natural inhibitor of TGF-β, reversed eosinophilic unresponsiveness. Our study suggests that the breakdown of tolerance and, by extension, the emergence of eosinophilic inflammation, requires two signals: one that triggers sensitization and one that interferes with negative regulation. Moreover, our study shows that dysregulated expression of an extracellular matrix protein may break established tolerance and lead to eosinophilic airway inflammation.

Original languageEnglish
Pages (from-to)2375-2386
Number of pages12
JournalEuropean Journal of Immunology
Volume34
Issue number9
Early online date5 Aug 2004
DOIs
Publication statusPublished - Sep 2004

Bibliographical note

Funding: This study was supported in part by the Canadian Institutes of Health Research, the Hamilton Health Sciences Corporation, and St. Joseph's Hospital. F.K.S. is holder of a K. M. Hunter/Canadian Institutes for Health Research (CIHR) Doctoral Research Award. C.S.R. and J.R.J. are holders of an Ontario Graduate Scholarship (OGS).

Keywords

  • Allergy
  • GM-CSF
  • Lung
  • TGF-β
  • Tolerance

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