Basic and Clinical Immunology
Effect of GM-CSF on immune, inflammatory, and clinical responses to ragweed in a novel mouse model of mucosal sensitization,☆☆

https://doi.org/10.1067/mai.2003.1460Get rights and content

Abstract

Background: Conventional models of allergic airway inflammation involve intraperitoneal administration of ovalbumin in conjunction with a chemical adjuvant (generally aluminum hydroxide) to generate allergic airways inflammation. Here we have investigated the effect of respiratory mucosal exposure to a ragweed extract in the absence of chemical adjuvant on the generation of allergic responses. Objectives: We sought to develop a mouse model of ragweed-induced allergic airway inflammation through mucosal sensitization and to investigate the role of GM-CSF in this process. Methods: Ragweed was delivered intranasally to an airway microenvironment enriched with GM-CSF, which was achieved by means of either multiple coadministrations of recombinant GM-CSF or a single delivery of an adenoviral vector carrying the GM-CSF transgene. Results: Administration of a purified ragweed extract leads to TH2 sensitization (and not inhalation tolerance) accompanied by mild airway inflammation, modest clinical symptoms, and moderate production of TH2 cytokines by splenocytes on ragweed restimulation. The administration of anti-GM-CSF antibodies in conjunction with ragweed diminished TH2-associated cytokine production. These responses were amplified by enriching the airway microenvironment with GM-CSF. Under these conditions, all TH2-associated immune-inflammatory responses, as well as the clinical responses, were considerably enhanced. To investigate the mechanism underlying these effects, we examined lung mononuclear cells by means of flow cytometry and detected a substantial expansion of antigen-presenting cells, particularly dendritic cells, as well as a substantially increased activation of these antigen-presenting cells, as demonstrated by the expression of B7 molecules, particularly B7.2. Conclusion: GM-CSF plays an important role in the generation of allergic immune-inflammatory responses to ragweed. (J Allergy Clin Immunol 2003;111:1076-86.)

Section snippets

Animals

Female BALB/c mice (6-8 weeks old) were purchased from Charles River Laboratories (Montreal, Quebec, Canada). The mice were housed in a specific-pathogen-free environment under a 12-hour light-dark cycle. All experiments described here were approved by the Animal Research Ethics Board of McMaster University.

I. Exposure protocol with Ad/GM-CSF

A replication-deficient human type 5 adenoviral construct carrying mouse GM-CSF cDNA in the E1 region of the viral genome (Ad/GM-CSF)1 was delivered intranasally to isoflurane-anesthetized

Clinical assessment

Mice receiving RW alone experienced clinical symptoms that consisted of mild sneezing and face rubbing. Clinical manifestations were observed when the mice had recovered from anesthesia. Symptoms began consistently as early as the third RW administration in all groups. In contrast to mice that received RW alone, mice that received RW in conjunction with Ad/GM-CSF (GM/RW) displayed symptoms that increased in severity with subsequent RW administrations. These animals typically showed, toward the

Discussion

Ragweed is an aeroallergen of considerable clinical relevance, particularly in North America. Despite its importance, there is a limited amount of data available with respect to airway immune-inflammatory responses to ragweed in murine systems. Although a number of groups have established models of ragweed-induced allergic conjunctivitis6, 7, 8, 9, 10, 11, 12 and eosinophilic peritonitis,13, 14, 15 data on airway inflammatory responses to ragweed, as compared with OVA, are surprisingly scarce.

Acknowledgements

We thank Joanna deJong, Stacey A. Ritz, Clinton Robbins, Theresa Shea, Martin R. Stämpfli, and Ryan E. Wiley for both their assistance with experiments and their critical appraisal of the manuscript. We further acknowledge the generous administrative assistance of Mary Kiriakopoulos.

References (39)

  • S Sur et al.

    Immunomodulatory effects of IL-12 on allergic lung inflammation depend on timing of doses

    J Immunol

    (1996)
  • BU Gajewska et al.

    Generation of experimental allergic airways inflammation in the absence of draining lymph nodes

    J Clin Invest

    (2001)
  • SA Ritz et al.

    Granulocyte macrophage colony-stimulating factor-driv-en respiratory mucosa sensitization induces Th2 differentiation and function independently of interleukin-4

    Am J Respir Cell Mol Biol

    (2002)
  • EC Strauss et al.

    Soluble P-selectin glycoprotein ligand 1 inhibits ocular inflammation in a murine model of allergy

    Invest Ophthalmol Vis Sci

    (1999)
  • MT Magone et al.

    Systemic or mucosa administration of immunostimulatory DNA inhibits early and late phases of murine allergic conjunctivitis

    Eur J Immunol

    (2000)
  • D Miyazaki et al.

    Prevention of acute allergic conjunctivitis with immunostimulatory DNA sequences

    Invest Ophthalmol Vis Sci

    (2000)
  • C Walker et al.

    IL-5 production by NK cells contributes to eosinophil infiltration in a mouse model of allergic inflammation

    J Immunol

    (1998)
  • SD Robinson et al.

    Multiple, targeted deficiencies in selectins reveal a predominant role for P-selectin in leukocyte recruitment

    Proc Natl Acad Sci U S A

    (1999)
  • PG Holt et al.

    Inhibition of specific IgE responses in mice by pre-exposure to inhaled antigen

    Immunology

    (1981)
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    Supported by the Canadian Institutes of Health Research. Elizabeth C. Cates is supported by an Ontario Graduate Scholarship.

    ☆☆

    Reprint requests: Manel Jordana, MD, PhD, HSC-4H21, Department of Pathology and Molecular Medicine, McMaster University, 1200 Main St W, Hamilton, Ontario, L8S 3Z5, Canada.

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