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

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.)