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


OBJECTIVE
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 T(H)2 sensitization (and not inhalation tolerance) accompanied by mild airway inflammation, modest clinical symptoms, and moderate production of T(H)2 cytokines by splenocytes on ragweed restimulation. The administration of anti-GM-CSF antibodies in conjunction with ragweed diminished T(H)2-associated cytokine production. These responses were amplified by enriching the airway microenvironment with GM-CSF. Under these conditions, all T(H)2-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.


CONCLUSIONS
GM-CSF plays an important role in the generation of allergic immune-inflammatory responses to ragweed.
Department of Pathology and Molecular Medicine and the Centre for Gene Therapeutics, Division of Respiratory Diseases and Allergy, McMaster University, Hamilton, Ontario, Canada.
Elizabeth C
EC
Cates
Beata U
BU
Gajewska
Susanna
S
Goncharova
David
D
Alvarez
Ramzi
R
Fattouh
Anthony J
AJ
Coyle
José-Carlos
JC
Gutierrez-Ramos
Manel
M
Jordana
D031164:Ambrosia / Q000276:immunology*; D000818:Animals; D001249:Asthma / Q000209:etiology*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology*; D006967:Hypersensitivity / Q000209:etiology*; D007249:Inflammation / Q000209:etiology*; D008168:Lung / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D010047:Ovalbumin / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D018418:Th2 Cells / Q000276:immunology
D016207:Cytokines; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D010047:Ovalbumin