Local treatment with IL-12 is an effective inhibitor of airway hyperresponsiveness and lung eosinophilia after airway challenge in sensitized mice.
BACKGROUND
Systemic administration of IL-12 can prevent airway hyperresponsiveness (AHR) in mice after sensitization and repeated allergen challenge. However, systemic IL-12 has been associated with severe adverse effects.


OBJECTIVE
We determined whether IL-12 administration to the airways in a dose sufficiently low so as not to result in systemic effects can modify allergic inflammation and AHR after allergen challenge.


METHODS
Mice were sensitized to ovalbumin by intraperitoneal injection and challenged with ovalbumin aerosol on 3 consecutive days. During the period of challenge, IL-12 was administered intranasally following 2 regimens, designated high (1500 ng) or low (150 ng). We monitored airway responsiveness to inhaled methacholine by barometric body plethysmography, lung inflammatory cells, local cytokine production, and, to assess systemic effects of IL-12 treatment, spleen weights and numbers of eosinophils in the bone marrow.


RESULTS
Allergen challenge resulted in increases in airway responsiveness and in numbers of lung eosinophils. These increases were prevented by both high- and low-dose IL-12. Additionally, IL-12 administration resulted in enhanced local interferon-gamma production and prevented the increases in local IL-4 and IL-5 production after airway challenge. A high dose, but not a low dose, of IL-12 resulted in increased spleen weights and prevented the increase in numbers of bone marrow eosinophils after allergen challenge.


CONCLUSIONS
These data indicate that local administration of IL-12 can prevent AHR and reduce lung eosinophilia after allergen challenge in sensitized mice without eliciting systemic adverse effects. IL-12 exerts these effects by inducing local T(H1)-type responses in the airways in a setting that is normally dominated by T(H2)-type responses.
Department of Pediatrics, National Jewish Medical and Research Center, Denver 80206, USA.
J
J
Schwarze
E
E
Hamelmann
G
G
Cieslewicz
A
A
Tomkinson
A
A
Joetham
K
K
Bradley
E W
EW
Gelfand
D000485:Allergens / Q000276:immunology*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004802:Eosinophilia / Q000209:etiology / Q000517:prevention & control*; D005260:Female; D006967:Hypersensitivity / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D007074:Immunoglobulin G; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D015847:Interleukin-4 / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear; D008168:Lung / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use
D000485:Allergens; D007074:Immunoglobulin G; D015848:Interleukin-5; D011994:Recombinant Proteins; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D010047:Ovalbumin