Resistance to antigen-induced airway hyperresponsiveness requires endogenous production of IL-12.
We have demonstrated previously that susceptibility of murine strains to the development of allergic airway responses is associated with a type 2 cytokine pattern. In the present study, we examine the in vivo role of IL-12 in the immune response to allergen exposure in susceptible (A/J) and resistant (C3H/HeJ, C3H) strains of mice. OVA sensitization and challenge induced significant increases in airway reactivity in A/J mice as compared with their PBS-challenged controls, while no increases in airway reactivity were observed in OVA-challenged C3H mice. OVA exposure of A/J mice resulted in marked increases in the Th2 cytokines, IL-4 and IL-10, in the bronchoalveolar lavage fluid, whereas increases in IFN-gamma were observed in C3H mice. Strikingly, anti-IL-12 mAb (1 mg/mouse) treatment resulted in threefold increases in airway reactivity in OVA-challenged resistant C3H mice, concomitant with significant increases in bronchoalveolar lavage levels of Th2 cytokines and decreases in IFN-gamma. IL-12 depletion of C3H mice also suppressed OVA-specific serum IgG2a levels and increased both serum OVA-specific IgG1 and IgE levels. Blockade of endogenous IL-12 levels in susceptible A/J mice resulted in further augmentation of type 2 immune responses. These results demonstrate that endogenous production of IL-12 is essential for resistance to Ag-induced airway hyperresponsiveness, and furthermore, that dysregulation of IL-12 production may lead to the development of deleterious type 2 immune responses to inhaled allergens.
Department of Environmental Health Sciences, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, MD 21205, USA.
A
A
Keane-Myers
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M
Wysocka
G
G
Trinchieri
M
M
Wills-Karp
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000276:immunology* / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D004198:Disease Susceptibility; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D007106:Immune Sera / Q000008:administration & dosage; D007113:Immunity, Innate; D007073:Immunoglobulin E / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000276:immunology / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008809:Mice, Inbred C3H; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology*; D018418:Th2 Cells / Q000378:metabolism
D000911:Antibodies, Monoclonal; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007106:Immune Sera; D007074:Immunoglobulin G; D018664:Interleukin-12; D007073:Immunoglobulin E; D010047:Ovalbumin