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*
Department of Environmental Health Sciences, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, MD 21205; and
Wistar Institute, Philadelphia, PA 19104
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-
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-. 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.
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