Sh. Gavett et al., INTERLEUKIN-12 INHIBITS ANTIGEN-INDUCED AIRWAY HYPERRESPONSIVENESS, INFLAMMATION, AND TH2 CYTOKINE EXPRESSION IN MICE, The Journal of experimental medicine, 182(5), 1995, pp. 1527-1536
Allergic asthma is characterized by ah-way hyperresponsiveness and pul
monary eosinophilia, and may be mediated by T helper (Th) lymphocytes
expressing a Th2 cytokine pattern. Interleukin (IL) 12 suppresses the
expression of Th2 cytokines and their associated responses, including
eosinophilia, serum immunoglobulin E, and mucosal mastocytosis. We hav
e previously shown in a murine model that antigen-induced increases in
airway hyperresponsiveness and pulmonary eosinophilia are CD4(+) T ce
ll dependent. We used this model to determine the ability of IL-12 to
prevent antigen-induced increases in airway hyperresponsiveness, bronc
hoalveolar lavage (BAL) eosinophils, and lung Th2 cytokine expression.
Sensitized A/J mice developed airway hyperresponsiveness and increase
d numbers of BAL eosinophils and other inflammatory cells after single
or repeated intratracheal challenges with sheep red blood cell antige
n. Pulmonary mRNA and protein levels of the Th2 cytokines IL-I and IL-
5 were increased after antigen challenge. Administration of IL-12 (1 m
u g/d X 5 d) at the time of a single antigen challenge abolished the a
irway hyperresponsiveness and pulmonary eosinophilia and promoted an i
ncrease in interferon (IFN) gamma and decreases in IL-4 and IL-5 expre
ssion. The effects of IL-12 were partially dependent on IFN-gamma, bec
ause concurrent treatment with IL-12 and anti-IFN-gamma monoclonal ant
ibody partially reversed the inhibition of airway hyperresponsiveness
and eosinophilia by IL-12. Treatment of mice with IL-12 at the time of
a second antigen challenge also prevented airway hyperresponsiveness
and significantly reduced numbers of BAL inflammatory cells, reflectin
g the ability of IL-12 to inhibit responses associated With Ongoing an
tigen-induced pulmonary inflammation. These data show that antigen-ind
uced airway hyperresponsiveness and inflammation can be blocked by IL-
12, which suppresses Th2 cytokine expression. Local administration of
IL-12 may provide a novel immunotherapy for the treatment of pulmonary
allergic disorders such as atopic asthma.