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*
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and
Novartis, Horsham, United Kingdom
IL-13 and IL-4 are key contributors to the asthmatic phenotype. The
temporal role of these cytokines in airway function, inflammation, and
remodeling were assessed in a chronic murine model of
Asperigillus fumigatus-induced allergic asthma. IL-13
and IL-4 protein levels were significantly elevated by 30 days after
conidia challenge in A. fumigatus-sensitized mice.
Furthermore, IL-13R
1 mRNA expression was significantly elevated 7
days after conidia challenge and remained elevated until day 21. In
contrast, IL-13R2 mRNA expression, although constitutively expressed
in naive lung, was absent in the lungs of A.
fumigatus-sensitized mice both before and after conidia
challenge. Membrane-bound IL-4R mRNA expression was significantly
elevated 7 days after conidia challenge; however, soluble IL-4R mRNA
expression was increased 30 days after conidia challenge.
Immunoneutralization of IL-13 between days 14 and 30 or days 30 and 38
after fungal sensitization and challenge significantly attenuated
airway hyperresponsiveness, collagen deposition, and goblet cell
hyperplasia at day 38 after conidia challenge; however, the effects of
IL-4 immunoneutralization during the same time periods were not as
marked. IFN-
and IL-12 release after Aspergillus Ag
restimulation was elevated from spleen cells isolated from mice treated
with IL-4 anti-serum compared with IL-13 anti-serum or normal
rabbit serum-treated mice. This study demonstrates a pronounced
therapeutic effect of IL-13-immunoneutralization at extended time
points following the induction of chronic asthma. Most importantly,
these therapeutic effects were not reversed following cessation of
treatment, and IL-13 anti-serum treatment did not alter the
systemic immune response to Ag restimulation, unlike IL-4
immunoneutralization. Therefore, IL-13 provides an attractive
therapeutic target in allergic asthma.
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