Allergic
asthma is strongly associated with the airway
inflammation caused by the dysregulated production of
cytokines secreted by the
allergen-specific type-2 T helper (Th2) cells.
Interleukin (IL)-12 is a heterodimeric
cytokine, which strongly promotes the differentiation of naive CD4(+) T cells to the type-1 T helper (Th1) phenotype and suppresses the expression of Th2
cytokines. Therefore,
immunotherapy with
IL-12 has been suggested as a possible
therapy for
asthma. In previous studies, we developed a murine model of airway
inflammation based on the purified, house dust-mite
allergen Der p 1 (Dermatophagodies pteronyssinus) as a clinically relevant
allergen. We hypothesized that the expression of
IL-12 in the airway may represent an effective
therapy for allergic airway diseases. In this study, we investigate whether the local transfer of the
IL-12 gene to respiratory tissues modifies allergic
inflammation and
airway hyper-responsiveness (AHR) in our disease model. To enhance the in vivo delivery of the
IL-12 gene, we expressed the murine single-chain
IL-12 protein from a nonviral vector to which the two
IL-12 subunits (p35 and p40) were linked by a 14- to 18-amino-acid linker. One of these single-chain IL-12s, containing an 18
amino-acid polypeptide linker, was stably expressed and had a high level of
biological activity comparable to that of native
IL-12 in vitro. In mice with Der p 1-induced
asthma, the local administration of this
IL-12 fusion gene into the lungs significantly prevented the development of AHR, abrogated airway
eosinophilia, and inhibited type-2
cytokine production. These findings indicate that the local transfer of the single-chain
IL-12 gene is effective in modulating pulmonary allergic responses and may be a convenient method for future applications of
DNA vaccination.