A single intramuscular injection with an adenovirus expressing IL-12 protects BALB/c mice against Leishmania major infection, while treatment with anIL-4-expressing vector increases disease susceptibility in B10.D2 mice

Experimental infection of the susceptible BALB/c (H-2(d)) mouse with the in tracellular parasite Leishmania major induces a predominant Th2-type T cell response that eventually leads to death. In contrast, the resistant B10.D2 (H-2(d)) strain develops Th1 cells that control parasite replication and d isease. In this study, we tested the ability of a recombinant adenovirus ve ctor-expressing IL-12 to skew the immune response in a Th1 direction and pr event leishmaniasis in susceptible mice. We report that BALB/c mice treated with the Ad5IL-12 vector on the same day as parasitic challenge are signif icantly protected against leishmaniasis and acquired long-lasting immunity, because upon rechallenge with L. major parasites they were resistant to di sease. The vector-derived IL-12 expression was transient and highly localiz ed to the tissue after i.m. injection; it caused an increase in the number of Ag-specific IFN-gamma-secreting lymphocytes and enhanced NK cell activit y in the draining popliteal node. In contrast, resistant B10.D2 mice given i.m. injections with a recombinant adenovirus-expressing IL-4 displayed gre ater susceptibility to disease, and severe lesions were produced in some of the infected animals. These results suggest the potential use of recombina nt adenoviruses expressing cytokines as potent immunomodulatory agents for the generation of protective immune responses against intracellular pathoge ns.