IL-12 induction of resistance to pulmonary blastomycosis

Background: Why severity varies in blastomycosis outbreaks remains unresolved. In experimental pulmonary blastomycosis, susceptibility varied in mouse strains. In susceptible BALB/c the response is Th-2, in immunized, resistance is associated with Th-1. Can susceptibility be redirected by IL-12? Methods, results: BALB/c bronchoalveolar and peritoneal macrophages (PM) were shown deficient in IL-12 production in response to IFN-gamma + LPS. High dose IL-12 (1 mu g, subcutaneously) treatment of BALB/c infected intranasally with Blastomyces resulted in enhanced survival (P < 0.008). Since IL-12 was poorly tolerated, a new protocol for infected mice, IL-12 0.1 or 0.3 mu g, every other day, resulted in minimal toxicity; almost all treated mice survived (P < 0.002 vs. controls). When lungs of surviving mice were cultured, the 0.1 mu g regimen resulted in fewer (P < 0.02) cfu. For weeks after treatment, in vitro IFN-gamma treatment enabled PM Blastomyces killing. After infection spleen cells from IL-12 treated mice produced 4-fold more IFN-gamma and 3-fold less IL-10 in response to Blastomyces. IL-10 abrogated activation of macrophages by IFN-gamma for enhanced Blastomyces killing. Conclusions: A proper IL-12 treatment protocol induces resistance (survival and decreased growth in lungs), low toxicity, macrophage responsiveness to IFN-gamma for killing Blastomyces, up-regulation of IFN-gamma and down-regulation of IL-10 production. (c) 2006 Elsevier Ltd. All rights reserved.