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 microg, 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 microg, 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 microg 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.
Brummer
Elmer
E
Department of Medicine, Santa Clara Valley Medical Center, San Jose, CA 95128-2699, USA.
Vinoda
V
V
Stevens
David A
DA
D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000494:pharmacology*; D000818:Animals; D001758:Blastomyces / Q000276:immunology; D001759:Blastomycosis / Q000188:drug therapy / Q000276:immunology*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D013045:Species Specificity; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma