Endogenous IL-12 is required for control of Th2 cytokine responses capable of exacerbating leishmaniasis in normally resistant mice.
We investigated the mechanisms by which treatment with anti-IL-12 Ab prevents cure of infection with Leishmania major in resistant C57BL/6 mice. Consistent with delayed production of IL-12, anti-IL-12 Abs could be administered as late as 2 wk after infection to exacerbate disease. Starting at 2 wk of infection, the cultured lymph node cells from mice treated with either polyclonal or monoclonal anti-IL-12 Abs persistently generated 3- to 10-fold more IL-4 and IL-10 in response to L. major Ag compared with cells from mice receiving preimmune goat IgG. Reciprocal decreases in Ag-specific IFN-gamma production were observed in mice receiving anti-IL-12 Abs. A similar reversal of IFN-gamma and IL-4 production accompanied progressive disease induced by pretreatment with a single dose of anti-IFN-gamma mAb. Although IFN-gamma production was suppressed for up to 4 wk in mice treated with monoclonal anti-IL-12 or anti-IFN-gamma, coadministration of neutralizing anti-IL-4 IgG reversed progressive illness. These findings demonstrate that IL-12 produced in vivo is necessary for both the emergence of IFN-gamma producing cells and the down-regulation of Th2 cell responses during murine leishmaniasis. Furthermore, the uninhibited production of IL-4 was required to sustain progressive infection initiated by the decreased IFN-gamma synthesis observed in anti-IL-12 and anti-IFN-gamma-treated mice.
Heinzel
F P
FP
Division of Geographic Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Rerko
R M
RM
Ahmed
F
F
Pearlman
E
E
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001483:Base Sequence; D001667:Binding, Competitive / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D007113:Immunity, Innate / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology / Q000502:physiology*; D015847:Interleukin-4 / Q000235:genetics; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D016207:Cytokines; D012333:RNA, Messenger; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma