ENDOGENOUS IL-12 IS REQUIRED FOR CONTROL OF TH2 CYTOKINE RESPONSES CAPABLE OF EXACERBATING LEISHMANIASIS NORMALLY RESISTANT MICE

We investigated the mechanisms by which treatment with anti-IL-12 Ab p revents cure of infection with Leishmania major in resistant C57BL/6 m ice. 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 mi ce treated with either polyclonal or monoclonal anti-IL-12 Abs persist ently generated 3- to 10-fold more IL-4 and IL-10 in response to L. ma jor Ag compared with cells from mice receiving preimmune goat IgG. Rec iprocal 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 productio n was suppressed for up to 4 wk in mice treated with monoclonal anti-I L-12 or anti-IFN-gamma, coadministration of neutralizing anti-IL-4 IgG reversed progressive illness. These findings demonstrate that IL-12 p roduced in vivo is necessary for both the emergence of IFN-gamma produ cing cells and the down-regulation of Th2 cell responses during murine leishmaniasis. Furthermore, the uninhibited production of IL-4 was re quired to sustain progressive infection initiated by the decreased IFN -gamma synthesis observed in anti-IL-12 and anti-IFN-gamma-treated mic e.