PARASITE-INDUCED IL-12 STIMULATES EARLY IFN-GAMMA SYNTHESIS AND RESISTANCE DURING ACUTE INFECTION WITH TOXOPLASMA-GONDII

In vitro and in vivo studies were performed to assess the involvement of IL-12 in resistance to acute and chronic infection with an avirulen t strain of Toxoplasma gondii. Our previous findings implicated macrop hages as a major source of parasite-induced IL-12. This finding was co nfirmed by showing that peritoneal macrophages exposed to either live parasites or soluble tachyzoite Ags produce IL-12 protein. In mice, in creased expression of IL-12 (p40) mRNA in both spleen and peritoneal c ells was detected as early as 2 days postinfection. Treatment with neu tralizing mAbs against IL-12 increased the susceptibility of C57BL/6, BALB/c, and severe combined immunodeficient (SCID) mice to acute infec tion, which resulted in 100% mortality within the first 15 days after parasite inoculation. In contrast, neutralization of endogenously prod uced IL-12 had no effect when given during chronic infection. In agree ment with the survival data, treatment with anti-IL-12 resulted in dec reased IFN-gamma and enhanced Th2 (IL-4 and IL-10) cytokine synthesis by splenocytes when given during acute, but not chronic, toxoplasmosis . Sorting experiments on spleen cells from acutely infected mice indic ated that both CD4(+) lymphocytes and NK1.1(+)/CD3(-) cells contribute to the early IFN-gamma response. In contrast, CD4(+) cells were found to be the major source of the cytokine during chronic disease. Togeth er, these results suggest that the stimulation of macrophage-derived I L-12 plays a major role in both the induction of resistance and Th1 ce ll subset selection in acute T. gondii infection, but may not be requi red to maintain established immunity.