INTERLEUKIN-12 ENHANCES IN-VIVO PARASITICIDAL EFFECT OF BENZNIDAZOLE DURING ACUTE EXPERIMENTAL-INFECTION WITH A NATURALLY DRUG-RESISTANT STRAIN OF TRYPANOSOMA-CRUZI

The roles of gamma interferon (IFN-gamma) and interleukin-12 (IL-12) i n mediating and/or enhancing the in vivo trypanosomicidal activity of the nitroheterocyclic derivative benznidazole (Bz) were evaluated duri ng early stages of experimental Chagas' disease. Our results show that treatment of Trypanosoma cruzi-infected mice with anti-cytokine monoc lonal antibodies (MAbs) had no apparent effect when the optimal dose o f Bz (100 mg/kg of body weight) was used. In contrast, treatment with anti-IL-12, or anti-IFN-gamma MAbs enhanced the parasitemia and accele rated the mortality of mice treated with a suboptimal dose of Bz (25 m g/kg). Simultaneous treatment with a suboptimal dose of Bz and recombi nant IL-12 (rIL-12) enhanced the efficacy of drug treatment in terms o f parasitemia and mouse survival. Interestingly, we found that drug-re sistant T. cruzi strains were found to be poor inducers of IL-12 bath in vitro and in vivo compared to strains of T. cruzi which are suscept ible or partially resistant to Bz treatment. These results suggest tha t early activation of the cellular compartment of the immune system by IL-12 may favor in vivo Br; activity against T, cruzi. In order to te st this hypothesis mice infected with the drug-resistant Colombiana st rain of T. cruzi were treated with 100 mg of Bz per kg plus different concentrations of rIL-12. By using the results of PCR and serological and parasitological methods as the criteria of a cure, our results ind icate that a higher percentage of mice treated with Bz combined with r IL-12 than mice treated with Bz alone are cured.