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) in mediating and/or enhancing the in vivo trypanosomicidal activity of the nitroheterocyclic derivative benznidazole (Bz) were evaluated during early stages of experimental Chagas' disease. Our results show that treatment of Trypanosoma cruzi-infected mice with anti-cytokine monoclonal antibodies (MAbs) had no apparent effect when the optimal dose of 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 accelerated the mortality of mice treated with a suboptimal dose of Bz (25 mg/kg). Simultaneous treatment with a suboptimal dose of Bz and recombinant IL-12 (rIL-12) enhanced the efficacy of drug treatment in terms of parasitemia and mouse survival. Interestingly, we found that drug-resistant T. cruzi strains were found to be poor inducers of IL-12 both in vitro and in vivo compared to strains of T. cruzi which are susceptible or partially resistant to Bz treatment. These results suggest that early activation of the cellular compartment of the immune system by IL-12 may favor in vivo Bz activity against T. cruzi. In order to test this hypothesis mice infected with the drug-resistant Colombiana strain 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 indicate that a higher percentage of mice treated with Bz combined with rIL-12 than mice treated with Bz alone are cured.
Michailowsky
V
V
Department of Biochemistry and Immunology, Federal University of Minas Gerais, 30270-010 Belo Horizonte, MG, Centro de Pesquisas René Rachou, Oswaldo Cruz Foundation, 30190-002 Belo Horizonte, MG, Brazil.
Murta
S M
SM
Carvalho-Oliveira
L
L
Pereira
M E
ME
Ferreira
L R
LR
Brener
Z
Z
Romanha
A J
AJ
Gazzinelli
R T
RT
D000208:Acute Disease; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy*; D004351:Drug Resistance; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009593:Nitroimidazoles / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D014344:Trypanocidal Agents / Q000627:therapeutic use*
D009593:Nitroimidazoles; D014344:Trypanocidal Agents; D018664:Interleukin-12; D007371:Interferon-gamma; C009999:benzonidazole