Michailowsky V, Murta S M, Carvalho-Oliveira L, Pereira M E, Ferreira L R, Brener Z, Romanha A J, Gazzinelli R T
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.
Antimicrob Agents Chemother. 1998 Oct;42(10):2549-56. doi: 10.1128/AAC.42.10.2549.
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.
在实验性恰加斯病的早期阶段，评估了γ干扰素（IFN-γ）和白细胞介素-12（IL-12）在介导和/或增强硝基杂环衍生物苯硝唑（Bz）体内杀锥虫活性中的作用。我们的结果表明，当使用最佳剂量的Bz（100mg/kg体重）时，用抗细胞因子单克隆抗体（MAb）治疗克氏锥虫感染的小鼠没有明显效果。相反，用抗IL-12或抗IFN-γ MAb治疗可提高接受次优剂量Bz（25mg/kg）治疗的小鼠的寄生虫血症，并加速其死亡。用次优剂量的Bz与重组IL-12（rIL-12）同时治疗，在寄生虫血症和小鼠存活方面提高了药物治疗的效果。有趣的是，我们发现与对Bz治疗敏感或部分耐药的克氏锥虫菌株相比，耐药的克氏锥虫菌株在体外和体内诱导IL-12的能力较差。这些结果表明，IL-12对免疫系统细胞区室的早期激活可能有利于Bz在体内对克氏锥虫的活性。为了验证这一假设，用每公斤100mg的Bz加不同浓度的rIL-12治疗感染耐药克氏锥虫哥伦比亚菌株的小鼠。以PCR、血清学和寄生虫学方法的结果作为治愈标准，我们的结果表明，与单独用Bz治疗的小鼠相比，用Bz联合rIL-12治疗的小鼠有更高比例被治愈。
