title: Immucillins ImmA and ImmH Are Effective and Non-toxic in the Treatment of Experimental Visceral Leishmaniasis.
abstract: BACKGROUND
  Immucillins ImmA (IA), ImmH (IH) and SerMe-ImmH (SMIH) are synthetic deazapurine nucleoside analogues that inhibit Leishmania (L.) infantum chagasi and Leishmania (L.) amazonensis multiplication in vitro without macrophage toxicity. Immucillins are compared to the Glucantime standard drug in the chemotherapy of Leishmania (L.) infantum chagasi infection in mice and hamsters. These agents are tested for toxicity and immune system response.
  
  
  RESULTS
  BALB/c mice were infected with 107 amastigotes, treated with IA, IH, SMIH or Glucantime (2.5mg/kg/day) and monitored for clinical variables, parasite load, antibody levels and splenocyte IFN-γ, TNF-α, and IL-10 expression. Cytokines and CD4+, CD8+ and CD19+ lymphocyte frequencies were assessed in uninfected controls and in response to immucillins. Urea, creatinine, GOT and GPT levels were monitored in sera. Anti-Leishmania-specific IgG1 antibodies (anti-NH36) increased in untreated animals. IgG2a response, high levels of IFN-γ, TNF-α and lower levels of IL-10 were detected in mice treated with the immucillins and Glucantime. Immucillins permitted normal weight gain, prevented hepato-splenomegaly and cleared the parasite infection (85-89%) without renal and hepatic toxicity. Immucillins promoted 35% lower secretion of IFN-γ in uninfected controls than in infected mice. IA and IH increased the CD4+ T and CD19+ B cell frequencies. SMIH increased only the proportion of CD-19 B cells. IA and IH also cured infected hamsters with lower toxicity than Glucantime.
  
  
  CONCLUSIONS
  Immucillins IA, IH and SMIH were effective in treating leishmaniasis in mice. In hamsters, IA and IH were also effective. The highest therapeutic efficacy was obtained with IA, possibly due to its induction of a TH1 immune response. Low immucillin doses were required and showed no toxicity. Our results disclose the potential use of IA and IH in the therapy of visceral leishmaniasis.
authors.affiliation: Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.|Department of Biochemistry, Albert Einstein College of Medicine, Yeshiva University, New York, New York, United States.
authors.forename: Elisangela Oliveira
authors.initials: EO
authors.lastname: Freitas
authors.affiliation: Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Dirlei
authors.initials: D
authors.lastname: Nico
authors.affiliation: Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Marcus Vinícius
authors.initials: MV
authors.lastname: Alves-Silva
authors.affiliation: Departamento de Imunologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Morrot
authors.affiliation: The Ferrier Research Institute, Victoria University of Wellington, Wellington, New Zealand.
authors.forename: Keith
authors.initials: K
authors.lastname: Clinch
authors.affiliation: The Ferrier Research Institute, Victoria University of Wellington, Wellington, New Zealand.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Evans
authors.affiliation: The Ferrier Research Institute, Victoria University of Wellington, Wellington, New Zealand.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Tyler
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Yeshiva University, New York, New York, United States.
authors.forename: Vern L
authors.initials: VL
authors.lastname: Schramm
authors.affiliation: Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Clarisa B
authors.initials: CB
authors.lastname: Palatnik-de-Sousa
mesh_terms: D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000241:Adenosine / Q000031:analogs & derivatives; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D000981:Antiprotozoal Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001774:Blood Chemical Analysis; D004195:Disease Models, Animal; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D015870:Gene Expression; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D007891:Leishmania; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008647:Mesocricetus; D008807:Mice, Inbred BALB C; D059208:Parasite Load; D011684:Purine Nucleosides / Q000009:adverse effects / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000009:adverse effects / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000009:adverse effects / Q000627:therapeutic use*; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000913:Antibodies, Protozoan; D000981:Antiprotozoal Agents; D011684:Purine Nucleosides; D011744:Pyrimidinones; D011759:Pyrrolidines; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C113101:forodesine; D007371:Interferon-gamma; D000225:Adenine; D000241:Adenosine; C517546:galidesivir