Immucillins ImmA and ImmH Are Effective and Non-toxic in the Treatment of Experimental Visceral Leishmaniasis

Elisangela Oliveira Freitas, Dirlei Nico, Marcus Vinícius Alves-Silva, Alexandre Morrot, Keith Clinch, Gary B. Evans, Peter C. Tyler, Vern L. Schramm, Clarisa B. Palatnik-de-Sousa

Research output: Contribution to journalArticle

8 Citations (Scopus)

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. Methodology/Principal Findings: BALB/c mice were infected with 107amastigotes, 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/Significance: 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.

Original languageEnglish (US)
Article numbere0004297
JournalPLoS Neglected Tropical Diseases
Volume9
Issue number12
DOIs
StatePublished - Dec 23 2015

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Visceral Leishmaniasis
Leishmania infantum
Cricetinae
Interleukin-10
B-Lymphocytes
Parasite Load
Therapeutics
Parasitic Diseases
Leishmaniasis
Leishmania
Splenomegaly
Nucleosides
Weight Gain
Urea
Anti-Idiotypic Antibodies
Immune System
Creatinine
Immunoglobulin G
Macrophages
Lymphocytes

ASJC Scopus subject areas

  • Infectious Diseases
  • Public Health, Environmental and Occupational Health
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Freitas, E. O., Nico, D., Alves-Silva, M. V., Morrot, A., Clinch, K., Evans, G. B., ... Palatnik-de-Sousa, C. B. (2015). Immucillins ImmA and ImmH Are Effective and Non-toxic in the Treatment of Experimental Visceral Leishmaniasis. PLoS Neglected Tropical Diseases, 9(12), [e0004297]. https://doi.org/10.1371/journal.pntd.0004297

Immucillins ImmA and ImmH Are Effective and Non-toxic in the Treatment of Experimental Visceral Leishmaniasis. / Freitas, Elisangela Oliveira; Nico, Dirlei; Alves-Silva, Marcus Vinícius; Morrot, Alexandre; Clinch, Keith; Evans, Gary B.; Tyler, Peter C.; Schramm, Vern L.; Palatnik-de-Sousa, Clarisa B.

In: PLoS Neglected Tropical Diseases, Vol. 9, No. 12, e0004297, 23.12.2015.

Research output: Contribution to journalArticle

Freitas, EO, Nico, D, Alves-Silva, MV, Morrot, A, Clinch, K, Evans, GB, Tyler, PC, Schramm, VL & Palatnik-de-Sousa, CB 2015, 'Immucillins ImmA and ImmH Are Effective and Non-toxic in the Treatment of Experimental Visceral Leishmaniasis', PLoS Neglected Tropical Diseases, vol. 9, no. 12, e0004297. https://doi.org/10.1371/journal.pntd.0004297
Freitas, Elisangela Oliveira ; Nico, Dirlei ; Alves-Silva, Marcus Vinícius ; Morrot, Alexandre ; Clinch, Keith ; Evans, Gary B. ; Tyler, Peter C. ; Schramm, Vern L. ; Palatnik-de-Sousa, Clarisa B. / Immucillins ImmA and ImmH Are Effective and Non-toxic in the Treatment of Experimental Visceral Leishmaniasis. In: PLoS Neglected Tropical Diseases. 2015 ; Vol. 9, No. 12.
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AU - Morrot, Alexandre

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AU - Evans, Gary B.

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N2 - 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. Methodology/Principal Findings: BALB/c mice were infected with 107amastigotes, 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/Significance: 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.

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