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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Vet. Sci. | doi: 10.3389/fvets.2019.00362

Meglumine antimoniate and miltefosine combined with allopurinol sustain pro-inflammatory immune environments during canine leishmaniosis treatment

 Marcos F. Santos1, Graça Alexandre-Pires1,  Maria A. Pereira2,  Cátia S. Marques1, Joana Gomes1, Jorge Correia1, Ana Duarte1, Lídia Gomes1,  Armanda Rodrigues2, Alexandra Basso1, Ana Reisinho1,  José Meireles1, David Santos-Mateus2, Maria T. Brito1, Luís Tavares1,  Gabriela Santos-Gomes2 and  Isabel P. da Fonseca1*
  • 1Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Portugal
  • 2Global Health and Tropical Medicine, Institute of Hygiene and Tropical Medicine, New University of Lisbon, Portugal

Canine leishmaniosis (CanL) caused by Leishmania infantum is a zoonotic disease of global concern. Antileishmanial drug therapies commonly used to treat sick dogs improve their clinical condition, although when discontinued relapses can occur. Thus, the current study aims to evaluate the effect of CanL treatments in peripheral blood, lymph node, and bone marrow cytokine profile associated with clinical recovery.
Two groups of six dogs diagnosed with CanL were treated with miltefosine combined with allopurinol and meglumine antimoniate combined with allopurinol (MT+A and MG+A) respectively. At diagnosis and after treatment, during a three-month follow-up, clinical signs, hematological and biochemical parameters, urinalysis results and antileishmanial antibody titers were registered. Furthermore, peripheral blood, popliteal lymph node, and bone marrow samples were collected to assess the gene expression of IL-2, IL-4, IL-5, IL-10, IL-12, TNF-α, TGF-β and IFN-γ by qPCR. In parallel, were also evaluated samples obtained from five healthy dogs.
Both treatment protocols promoted the remission of clinical signs as well as normalization of hematological and biochemical parameters and urinalysis values. Antileishmanial antibodies returned to non-significant titers in all dogs. Sick dogs showed a generalized upregulation of IFN-γ and downregulation of IL-2, IL-4 and TGF-β, while gene expression of IL-12, TNF-α, IL-5 and IL-10 varied between groups and according to evaluated tissue. A trend to the normalization of cytokine gene expression was induced by both miltefosine and meglumine antimoniate combined therapies. However, IFN-γ gene expression was still up-regulated in the three evaluated tissues. Furthermore, the effect of treatment in the gene expression of cytokines that were not significantly changed by infection, indicates that miltefosine and meglumine antimoniate combined therapy directly affects cytokine generation.
Both combined therapies are effective in CanL treatment, leading to sustained pro-inflammatory immune environments that can compromise parasite survival and favor dogs’ clinical cure. In the current study, anti-inflammatory and regulatory cytokines do not seem to play a prominent role in CanL or during clinical recovery.

Keywords: Canine leishmaniosis, Peripheral blood mononuclear cells (PB MNC), Lymph Node (LN), Bone marrow (BM), Cytokine gene expression, Meglumine antimoniate (Glucantime), miltefosine, Allopurinol

Received: 15 Jun 2019; Accepted: 01 Oct 2019.

Copyright: © 2019 Santos, Alexandre-Pires, Pereira, Marques, Gomes, Correia, Duarte, Gomes, Rodrigues, Basso, Reisinho, Meireles, Santos-Mateus, Brito, Tavares, Santos-Gomes and da Fonseca. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: DVM, PhD. Isabel P. da Fonseca, Centre for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Lisboa, Portugal, ifonseca@fmv.ulisboa.pt