Abstract
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 3-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.
Highlights
Leishmaniosis constitute a group of parasitic diseases of worldwide concern, that are considered by the World Health Organization as neglected tropical diseases [1]
Lymph node and bone marrow smears of dogs from both more clinicopathological signs (MT+A) and meglumine antimoniate in combination with allopurinol (MG+A) groups presented amastigote forms inside macrophages associated with lymphoid hyperplasia
Presenting higher Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) values, combined treatment of miltefosine and allopurinol promoted the decrease of AST and ALT in dogs from the MT+A group, albeit slower, with urinalysis values returning to normal
Summary
Leishmaniosis constitute a group of parasitic diseases of worldwide concern, that are considered by the World Health Organization as neglected tropical diseases [1]. Previous studies differentiated sick dogs into symptomatic, oligosymptomatic and polysymptomatic [3,4,5,6] more recently it has been proposed an improved system to stage dog’s clinical condition [7, 8]. This classification system takes into account the physical examination, clinicopathological abnormalities, anti-Leishmania antibody titer, and the evaluation of renal function according to the International Renal Interest Society guidelines [9]. Meglumine antimoniate is a pentavalent antimonial-based drug whose precise mechanism of action is not yet well-understood, but being considered a multifactorial drug with probable
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