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Domestic dogs are the main reservoir of Leishmania infantum, a causative agent of visceral leishmaniasis (VL). The number of human disease cases is associated with the rate of canine infection. Currently available drugs are not efficient at treating canine leishmaniasis (CanL) and months after the treatment most dogs show disease relapse, therefore the development of new drugs or new therapeutic strategies should be sought. In CanL, dogs lack the ability to mount a specific cellular immune response suitable for combating the parasite and manipulation of cytokine signaling pathway has the potential to form part of effective immunotherapeutic methods. In this study, recombinant canine cytokines (rcaIL-12, rcaIL-2, rcaIL-15 and rcaIL-7) and soluble receptor IL-10R1 (rcasIL-10R1), with antagonistic activity, were evaluated for the first time in combination (rcaIL-12/rcaIL-2, rcaIL-12/rcaIL-15, rcaIL-12/rcasIL-10R1, rcaIL-15/rcaIL-7) or alone (rcasIL-10R1) to evaluate their immunomodulatory capacity in peripheral blood mononuclear cells (PBMC) from dogs with leishmaniasis. All the combinations of recombinant proteins tested were shown to improve lymphoproliferative response. Further, the combinations rcaIL-12/rcaIL-2 and rcaIL-12/rcaIL-15 promoted a decrease in programmed cell death protein 1 (PD-1) expression in lymphocytes. These same combinations of cytokines and rcaIL-12/rcasIL-10R1 induced IFN-γ and TNF-α production in PBMC. Furthermore, the combination IL-12/IL-15 led to an increased in T-bet expression in lymphocytes. These findings are encouraging and indicate the use of rcaIL-12 and rcaIL-15 in future in vivo studies aimed at achieving polarization of cellular immune responses in dogs with leishmaniasis, which may contribute to the development of an effective treatment against CanL. Author summary: Dogs are the main reservoir of Leishmania infantum, a protozoan parasite that causes lethal systemic disease in human beings (Visceral Leishmaniasis, VL) and dogs (Canine Leishmaniasis, CanL). In dogs, the disease is often associated with extensive skin lesions. Curbing canine infection could help control human VL. Currently available drugs are not effective in treating CanL, and treated dogs frequently relapse, even when removed from an endemic area. Developing new drugs or alternative therapeutic strategies are essential for the proper treatment of CanL. Dogs that acquire the parasite can develop the disease or control the infection, depending on the body's immune response. Cellular immune responses lead to infection control and prevent the disease from developing. Some proteins called cytokines, produced mainly by cells of the immune system, can favor the development of cellular immune responses. In this study, several recombinant cytokines and/or one cytokine blocking protein were tested, alone or in combination, for their ability to promote cellular immune response in dogs with leishmaniasis. One of the combinations of recombinant protein tested was the best at facilitating these cellular immunes responses. The findings reported here are encouraging and indicate the use of a combination of two recombinant cytokines (rcaIL-12/rcaIL-15) in future immunotherapeutic trials for CanL. [ABSTRACT FROM AUTHOR]