CD279 (PD-1) e seus ligantes CD273 (PD-L1) e CD274 (PD-L2) regulam a linfoproliferação, a produção de il-10 e do óxido nítrico na leishmaniose visceral canina
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Data
2016-08-19
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Universidade Estadual Paulista (Unesp)
Resumo
PD-1 ligado a PD-L1 ou PD-L2, desencadeia sinais incapacitantes às células T, podendo estar envolvidos na supressão das respostas imunes na LVC. Investigamos a expressão de PD-1 e seus ligantes no baço na LVC, e sua correlação com a carga parasitária. Para confirmar o seu papel regulador na leishmaniose, estes receptores foram avaliados após infecção in vitro por L. infantum. Em cães infectados, foi avaliado o bloqueio destes receptores na produção de citocinas e seus efeitos no sobrenadante da cultura, de linfoproliferação com antígeno solúvel (AtgS) de L. infantum. Foram selecionados 23 cães saudáveis e 54 com LV. PD-1 e seus ligantes foram determinados por imunohistoquímica em tecidos esplênicos. A carga parasitária de cães infectados foi avaliada por PCR em tempo real. As citocinas nos sobrenadantes de cultura foram determinados por ELISA de captura e o NO por Griess. A Linfoproliferação das células do linfonodo e expressão de PD-1 e seus ligantes após infecção in vitro por L. infantum foram avaliadas por citometria de fluxo. Observou-se que a infecção por L. infantum, aumenta a expressão de PD1 e seus ligantes. Uma correlação positiva foi observada entre a expressão de PD-1 e PD-L1 em linfócitos B e o aumento da carga parasitária. O bloqueio destes receptores restaura a proliferação de linfócitos, aumenta a produção de NO e diminui a IL-4 e IL-10. L. infantum modula a expressão de PD-1 e seus ligantes na LVC, suprimi a linfoproliferação, alterando a produção de citocinas, podendo facilitar a persistência dos parasitas nos macrófagos, e podem ser direcionados para o desenvolvimento de drogas que estimulem a resposta imune na LVC.
PD-1 when bound to PD-L1 or PD-L2, triggers signals disabling T cells, and they may be involved in the suppression of cellular immune responses in CVL. We investigated the expression of PD-1 and its ligands in spleen in CVL, and its correlation with parasite burden in this tissue, to confirm its regulatory role in leishmaniasis. These receptors were evaluated after in vitro infection by L. infantum. In infected dogs, we evaluated the blocking of these receptors in the production of cytokines in the effects of supernatant of cultured cells, and antigen specific lymphoproliferation. We selected 23 healthy dogs and 54 with VL. PD-1 and its ligands were determined by immunohistochemistry in splenic tissues. Parasitic load of infected dogs was evaluated by RT-PCR. Cytokines in culture supernatants were determined by capture ELISA and NO by Griess. Lymphoproliferation lymph nodes and expression of PD-1 and its ligand after in vitro infection by L. infantum was evaluated by flow cytometry. We observed that L. infantum infection increases expression of PD-1 and its ligands. A positive correlation was observed between the expression of PD-1 and PD-L1 B lymphocytes and an increase in parasite load. Blockade these receptors restores lymphocyte proliferation, increases the production of NO and decreases IL-4 and IL-10. In conclusion, L. infantum modulates expression of PD-1 and its ligands in CVL, suppressing lymphoproliferative response and altering cytokine production, which in turn can facilitate parasitic persistence in the macrophages. PD-1 and its ligands can be targeted for the development of drugs stimulating the immune response in CVL.
PD-1 when bound to PD-L1 or PD-L2, triggers signals disabling T cells, and they may be involved in the suppression of cellular immune responses in CVL. We investigated the expression of PD-1 and its ligands in spleen in CVL, and its correlation with parasite burden in this tissue, to confirm its regulatory role in leishmaniasis. These receptors were evaluated after in vitro infection by L. infantum. In infected dogs, we evaluated the blocking of these receptors in the production of cytokines in the effects of supernatant of cultured cells, and antigen specific lymphoproliferation. We selected 23 healthy dogs and 54 with VL. PD-1 and its ligands were determined by immunohistochemistry in splenic tissues. Parasitic load of infected dogs was evaluated by RT-PCR. Cytokines in culture supernatants were determined by capture ELISA and NO by Griess. Lymphoproliferation lymph nodes and expression of PD-1 and its ligand after in vitro infection by L. infantum was evaluated by flow cytometry. We observed that L. infantum infection increases expression of PD-1 and its ligands. A positive correlation was observed between the expression of PD-1 and PD-L1 B lymphocytes and an increase in parasite load. Blockade these receptors restores lymphocyte proliferation, increases the production of NO and decreases IL-4 and IL-10. In conclusion, L. infantum modulates expression of PD-1 and its ligands in CVL, suppressing lymphoproliferative response and altering cytokine production, which in turn can facilitate parasitic persistence in the macrophages. PD-1 and its ligands can be targeted for the development of drugs stimulating the immune response in CVL.
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Palavras-chave
L. infantum, Leishmaniose visceral, Visceral leishmaniasis, Costimulatory molecules, Cão, Dog, Moléculas coestimulatórias