لخّصلي

Leishmaniasis is a neglected--though widely distributed--tropical disease caused by protozoan parasites of the genus Leishmania .Methotrexate (MTX), an antagonist of folic acid, blocks the synthesis of purines and pyrimidines .Commonly used to treat autoimmune diseases, its precise mechanism of action remains unknown, although it has been described to reduce the inflammation associated with these diseases .It also reduces the multiplication of lymphocytes, and thus has a direct effect on immune system function .it might, therefore, influence the development of an adequate immune response to Leishmania infection.However, the murine model of L. infantum infection allows the study of the immune response and of the mechanisms affecting protection against/susceptibility towards the development of VL .This immune response is organ-specific; the infection is usually cleared from the liver in the first few weeks, but it becomes chronic in the spleen and bone marrow .The present work characterises the parasite load developed in, and immune response to, L. infantum-induced VL in C57BL/6 mice that, prior to and during infection, received immunosuppressant treatment with MPDN, anti-TNF antibodies, or MTXHowever, an increase in cases of VL has also been detected among recipients of solid organ transplants and patients receiving immunosuppressants to treat autoimmune diseases such as rheumatoid arthritis, lupus erythematous and inflammatory bowel disease .After their bonding to the target molecule, the multiplication of amastigotes in infected macrophages is favoured, increasing the chances of developing clinical leishmaniasis--an outcome confirmed in animal models lacking the gene for TNF .

Leishmaniasis is a neglected—though widely distributed—tropical disease caused by protozoan parasites of the genus Leishmania . Visceral leishmaniasis (VL), the most severe form of the disease in which parasites invade different internal organs, is associated with high morbidity and mortality . In the Mediterranean Basin, Central Asia and Brazil, Leishmania infantum is the species mainly responsible. Successful resolution of the infection requires the host to mount an adequate Th1-type immune response characterised by the production of IFN-γ, TNF and IL-2 by CD4+ and CD8+ T cells .

Being in an immunosuppressed state is major risk factor for developing severe VL. For example, co-infection with HIV increases by some 100–2320 fold the chances of developing active VL . Indeed, HIV-associated immunosuppression has been identified as a major emerging challenge in the control of VL . However, an increase in cases of VL has also been detected among recipients of solid organ transplants and patients receiving immunosuppressants to treat autoimmune diseases such as rheumatoid arthritis, lupus erythematous and inflammatory bowel disease . Ever more frequently used in these contexts, these drugs may increase the number of people susceptible to Leishmania infection as well as condition the severity of disease. For example, VL caused by both L. infantum and L. donovani has been reported in patients treated with methylprednisolone (MPDN) for rheumatoid arthritis, along with reactivated disease, likely due to the immunosuppression induced .

Tumour necrosis factor (TNF) is a key cytokine in the activation of macrophages infected by Leishmania, and it plays a central role in the development of a protective Th1 immune response . Antagonists of TNF, such as anti-TNF antibodies, are also used in the treatment of autoimmune disease. After their bonding to the target molecule, the multiplication of amastigotes in infected macrophages is favoured, increasing the chances of developing clinical leishmaniasis—an outcome confirmed in animal models lacking the gene for TNF .

Methotrexate (MTX), an antagonist of folic acid, blocks the synthesis of purines and pyrimidines .Commonly used to treat autoimmune diseases, its precise mechanism of action remains unknown, although it has been described to reduce the inflammation associated with these diseases .It also reduces the multiplication of lymphocytes, and thus has a direct effect on immune system function .it might, therefore, influence the development of an adequate immune response to Leishmania infection.

The effects of the above agents on the immune response to and severity of VL have never been examined comparatively in standard experimental models. However, the murine model of L. infantum infection allows the study of the immune response and of the mechanisms affecting protection against/susceptibility towards the development of VL .This immune response is organ-specific; the infection is usually cleared from the liver in the first few weeks, but it becomes chronic in the spleen and bone marrow .The present work characterises the parasite load developed in, and immune response to, L. infantum-induced VL in C57BL/6 mice that, prior to and during infection, received immunosuppressant treatment with MPDN, anti-TNF antibodies, or MTX