antimony-sodium-gluconate and Liver-Diseases--Parasitic

In C57BL/6 mice, Leishmania donovani infection in the liver provoked IFN-γ-induced expression of the immunity-related GTPases (IRG), Irgm1 and Irgm3. To gauge the antileishmanial effects of these macrophage factors in the liver, intracellular infection was analyzed in IRG-deficient mice. In early- (but not late-) stage infection, Irgm3(-/-) mice failed to properly control parasite replication, generated little tissue inflammation and were hyporesponsive to pentavalent antimony (Sb) chemotherapy. Observations limited to early-stage infection in Irgm1(-/-) mice demonstrated increased susceptibility and virtually no inflammatory cell recruitment to heavily-parasitized parenchymal foci but an intact response to chemotherapy. In L. donovani infection in the liver, the absence of either Irgm1 or Irgm3 impairs early inflammation and initial resistance; the absence of Irgm3, but not Irgm1, also appears to impair the intracellular efficacy of Sb chemotherapy.

Topics: Animals; Antimony Sodium Gluconate; Antiprotozoal Agents; Female; Gene Expression Regulation; GTP Phosphohydrolases; GTP-Binding Proteins; Interferon-gamma; Leishmania donovani; Leishmaniasis, Visceral; Liver; Liver Diseases, Parasitic; Macrophages; Mice; Microarray Analysis

Chronic infectious diseases and cancers are often associated with suboptimal effector T cell responses. Enhancement of T cell costimulatory signals has been extensively studied for cancer immunotherapy but not so for the treatment of infectious disease. The few previous attempts at this strategy using infection models have lacked cellular specificity, with major immunoregulatory mechanisms or innate immune cells also being targeted. In this study, we examined the potential of promoting T cell responses via the glucocorticoid-induced TNF receptor (GITR) family-related protein in a murine model of visceral leishmaniasis. GITR stimulation during established infection markedly improved antiparasitic immunity. This required CD4(+) T cells, TNF, and IFN-gamma, but crucially, was independent of regulatory T (Treg) cells. GITR stimulation enhanced CD4(+) T cell expansion without modulating Treg cell function or protecting conventional CD4(+) T cells from Treg cell suppression. GITR stimulation substantially improved the efficacy of a first-line visceral leishmaniasis drug against both acute hepatic infection and chronic infection in the spleen, demonstrating its potential to improve clinical outcomes. This study identifies a novel strategy to therapeutically enhance CD4(+) T cell-mediated antiparasitic immunity and, importantly, achieves this goal without impairment of Treg cell function.

Topics: Animals; Antibodies, Monoclonal; Antimony Sodium Gluconate; Antiprotozoal Agents; Apoptosis; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Drug Synergism; Female; Glucocorticoid-Induced TNFR-Related Protein; Immunity, Cellular; Interferon-gamma; Leishmania donovani; Leishmaniasis, Visceral; Liver; Liver Diseases, Parasitic; Male; Mice; Mice, Inbred C57BL; Receptors, Nerve Growth Factor; Receptors, Tumor Necrosis Factor; T-Lymphocytes, Regulatory; Tumor Necrosis Factor-alpha

We present a 35 years-old man with fever related leishmania infection as the first complication of a previously undiagnosed cirrhosis. Diagnosis of leishmaniasis is often complicated. Clinical and therapeutical aspects are commented.

Topics: Adult; Animals; Antibodies, Protozoan; Antimony Sodium Gluconate; Humans; Leishmania; Leishmaniasis; Liver Cirrhosis; Liver Diseases, Parasitic; Male; Treatment Outcome

Topics: Antimony Sodium Gluconate; Humans; India; Leishmaniasis, Visceral; Liver Diseases, Parasitic