Abstract
Immune activating cytokines Interferon (IFN)-γ and Tumor necrosis factor (TNF)-α are known to activate macrophages for killing of Leishmania parasite. IFN-γ provides therapeutic potential while TNF-α has been recognized to mediate protection in visceral model of infection. In the present study we investigated whether combination of IFN-γ and TNF-α has better therapeutic strength than individually using one of these cytokines in Visceral Leishmaniasis (VL) patients. We performed combined blockade of IFN-γ and TNF-α in VL splenic biopsies and demonstrated it’s impact on number of viable amastigotes and cytokine production. Additionally, selective depletion of splenic cell subsets was performed to establish the cellular sources of IFN-γ and TNF-α. Treatment of splenic aspirate cells with combination of anti-IFN-γ and anti-TNF-α monoclonal antibodies for 72 hours enabled no direct additive impact of these cytokines on parasite replication and IL-10 secretion, but IL-4 production was induced. Further assessment of splenic biopsies put forward CD4+ T cells as a source of IFN-γ whereas CD14+ cells contribute towards TNF-α production. Overall our results suggest, the interplay of pro-inflammatory cytokines IFN-γ derived from CD4+T lymphocytes and TNF-α from CD14+ cells has no direct additive impact on parasite replication but induces IL-4 production. Our data does not support direct targeting of IFN-γ and TNF-α for combination therapy but targeting these cytokines as an adjuvant in patients with exaggerated tissue inflammatory responses can have favourable patient outcome.
Highlights
Visceral Leishmaniasis (VL) is a principal public health problem in developing countries and is amongst the utmost neglected tropical diseases [1]
Splenic aspirate (SA) biopsies treated with combination of anti-IFN-γ mAb and anti-Tumor necrosis factor (TNF)-α mAb display significant increase in parasite burden (ÃÃP = 0.01) in 59% of SA cultures (16/27) while no changes in 26% of cultures were reported (7/27) and 14.8% (4/27) SA showed decrease in parasite numbers (Fig 2A)
Since we did not observed any additional effect of combine blockade, this would imply that increase in parasite survival can be effect of IFN-γ only and combination of these two cytokines may be inactive in this respect
Summary
Visceral Leishmaniasis (VL) is a principal public health problem in developing countries and is amongst the utmost neglected tropical diseases [1]. Majority of VL infection remains asymptomatic and the mechanisms through which parasite are cleared remains unknown [2]. IFN-γ and TNF-α blockade in VL splenic biopsies
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