The effect of TNF-α neutralization on parasite load and cytokine production in human visceral leishmaniasis
Year: 2016
Type: article
Abstract: Background: The pro-inflammatory cytokine tumor necrosis factor (TNF)-α has an important role in control of experimental Leishmania donovani infection. Less is known about the role of TNF-α in human visceral leishmaniasis (VL). Direct evidence is primarily based on case reports of development of VL in individuals treated with TNF-α neutralizing antibody. Blockade of TNF-α can result in increased susceptibility to infections such as TB and leishmaniasis or reactivation of disease following cure. This indicates that TNF-α plays an important role in the control of intracellular pathogens, especially those that infect macrophages. In mice, TNF-α was found to be required for the control of L. donovani infection and for the formation of granulomas. To better understand the role of TNF-α in host defence against human L. donovani infection, we tested the effect of TNF-α blockade on splenic aspirate (SA) cell cultures, a cell culture system previously established to examine the role of cells and cytokines in tissue from an important site of disease in VL patients. Methods & Materials: The effect of TNF-α on parasite burden was measured by neutralization of TNF-α and/or Enbrel in SA cultures from active VL patients. The SA suspension was divided into three equal parts and treated with purified mouse monoclonal antibodies against TNF-α or Enbrel. Control SA were incubated with IgG or IgG1 isotype antibody.SA were incubated for 3 days at 37oC in 5% CO2. SA culture supernatants was used to measure IFN-γ and IL-10 levels. Left over SA was then cultured in 1:3 serial dilution to determine the number of viable parasites in the culture. Cell mediated antigen specific responses was also evaluated using TNF-α blocking in SLA stimulated whole blood cultures. Results: Neutralization of TNF-α did not affect parasite numbers in ex vivo SA cultures. Interferon(IFN)-γ levels were significantly reduced in these cultures, but there was no effect on interleukin (IL)-10 levels. Conclusion: In contrast to expectations, we found no direct effect of TNF-α neutralization on parasite burden. However, there was significant decrease in IFN-γ levels, which suggests that during active human VL, TNF-α stimulates IFN-γ production, but with no direct effect on parasite replication.
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,900
OpenAlex ID: W2317250107