Anti-Tumor Necrosis Factor ? Therapeutics Differentially Affect Leishmania Infection of Human Macrophages.

ABSTRACT: Tumor necrosis factor ? (TNF?) drives the pathophysiology of human autoimmune diseases and consequently, neutralizing antibodies (Abs) or Ab-derived molecules directed against TNF? are essential therapeutics. As treatment with several TNF? blockers has been reported to entail a higher risk of infectious diseases such as leishmaniasis, we established an in vitro model based on Leishmania-infected human macrophages, co-cultured with autologous T-cells, for the analysis and comparison of anti-TNF? therapeutics. We demonstrate that neutralization of soluble TNF? (sTNF?) by the anti-TNF? Abs Humira^®, Remicade^®, and its biosimilar Remsima^® negatively affects infection as treatment with these agents significantly reduces Leishmania-induced T-cell proliferation and increases the number of infected macrophages. By contrast, we show that blockade of sTNF? by Cimzia^® does not affect T-cell proliferation and infection rates. Moreover, compared to Remicade^®, treatment with Cimzia^® does not impair the expression of cytolytic effector proteins in proliferating T-cells. Our data demonstrate that Cimzia^® supports parasite control through its conjugated polyethylene glycol (PEG) moiety as PEGylation of Remicade^® improves the clearance of intracellular Leishmania. This effect can be linked to complement activation, with levels of complement component C5a being increased upon treatment with Cimzia^® or a PEGylated form of Remicade^®. Taken together, we provide an in vitro model of human leishmaniasis that allows direct comparison of different anti-TNF? agents. Our results enhance the understanding of the efficacy and adverse effects of TNF? blockers and they contribute to evaluate anti-TNF? therapy for patients living in countries with a high prevalence of leishmaniasis.

SUBMITTER: Arens K 

PROVIDER: S-EPMC6079256 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature