Therapeutic anti-TNFα antibodies differentially affect Leishmania infection of primary human macrophages

Abstract

Excessive production of the pro-inflammatory cytokine tumor necrosis factor α (TNFα) is associated with the pathophysiology of human autoimmune diseases. As a consequence, neutralizing antibodies or antibody-derived molecules directed against TNFα have emerged as important therapeutics. Despite the great success of anti-TNFα treatment, serious adverse effects remain and complications include a higher risk for infectious diseases such as leishmaniasis. In this study, we developed an in vitro model based on Leishmania-infected human macrophages, co-cultured with autologous T-cells, for the analysis and comparison of currently marketed anti-TNFα agents and their potential to contribute to the onset of leishmaniasis. Using our in vitro model, we identified that neutralization of soluble TNFα (sTNFα) by the anti-TNFα antibodies Remicade®, Remsima® and Humira® negatively affected infection as treatment with these agents significantly reduced Leishmania-induced CD4 T-cell proliferation and increased the number of infected macrophages. In contrast, we showed that blockade of sTNFα by Cimzia® did not affect T-cell proliferation and infection rates. Moreover, compared to Remicade®, the application of Cimzia® did not impair the phenotype and effector functions of T-cells as shown by the expression levels of PD-1, CD45RO and cytolytic effector proteins. The latter are potentially implicated in intracellular killing of parasites. We confirmed that the diverging effects of Remicade® or Cimzia® treatment were independent of Fc-Fcγ receptor interaction. However, our data indicate that Cimzia® supports parasite control through its conjugated PEG moiety as PEGylation of Remicade® enhanced T-cell proliferation and thus improved the clearance of intracellular Leishmania. This effect was associated with complement activation, showing increased C5a expression upon treatment with PEGylated TNFα inhibitors. Altogether, our results enhance the understanding of the effectiveness and adverse effects of anti-TNFα treatment. Considering the emergence of leishmaniasis as complication of anti-TNFα therapy, our findings contribute to evaluate different anti-TNFα agents. Based on our results, we propose that the application of Cimzia® may be beneficial for patients living in countries with a high prevalence of leishmaniasis.