科研之友
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摘要
Tumor necrosis factor alpha (TNF alpha) drives the pathophysiology of human autoimmune diseases and consequently, neutralizing antibodies (Abs) or Ab-derived molecules directed against TNF alpha are essential therapeutics. As treatment with several TNF alpha 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 alpha therapeutics. We demonstrate that neutralization of soluble TNF alpha (sTNF alpha) by the anti-TNF alpha Abs Humira (R), Remicade (R), and its biosimilar Remsima (R) 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 alpha by Cimzia (R) does not affect T-cell proliferation and infection rates. Moreover, compared to Remicade (R), treatment with Cimzia (R) does not impair the expression of cytolytic effector proteins in proliferating T-cells. Our data demonstrate that Cimzia (R) supports parasite control through its conjugated polyethylene glycol (PEG) moiety as PEGylation of Remicade (R) 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 (R) or a PEGylated form of Remicade (R). Taken together, we provide an in vitro model of human leishmaniasis that allows direct comparison of different anti-TNF alpha agents. Our results enhance the understanding of the efficacy and adverse effects of TNF alpha blockers and they contribute to evaluate anti-TNF alpha therapy for patients living in countries with a high prevalence of leishmaniasis.
- 出版日期2018-7-31
