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

Abstract

Tumor necrosis factor α (TNFα) drives the pathophysiology of human autoimmune diseases and consequently, neutralizing antibodies (Abs) or Ab-derived molecules directed against TNFα are essential therapeutics. As treatment with several TNFα 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-TNFα therapeutics. We demonstrate that neutralization of soluble TNFα (sTNFα) by the anti-TNFα 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 sTNFα 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-TNFα agents. Our results enhance the understanding of the efficacy and adverse effects of TNFα blockers and they contribute to evaluate anti-TNFα therapy for patients living in countries with a high prevalence of leishmaniasis.

Leishmaniasis and tumor necrosis factor alpha antagonists in the Mediterranean basin. A switch in clinical expression

“…Taking into account published information, it seems reasonable reintroducing them once clinical cure has been achieved ensuring close clinical follow-up and blood RT-PCR. Although there is scarce information for its recommendation, etanercep or certolizumab have been suggested as a therapeutical option instead of re-introducing other anti-TNF-α monoclonal antibodies due to its possible lower risk of reactivating leishmaniasis [65–66].…”

Immunology study and the Assessment of parameters in difference Age, Sex of stage resistance infection leishmaniasis in Dayla

“…The higher cases were males (42) patients, while females were represented (31) of patients. Males and females shared a similar frequency in the age groups without significant differences between them, they were 31(42.47%), 9 (12.33%) and 26 (35.61%), 4 (5.48%) in age groups(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) and (15-50) of males and females respectively, as shown in the Table2. Statistical analysis proved that there were no significant (P ≤ 0.01) differences between genders of the studied groups.Table2:…”

“…However, various adverse effects are resulted from using these drugs including their toxicity to human, prolonged treatment, increased parasite resistance, leukopenia, liver problems, cardiotoxicity and cardiac arrhythmia [12]. TNF-α is secreted by macrophages and lymphocytes, it is considered a crucial mediator of many inflammatory reactions and contains a major role in innate response in pathogenesis in relevancy human diseases, to provide synthase stimulation oxygenated products and nitric oxide, components important for killing of Leishmania, via encounter Leishmania invasion, synergistically with other cytokines including IFN-γ [13,14]. Some macrophagesecreted cytokines are considered indirect biomarkers for leishmaniasis infection, including IFN-γ, TNF-α and IL-10 [15].…”

Cross‐sectional screening study for Leishmania DNA and antibodies in biologic‐treated patients with psoriasis living in an area endemic for leishmaniasis

“…Dear Editor, Biological drugs have revolutionized the control of immune‐mediated diseases, but most of the safety studies have not evaluated the risk of endemic infections, such as leishmaniasis, in underdeveloped regions . The control of this parasite is strongly dependent on the production of specific cytokines [interleukin (IL)‐1, IL‐6 and tumour necrosis factor (TNF)‐α], which are important targets of biological therapies.…”