Division of Immunology, Paul-Ehrlich-Institut, Langen, Germany.
Institute of Immunology, Johannes Gutenberg University, Mainz, Germany.
Front Immunol. 2018 Jul 31;9:1772. doi: 10.3389/fimmu.2018.01772. eCollection 2018.
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 model based on -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 -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 . 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 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.
肿瘤坏死因子 α（TNFα）驱动人类自身免疫性疾病的病理生理学，因此，针对 TNFα 的中和抗体（Abs）或 Ab 衍生分子是重要的治疗方法。由于几种 TNFα 阻滞剂的治疗已被报道会增加利什曼病等传染病的风险，我们建立了一个基于感染的人巨噬细胞的模型，与自体 T 细胞共培养，用于分析和比较抗 TNFα 治疗方法。我们证明，抗 TNFα Abs 类克、修美乐及其生物类似药雷米昔单抗中和可溶性 TNFα（sTNFα）会对感染产生负面影响，因为这些药物的治疗会显著降低 - 诱导的 T 细胞增殖并增加感染巨噬细胞的数量。相比之下，我们表明 Cimzia 阻断 sTNFα 不会影响 T 细胞增殖和感染率。此外，与 Remicade 相比，用 Cimzia 治疗不会损害增殖 T 细胞中细胞毒性效应蛋白的表达。我们的数据表明，Cimzia 通过其共轭聚乙二醇（PEG）部分支持寄生虫控制，因为 Remicade 的 PEG 化可改善细胞内寄生虫的清除。这种效果可以与补体激活相关联，用 Cimzia 或 PEG 化 Remicade 治疗会增加补体成分 C5a 的水平。总之，我们提供了一种人类利什曼病的模型，允许直接比较不同的抗 TNFα 药物。我们的结果增强了对 TNFα 阻滞剂疗效和不良反应的理解，并有助于评估抗 TNFα 治疗对生活在利什曼病高发国家的患者的疗效。
