Feraheme® suppresses immune function of human T lymphocytes through mitochondrial damage and mitoROS production

• Published in: Toxicology and applied pharmacology 2018-07, Vol.350, p.52-63
• Main Authors: Shah, Ankit, Mankus, Cassandra I., Vermilya, Alison M., Soheilian, Ferri, Clogston, Jeffrey D., Dobrovolskaia, Marina A.
• Format: Article
• Language: English
• Subjects: Cell Line, Transformed; Cell Line, Tumor; Cells, Cultured; Ferric Compounds - toxicity; Humans; Immunity, Cellular - drug effects; Immunity, Cellular - physiology; Immunosuppression; Immunotoxicity; Iron oxide; Membrane Potential, Mitochondrial - drug effects; Membrane Potential, Mitochondrial - physiology; Metal Nanoparticles - toxicity; Mitochondria - drug effects; Mitochondria - metabolism; Nanoparticles; Reactive Oxygen Species - metabolism; T Cells; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2018.04.028

Despite attractive properties for both therapeutic and diagnostic applications, the clinical use of iron oxide nanoparticles (IONPs) is limited to iron replacement in severely anemic patient populations. While several studies have reported about the immunotoxicity of IONPs, the mechanisms of this toxicity are mostly unknown. We conducted a mechanistic investigation using an injectable form of IONP, Feraheme®. In the cultures of primary human T cells, Feraheme induced miotochondrial oxidative stress and resulted in changes in mitochondrial dynamics, architecture, and membrane potential. These molecular events were responsible for the decrease in cytokine production and proliferation of mitogen-activated T cells. The induction of mitoROS by T cells in response to Feraheme was insufficient to induce total redox imbalance at the cellular level. Consequently, we resolved this toxicity by the addition of the mitochondria-specific antioxidant MitoTEMPO. We further used these findings to develop an experimental framework consisting of critical assays that can be used to estimate IONP immunotoxicity. We explored this framework using several immortalized T-cell lines and found that none of them recapitulate the toxicity observed in the primary cells. Next, we compared the immunotoxicity of Feraheme to that of other FDA-approved iron-containing complex drug formulations and found that the mitochondrial damage and the resulting suppression of T-cell function are specific to Feraheme. The framework, therefore, can be used for comparing the immunotoxicity of Feraheme with that of its generic versions, while other iron-based complex drugs require case-specific mechanistic investigation. •Feraheme induces mitochondrial damage in primary T-cell cultures.•Feraheme inhibits function of human T-cells in vitro.•The inhibition is reversed by MitoTempo, a known inhibitor of mitochondrial ROS.•We propose a battery of in vitro tests (so-called framework) to assess the toxicity.•The established assay framework is specific to Feraheme and primary cultures.