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

Toxicol Appl Pharmacol. 2018 Jul 1;350:52-63. doi: 10.1016/j.taap.2018.04.028. Epub 2018 Apr 30.

Abstract

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.

Keywords: Immunosuppression; Immunotoxicity; Iron oxide; Nanoparticles; T Cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cells, Cultured
  • Ferric Compounds / toxicity*
  • Humans
  • Immunity, Cellular / drug effects*
  • Immunity, Cellular / physiology
  • Membrane Potential, Mitochondrial / drug effects
  • Membrane Potential, Mitochondrial / physiology
  • Metal Nanoparticles / toxicity*
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Reactive Oxygen Species* / metabolism
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / metabolism

Substances

  • Ferric Compounds
  • Reactive Oxygen Species
  • ferric oxide