A Toxicokinetic Study of Nickel-Induced Immunosuppression in Rats

The aim of the present study was to investigate dose- and time-dependent effects of NiCl₂ on T-lymphocyte and macrophage-derived cytokine production in rats. Moreover we have determined the concentrations of nickel in the plasma that are required to elicit alterations in T-lymphocyte and macrophage function. NiCl₂ suppressed T-lymphocyte proliferation and Th1 (IFN-γ) and Th2 (IL-10) cytokine production in a dose- and time-dependent fashion. In addition, NiCl₂ inhibited production of the pro-inflammatory cytokine TNF-α and increased production of the anti-inflammatory cytokine IL-10 from lipopolysaccharide (LPS) stimulated cultures. We have determined that the minimal plasma concentrations of nickel required to provoke immunosuppression are in the range 209-585 ng/mL. In the time-course study NiCl₂ (3.3 mg/kg) provoked immunological changes that were maximal 1 h following administration, and some of these changes persisted for up to 24 h post administration. Overall these data clearly demonstrate that NiCl₂ suppresses T-cell function and promotes an immunosuppressive macrophage phenotype in rats. This study also indicates that measuring T-cell proliferation is as sensitive a marker of NiCl ₂-induced immunotoxicity as measuring T-cell or macrophage cytokine production. Co-measurement of circulating nickel concentrations and immune parameters yields valuable information with regard to the potency of nickel to alter immune function in vivo. These data also suggest that quite a large quantity of nickel needs to reach the systemic circulation before any adverse effects on immune function are observed.