Statins Prevent Bisphosphonate-Induced γ,δ-T-Cell Proliferation and Activation In Vitro

Authors

  • Keith Thompson,

    Corresponding author
    1. Bone Research Group, Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom
    • Address reprint requests to: K Thompson, PhD, Bone Research Group, Department of Medicine and Therapeutics, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK
    Search for more papers by this author
  • Michael J Rogers

    1. Bone Research Group, Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom
    Search for more papers by this author

  • Dr Rogers receives grants from Novartis and Procter & Gamble. Dr Thompson has no conflict of interest.

Abstract

The acute phase response is the major adverse effect of intravenously administered N-BPs. In this study we show that N-BPs cause γ,δ-T-cell activation and proliferation in vitro by an indirect mechanism through inhibition of FPP synthase, an effect that can be overcome by inhibiting HMG-CoA reductase with a statin. These studies clarify the probable initial cause of the acute phase response to N-BP drugs and suggest a possible way of preventing this phenomenon.

Introduction: The acute phase response is the major adverse effect of intravenously administered nitrogen-containing bisphosphonate drugs (N-BPs), used in the treatment of metabolic bone diseases. This effect has recently been attributed to their action as non-peptide antigens and direct stimulation of γ,δ-T-cells. However, because N-BPs are potent inhibitors of farnesyl diphosphate (FPP) synthase, they could cause indirect activation of γ,δ-T-cells owing to the accumulation of intermediates upstream of FPP synthase in the mevalonate pathway, such as isopentenyl diphosphate/dimethylallyl diphosphate, which are known γ,δ-T-cell agonists.

Materials and Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers and treated with N-BP, statin, or intermediates/inhibitors of the mevalonate pathway for 7 days in the presence of interleukin (IL)-2. Flow cytometric analysis of the T-cell-gated population was used to quantify the proportion of γ,δ-T-cells in the CD3+ population.

Results and Conclusions: The ability of N-BPs to stimulate proliferation of CD3+ γ,δ-T-cells in human PBMC cultures matched the ability to inhibit FPP synthase. γ,δ-T-cell proliferation and activation (interferon γ [IFNγ] and TNFα release) was prevented by mevastatin or lovastatin, which inhibit HMG-CoA reductase upstream of FPP synthase and prevent the synthesis of isopentenyl diphosphate/dimethylallyl diphosphate. Desoxolovastatin, an analog of lovastatin incapable of inhibiting HMG-CoA reductase, did not overcome the stimulatory effect of N-BP. Furthermore, statins did not prevent the activation of γ,δ-T-cells by a synthetic γ,δ-T-cell agonist or by anti-CD3 antibody. Together, these observations show that N-BPs indirectly stimulate the proliferation and activation of γ,δ-T-cells caused by inhibition of FPP synthase and intracellular accumulation of isopentenyl diphosphate/dimethylallyl diphosphate in PBMCs. Because activation of γ,δ-T-cells could be the initiating event in the acute phase response to bisphosphonate therapy, co-administration of a statin could be an effective approach to prevent this adverse effect.

Ancillary