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Statins Prevent Bisphosphonate‐Induced γ,δ‐T‐Cell Proliferation and Activation In Vitro
Author(s) -
Thompson Keith,
Rogers Michael J
Publication year - 2004
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.0301230
Subject(s) - mevalonate pathway , farnesyl diphosphate synthase , peripheral blood mononuclear cell , population , statin , t cell , bisphosphonate , cell growth , pharmacology , chemistry , medicine , biology , reductase , immunology , atp synthase , in vitro , immune system , enzyme , biochemistry , osteoporosis , environmental health
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.