title: Neutrophil uptake of nitrogen-bisphosphonates leads to the suppression of human peripheral blood γδ T cells.
abstract: Nitrogen-bisphosphonates (n-BP), such as zoledronate, are the main class of drugs used for the prevention of osteoporotic fractures and the management of cancer-associated bone disease. However, long-term or high-dose use has been associated with certain adverse drug effects, such as osteonecrosis of the jaw and the loss of peripheral of blood Vγ9Vδ2 T cells, which appear to be linked to drug-induced immune dysfunction. In this report we show that neutrophils present in human peripheral blood readily take up zoledronate, and this phenomenon is associated with the potent immune suppression of human peripheral blood Vγ9Vδ2 T cells. Furthermore, we found this zoledronate-mediated inhibition by neutrophils could be overcome to fully reconstitute Vγ9Vδ2 T cell proliferation by concomitantly targeting neutrophil-derived hydrogen peroxide, serine proteases, and arginase I activity. These findings will enable the development of targeted strategies to mitigate some of the adverse effects of n-BP treatment on immune homeostasis and to improve the success of immunotherapy trials based on harnessing the anticancer potential of peripheral blood γδ T cells in the context of n-BP treatment.
authors.affiliation: Institute of Immunology, Christian-Albrechts University Kiel, Arnold-Heller Strasse 3, Haus 17, 24105, Kiel, Germany, kalyan@immunologie.uni-kiel.de.
authors.forename: Shirin
authors.initials: S
authors.lastname: Kalyan
authors.forename: Vijayanand
authors.initials: V
authors.lastname: Chandrasekaran
authors.forename: Elgar S
authors.initials: ES
authors.lastname: Quabius
authors.forename: Thisbe K
authors.initials: TK
authors.lastname: Lindhorst
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004164:Diphosphonates / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects* / Q000493:pharmacokinetics*; D007108:Immune Tolerance / Q000187:drug effects; D018655:Lymphocyte Count; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D017672:Nitrogen Compounds / Q000009:adverse effects / Q000493:pharmacokinetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D017672:Nitrogen Compounds; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000077211:Zoledronic Acid