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Neutrophil uptake of nitrogen-bisphosphonates leads to the suppression of human peripheral blood γδ T cells

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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.

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Acknowledgments

SK was supported by a Fellowship from the Alexander von Humboldt Foundation of Germany and a Faculty of Medicine Grant from Christian-Albrechts University of Kiel. DK acknowledges grant support from the Deutsche Forschungsgemeinschaft (Ka 502/10-2 and “Inflammation-at-Interfaces” Cluster of Excellence). We would like to thank Hilke Clasen (Department of Immunology) for technical assistance, and Dr. Millan Patel (University of British Columbia) for review of the manuscript.

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All authors state that they have no conflicts of interest.

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Authors and Affiliations

  1. Institute of Immunology, Christian-Albrechts University Kiel, Arnold-Heller Strasse 3, Haus 17, 24105, Kiel, Germany

    Shirin Kalyan, Elgar S. Quabius & Dieter Kabelitz

  2. Otto Diels Institute of Organic Chemistry, Christian-Albrechts University Kiel, Kiel, Germany

    Vijayanand Chandrasekaran & Thisbe K. Lindhorst

  3. Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Schleswig–Holstein, Campus Kiel, Kiel, Germany

    Elgar S. Quabius

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  1. Shirin Kalyan
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  2. Vijayanand Chandrasekaran
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  4. Thisbe K. Lindhorst
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  5. Dieter Kabelitz
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Correspondence to Shirin Kalyan or Dieter Kabelitz.

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Kalyan, S., Chandrasekaran, V., Quabius, E.S. et al. Neutrophil uptake of nitrogen-bisphosphonates leads to the suppression of human peripheral blood γδ T cells. Cell. Mol. Life Sci. 71, 2335–2346 (2014). https://doi.org/10.1007/s00018-013-1495-x

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  • DOI: https://doi.org/10.1007/s00018-013-1495-x

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