Correspondence

γ/δ T-Cell Stimulation by Pamidronate

N Engl J Med 1999; 340:737-738March 4, 1999

Article

To the Editor:

Bisphosphonates are widely used to inhibit osteoclastic bone resorption. As analogues of pyrophosphate they share several structural homologies with recently identified non-peptide γ/δ T-cell ligands, such as isopentenyl pyrophosphate, that activate antigenic receptors of γ/δ T cells.1

We recently found that aminobisphosphonates (pamidronate, ibandronate, and alendronate) can stimulate the major subgroup of γ/δ T cells in peripheral blood (Vγ9Vδ2+ T cells), whereas non-aminobisphosphonates (clodronate and etidronate) are inactive. In our assays, pamidronate (concentration yielding half-maximal activity, 5 to 10 μM) induced the activation and selective expansion of γ/δ T cells in cultures of peripheral-blood mononuclear cells from normal, healthy subjects. Furthermore, pamidronate stimulated the secretion of interferon-γ in these cultures.2

We evaluated the importance of these observations by determining the proportion of peripheral-blood γ/δ T cells in 10 patients during a first course of treatment with pamidronate as the sole therapy for increased bone resorption. CD3+ γ/δ T cells were measured by flow cytometry before an intravenous infusion of 60 or 90 mg of pamidronate (Aredia, Novartis, Basel, Switzerland) and one to three weeks afterward. All patients were followed closely for the acute-phase reaction (fever and influenza-like symptoms) that occurs in 20 to 50 percent of patients after a first dose of an aminobisphosphonate.3

Four of the 10 patients had an acute-phase reaction after pamidronate treatment, and all 4 had a substantial increase in the percentage of γ/δ T cells in peripheral blood (Table 1Table 1Effect of Pamidronate on g/d T Cells in Four Patients with an Acute-Phase Reaction to the Initial Infusion of Pamidronate.), whereas the percentage of γ/δ T cells in the other 6 patients did not change. The intensity of the acute-phase reaction (as assessed by the increase in body temperature) seemed to correlate with the magnitude of increase in γ/δ T cells. Subsequent pamidronate infusions did not cause either acute-phase reactions or changes in the levels of γ/δ T cells in any of the patients.

These results suggest that aminobisphosphonates such as pamidronate can stimulate the production of a distinct subgroup of T cells in addition to inhibiting bone resorption. Therefore, activation of γ/δ T cells and release of cytokines (i.e., interferon-γ) might contribute to the acute-phase reaction after the first infusion of an aminobisphosphonate.

Volker Kunzmann, M.D.
Eva Bauer, M.D.
Martin Wilhelm, M.D.
Medizinische Poliklinik Wuerzburg, 97070 Wuerzburg, Germany

3 References

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   Gallacher SJ, Ralston SH, Patel U, Boyle IT. Side-effects of pamidronate. Lancet 1989;2:42-43
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