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Pre-Clinical Studies

Selective apoptosis of monocytes and monocyte-derived DCs induced by bortezomib (Velcade)

Abstract

Bortezomib, a proteasome inhibitor, has shown immunosuppressive activity in animal models of GVHD. In this study, we evaluated the effects of Bortezomib on the survival of monocytes, a major circulating source of DCs. PBMCs or purified CD14+ monocytes were cultured for 24 h with Bortezomib (0.1–100 ng/ml). Apoptosis was demonstrated on the basis of detection of phosphatydilserine. Bortezomib induced a significant dose-dependent depletion (P=0.008) of monocytes in PBMC preparations, with <1% CD14+ cells remaining at doses 5 ng/ml. Moreover, Bortezomib decreased the survival of purified monocytes within 24 h (P=0.004) (n=6). Monocyte loss was due to apoptosis (effective dose 50%, ED50, 1–10 ng/ml). In addition, both immature and mature monocyte-derived DC underwent apoptosis following exposure to Bortezomib. Kinetic experiments showed that apoptosis increased at 16 h through 24 h of culture. However, short term (4 h) incubation with Bortezomib irreversibly committed monocytes to undergo apoptosis at 24, 72 and 144 h. Instead, Bortezomib induced no apoptosis of purified CD19+ B, CD3+ T lymphocytes and CD34+ progenitor cells (ED50 >50 ng/ml). The inhibitory effect of Bortezomib on professional APCs, such as monocytes and DCs, suggests its possible use in GVHD prophylaxis.

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Acknowledgements

This research was partly supported by MURST (Rome, Italy) and Bologna AIL (Bologna, Italy).

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Correspondence to M Arpinati.

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Arpinati, M., Chirumbolo, G., Nicolini, B. et al. Selective apoptosis of monocytes and monocyte-derived DCs induced by bortezomib (Velcade). Bone Marrow Transplant 43, 253–259 (2009). https://doi.org/10.1038/bmt.2008.312

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