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

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.