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 >or=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%, ED(50), 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 (ED(50) >50 ng/ml). The inhibitory effect of Bortezomib on professional APCs, such as monocytes and DCs, suggests its possible use in GVHD prophylaxis.
Arpinati
M
M
Institute of Hematology and Medical Oncology L.&A.Seragnoli, University of Bologna, Bologna, Italy. arpinati@med.unibo.it
Chirumbolo
G
G
Nicolini
B
B
Agostinelli
C
C
Rondelli
D
D
D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*
D001897:Boronic Acids; D007166:Immunosuppressive Agents; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib