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.
Selective apoptosis of monocytes and monocyte-derived DCs induced by bortezomib (Velcade) / M. Arpinati; G. Chirumbolo; B. Nicolini; C. Agostinelli; D. Rondelli.. - In: BONE MARROW TRANSPLANTATION. - ISSN 0268-3369. - STAMPA. - 43:(2009), pp. 253-259. [10.1038/bmt.2008.312]
Selective apoptosis of monocytes and monocyte-derived DCs induced by bortezomib (Velcade).
ARPINATI, MARIO;CHIRUMBOLO, GABRIELLA;NICOLINI, BENEDETTA;AGOSTINELLI, CLAUDIO;
2009
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 >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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.