IMMUNOBIOLOGY Rapamycin induces apoptosis in monocyte- and CD34-derived dendritic cells but not in monocytes and macrophages

Rapamycin (Rapa), a recently introduced immunosuppressive drug, seems to be effective in preventing acute allograft re-jection. Although its antiproliferative ef-fect on T lymphocytes has been investi-gated extensively, its effect on the initiators of the immune response, the dendritic cells (DCs), is not known. There-fore, the effect of Rapa on monocyte-(mo-DCs) and CD341-derived DCs in vitro but also on other myeloid cell types, including monocytes and macrophages, was examined. The present study shows that Rapa does not affect phenotypic dif-ferentiation and CD40L-induced matura-tion of mo-DCs. However, Rapa dramati-cally reduced cell recovery (40%-50%). Relatively low concentrations of Rapa (1029 M) induced apoptosis in both mo-DCs and CD341-derived DCs, as visual-ized by phosphatidylserine exposure, nuclear condensation and fragmentation, and DNA degradation. In contrast, Rapa did not affect freshly isolated monocytes, macrophages, or myeloid cell lines. The sensitivity to Rapa-induced apoptosis was acquired from day 2 onward of mo-DC differentiation. Rapa exerts its apoptotic effect via a reversible binding to the cyto-solic receptor protein FKBP-12, as demon-strated in competition experiments with FK506, which is structurally related to Rapa. Partial inhibition of Rapa-induced apoptosis was obtained by addition of ZVAD-fmk, which implies caspase-depen-dent and caspase-independent pro-cesses. The fact that Rapa exerts a spe-cific effect on DCs but not on monocytes and macrophages might contribute to the unique actions of Rapa in the prevention of allograft rejection and other immune responses. (Blood. 2001;98:174-180) © 2001 by The American Society of Hematolog