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 rejection. Although its antiprolif erative effect on T lymphocytes has been: investigated extensively, its eff ect on the initiators of the immune response, the dendritic cells (DCs), is not known. Therefore, the effect of Rapa on: monocyte(mo-DCs) and CD34(+)- derived DCs in vitro but also on other myeloid cell types, including monocy tes and macrophages, was examined. The present study shows that Rapa does n ot affect phenotypic differentiation and CD40L-induced maturation of mo-DCs , However, Rapa dramatically reduced cell recovery (40%-50%). Relatively lo w concentrations of Rapa (10(-9) nn) induced apoptosis in both mo-DCs and C D34(+)-derived DCs, as visualized by phosphatidylserine exposure, nuclear c ondensation and fragmentation, and DNA degradation. In contrast, Rapa did n ot affect freshly isolated monocytes, macrophages, or myeloid cell lines. T he sensitivity to Rapa-induced apoptosis was acquired from day 2 onward of mo-DC differentiation. Rapa exerts its apoptotic effect via a reversible bi nding to the cytosolic receptor protein FKBP-12, as demonstrated in competi tion 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-dependent and caspase-independent processes. The fac t that Rapa exerts a specific effect on DCs but not on monocytes and macrop hages might contribute to the unique actions of Rapa in the prevention of a llograft rejection and other immune responses. (C) 2001 by The American Soc ietyof Hematology.