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Blood, 1 July 2001, Vol. 98, No. 1, pp. 174-180
IMMUNOBIOLOGY
Rapamycin induces apoptosis in monocyte- and CD34-derived
dendritic cells but not in monocytes and macrophages
Andrea M. Woltman,
Johan W. de Fijter,
Sylvia W. A. Kamerling,
Sandra W. van der
Kooij,
Leendert C. Paul,
Mohamed R. Daha, and
Cees van Kooten
From the Department of Nephrology, Leiden University
Medical Center, The Netherlands.
Rapamycin (Rapa), a recently introduced immunosuppressive drug,
seems to be effective in preventing acute allograft rejection. Although
its antiproliferative effect on T lymphocytes has been investigated
extensively, its effect 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 monocytes and macrophages, was
examined. The present study shows that Rapa does not affect phenotypic
differentiation and CD40L-induced maturation of mo-DCs. However, Rapa
dramatically reduced cell recovery (40%-50%). Relatively low
concentrations of Rapa (10 9 M) induced apoptosis in both
mo-DCs and CD34+-derived DCs, as visualized 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 cytosolic receptor protein FKBP-12, as demonstrated 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-dependent and
caspase-independent processes. The fact that Rapa exerts a specific
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.
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