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The immunosuppressant rapamycin blocks in vitro responses to hematopoietic
cytokines and inhibits recovering but not steady-state hematopoiesis in
vivo
VF Quesniaux, S Wehrli, C Steiner, J Joergensen, HJ Schuurman, P Herrman, MH Schreier and W Schuler
Sandoz Pharma Ltd, Basel, Switzerland.
The immunosuppressive drug rapamycin suppresses T-cell activation by
impairing the T-cell response to lymphokines such as interleukin-2 (IL- 2)
and interleukin-4 (IL-4). In addition, rapamycin blocks the proliferative
response of cell lines to a variety of hematopoietic growth factors,
including interleukin-3 (IL-3), interleukin-6 (IL-6), granulocyte-colony
stimulating factor (G-CSF), granulocyte macrophage- colony stimulating
factor (GM-CSF), and kit ligand (KL), suggesting that it should be a strong
inhibitor of hematopoiesis. In this report, we studied the effects of
rapamycin on different hematopoietic cell populations in vitro and in vivo.
In vitro, rapamycin inhibited the proliferation of primary bone marrow
cells induced by IL-3, GM-CSF, KL, or a complex mixture of factors present
in cell-conditioned media. Rapamycin also inhibited the multiplication of
colony-forming cells in suspension cultures containing IL-3 plus
interleukin-1 (IL-1) or interleukin-11 (IL-11) plus KL. In vivo, treatment
for 10 to 28 days with high doses of rapamycin (50 mg/kg/d, orally) had no
effect on myelopoiesis in normal mice, as measured by bone marrow
cellularity, proliferative capacity, and number of colony-forming
progenitors. In contrast, the same treatment strongly suppressed the
hematopoietic recovery normally seen 10 days after an injection of
5-fluorouracil (5- FU; 150 mg/kg, intravenously [i.v.]). Thus, rapamycin
may be detrimental in myelocompromised individuals. In addition, the
results suggest that the rapamycin-sensitive cytokine-driven pathways are
essential for hematopoietic recovery after myelodepression, but not for
steady-state hematopoiesis.
Volume 84,
Issue 5,
pp. 1543-1552,
09/01/1994
Copyright © 1994 by The American Society of Hematology
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