RAPAMYCIN BUT NOT FK506 INHIBITS THE PROLIFERATION OF MONONUCLEAR PHAGOCYTES INDUCED BY COLONY-STIMULATING FACTORS

FK506, CsA, and rapamycin are potent inhibitors of T lymphocyte activa tion; relatively little is known of their effects on cells of the mono cyte/macrophage lineage. Studies were undertaken to determine the effe cts of these drugs on the proliferative response of bone marrow-derive d mononuclear phagocytes (BMMP) to CSFs. Rapamycin inhibited the proli feration of BMMP cultured in the presence of 10% L cell-conditioned me dium, used as a source of macrophage CSF. The inhibition by rapamycin was dose dependent and apparent at concentrations of 0.1 nM or greater . In a similar fashion, rapamycin inhibited the proliferation of BMMP stimulated by the recombinant forms of murine IL-3 and murine granuloc yte-macrophage CSF, and human macrophage CSF. In contrast, neither FK5 06 nor CsA at concentrations as high as 1000 nM diminished the prolife ration of BMMP cultured under identical conditions. FK506, but not CsA , blocked the inhibitory effects of rapamycin on the response of BMMP to CSFs. In summary, these data indicate that rapamycin inhibits the p roliferation of BMMP in response to CSFs. These results imply that pat ients receiving rapamycin, but not FK506 or CsA, may have an impaired ability to generate a functional mononuclear phagocyte population.