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Mercalli A, Sordi V, Ponzoni M, Maffi P, De Taddeo F, Gatti G,
Servida P, Bernardi M, Bellio L, Bertuzzi F, Secchi A, Bonifacio E, Piemonti L.
Am J Transplant. 2006 Jun;6(6):1331-41
Rapamycin induces a caspase-independent cell death in human
monocytes.
Immunology of Diabetes Unit, San Raffaelle Scientific Institute,
via Olgettina 60, 20132 Milan, Italy.
The immunosuppressive activity of rapamycin (RAPA) and its efficacy
as an anti-rejection agent in organ transplantation have been ascribed
principally to its anti-proliferative effects on T cells, while the activity on
monocytes is partially unknown. In vitro, RAPA reduced monocyte survival by
inducing a caspase-independent cell death. RAPA-induced monocyte cell death
(RAPA-CD) was impeded by activation of granulocyte macrophage-colony stimulating
factor family receptors or toll-like receptor 4, and by exposure to inflammatory
cytokines. In vivo, in patients who received RAPA monotherapy as part of
pre-conditioning for islet transplantation, RAPA affected survival of myeloid
lineage cells. In the peripheral blood, CD33(+) and CD14(+) cells decreased,
whereas lymphocytes appeared unaffected. In the bone marrow, myeloid precursors
such as CD15(+) and CD15(+)/CD16(+) were selectively and significantly
decreased, but no major cytotoxic effects were observed. The RAPA-CD suggests a
dependence of monocytes on mammalian target of RAPA pathways for nutrient usage,
and this feature implies that RAPA could be selectively useful as a treatment to
reduce monocytes or myeloid cells in conditions where these cells negatively
affect patient, suggesting a potential anti-inflammatory action of this drug.
PMID: 16686757
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