The effect of desferrithiocin, an oral iron chelator, on T-cell function.
Desferrithiocin is a new, potent, orally available iron chelator. To determine whether this drug might be useful not only for iron-overload but also for immunosuppression, we studied the in vitro effects of desferrithiocin on T-lymphocyte function. Like deferoxamine, desferrithiocin inhibited, in a dose-dependent fashion, mitogen- and lectin-induced proliferation of both human and murine T cells. It was active at a concentration of 10 micrograms/mL. The inhibition of proliferation was reversed by ferrous chloride, but not by other metal salts, recombinant IL-2, or conditioned medium. Desferrithiocin also inhibited proliferation of constitutively dividing, and factor-independent EBV-transformed B cell and leukemic T-cell lines. Although desferrithiocin inhibited the induction of cytotoxic T lymphocyte (CTL) activity, it did not inhibit CTL- or natural killer-induced cytotoxicity. The agent did not inhibit the expression of activation antigens such as the IL-2 receptor on T cells, nor early measures of T-cell activation such as the influx of intracellular calcium. Thus, desferrithiocin, like deferoxamine, is a potent and reversible inhibitor of T-cell proliferation. This anti-proliferative effect inhibits T-cell function. Bioavailability after oral administration is a unique property of desferrithiocin, and would make it an attractive alternative to deferoxamine. Its immunomodulating properties may therefore be exploited in vivo to inhibit graft rejection or autoreactive T cells.
Bierer
B E
BE
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Nathan
D G
DG
D000954:Antigens, Surface / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology; D004095:Dihydropyridines / Q000494:pharmacology*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D007501:Iron / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology*
D000954:Antigens, Surface; D004095:Dihydropyridines; D007376:Interleukin-2; D007502:Iron Chelating Agents; D013844:Thiazoles; D007501:Iron; D003676:Deferoxamine; D002118:Calcium; C050223:desferrithiocin