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  • Title: Differential effects of the immunosuppressive macrolides FK-506 and rapamycin on activation-induced T-cell apoptosis.
    Author: Staruch MJ, Sigal NH, Dumont FJ.
    Journal: Int J Immunopharmacol; 1991; 13(6):677-85. PubMed ID: 1721613.
    Abstract:
    Activation of certain T-cell lines induces, besides lymphokine production, a suicide process (apoptosis) mediated by fragmentation of the cell's genome. This also occurs intrathymically during negative selection of the T-cell receptor (TcR) repertoire. Cyclosporin A (CsA) has been shown to block activation-driven T-cell apoptosis, an effect which may account for the perturbations of TcR repertoire selection caused by this agent in vivo. Recently, the macrolide FK-506 was demonstrated to suppress T-cell activation by inhibiting lymphokine production in a manner apparently similar to CsA. Thus, it seemed important to determine whether FK-506 would also prevent T-cell apoptosis. For the purpose of comparison, we also investigated rapamycin (RAP), a macrolide structurally related to FK-506, but that does not block lymphokine production and antagonizes the immunosuppressive action of FK-506. The DO-11.10 T-cell hybridoma stimulated with ionomycin plus PMA was used as a model system. FK-506 (1.2 nM) totally prevented DNA fragmentation detectable by agarose gel electrophoresis at 16 h of culture. FK-506 still inhibited this phenomenon when added 2 h after the initiation of the cultures but not later. In contrast, concentrations of RAP as high as 1 microM failed to block apoptosis. However, RAP (110 nM) reversed the apoptosis-inhibitory effect of FK-506, even if added 1-2 h after the latter to the cultures. Consistent with this antagonism, RAP also reversed the binding of a radiolabeled derivative of FK-506 in DO-11.10 cells. Therefore, FK-506 interferes with an early event of T-cell activation that leads to apoptosis whereas RAP does not.(ABSTRACT TRUNCATED AT 250 WORDS)
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