FK 506: an immunosuppressant for the 1990s?

MacLeod, Alison Murray; Thomson, A. W.

doi:10.1016/0140-6736(91)93341-6

Cited by 68 publications

(17 citation statements)

References 19 publications

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“…While Jurkat cells express high levels of immunophilins (1), quantitation of protein levels by Western blot indicates that calcineurin is expressed at 25-fold lower levels in Jurkat cells than in brain tissue (unpublished data). Perhaps a similar pattern of calcineurin and immunophilin expression occurs in renal cells, resulting in the nephrotoxicity commonly observed in patients treated with FK 506 or CsA (28).…”

Section: Top) When Added Tomentioning

confidence: 99%

Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A.

Fruman

Klee

Bierer

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

743

413

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The immunosuppressive agents cydosporin A (CsA) and FK 506 bind to distinct families of intracellular proteins (immunophilins) termed cyclophilin and FK 506-binding proteins (FKBPs). Recently, it has been shown that, in vitro, the complexes of CsA-cydophilin and FK 506-FKBP-12 bind to and inhibit the activity of calcineurin, a calciumdependent serine/threonine phosphatase. We have investigated the effects of drug treatment on phosphatase activity in T lymphocytes. Calcineurin is expressed in T cells, and its activity can be measured in cell lysates. Both CsA and FK 506 specificay inhibit cellular calcineurin at drug concentrations that inhibit interleukin 2 production in activated T cells. Rapamycin, which binds to FKBPs but exhibits different biological activities than FK 506, has no effect on calcineurin activity. Furthermore, excess concentrations of rapamycin prevent the effects of FK 506, apparently by displacing FK 506 from FKBPs. These results show that calcineurin is a target of drug-immunophilin complexes in vivo and establish a physiological role for calcineurin in T-cell activation.The immunosuppressants cyclosporin A (CsA), FK 506, and rapamycin have proven to be valuable probes for studying T-cell signal transduction (1, 2). While CsA and FK 506 bind to distinct cellular receptors, these agents exhibit essentially identical effects on T-cell activation: both inhibit Ca2+-dependent activation pathways that lead to transcription of lymphokine genes (1-6). Rapamycin, like FK 506, binds to FK 506-binding proteins (FKBPs), but inhibits T-cell activation by interfering with distinct Ca2+-independent signaling pathways (7-9). Rapamycin reverses the action of FK 506, apparently by competitive binding to FKBPs (1, 2, 8, 9). These and other findings have led to the model that an immunosuppressant bound to its cellular receptor (immunophilin) forms an inhibitory complex that interferes with signal transduction (1, 2, 9-11). The complexes of CsA-cyclophilin and FK 506-FKBP are postulated to affect the same signaling component, while rapamycin-FKBP affects a distinct component.Calcineurin, also known as phosphatase 2B, is a Ca2+-and calmodulin-dependent serine/threonine phosphatase consisting of two subunits with predicted molecular masses of 59 kDa and 19 kDa (12). It is expressed ubiquitously in eukaryotic cells, including yeast (13). In mammals, calcineurin is most abundant in brain (12) but also has been detected in T cells (14,15 10%6 (vol/vol) heat-inactivated fetal calf serum (FCS), 100 units of penicillin per ml, 100 j&g of streptomycin per ml, 10 mM Hepes, 2 mM L-glutamine, and 25 juM 2-mercaptoethanol (termed "complete medium") at 370C in humidified air containing 5% CO2. PC12 cells were obtained from K. Wood (Dana-Farber Cancer Institute) and cultured in Dulbecco's modified Eagle's medium containing 10% heat-inactivated FCS, 5% heat-inactivated horse serum, 100 units of penicillin per ml, 100 jug of streptomycin per ml, and 2 mM L-glutamine at 370C in humified air containing 10% CO2.Immunobl...

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Section: Top) When Added Tomentioning

confidence: 99%

Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A.

Fruman

Klee

Bierer

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

743

413

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“…In this experiment, the clear-cut capacity of DSP to diminish IFN-y secretion and to reduce the percentages of Ly-6C+ SLC enriches and complements these data and supports the hypothesis that DSP-induced suppression of IFN-y production from autoreactive diabetogenic clones in vivo might have contributed to prevent IDDM in NOD/WEHI mice. It is noteworthy that the inhibitory action on IFN-y secretion obtained with 2-5 mg/kg body weight per day DSP was comparable to that achieved with a similar dose (2 mg) of FK506, which is, to date, one of the most powerful and promising immunosuppressants (see [26,29] for reviews).…”

Section: Resultsmentioning

confidence: 96%

Prevention of cyclophosphamide-induced diabetes in the NOD/WEHI mouse with deoxyspergualin

Nicoletti

Borghi

Meroni

et al. 1993

Clinical and Experimental Immunology

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SUMMARYTen out of 20 (50%) 17-week-old female NOD/WEHI mice developed an acute form of autoimmune diabetes when injected with two large doses of cyclophosphamide (CY), given at 14-day intervals. If these mice were treated under a prophylactic regimen with 2 5 mg/kg body weight per day of the novel immunosuppressant deoxyspergualin (DSP) the onset of diabetes was completely prevented. Moreover, DSP-treated animals showed reduced signs of pancreatic insulitis, had lower percentages of splenic lymphoid cells (SLC) expressing IL-2 receptors and Ly-6C antigens on their surfaces, and these cells released lower amounts of interferon-gamma (IFN) when stimulated in vitro. These data, providing evidence for the capacity of DSP to protect NOD/WEHI mice from experimental autoimmune diabetes and to modulate histo-immunological pathogenic pathways, indicate DSP as a drug of potential interest in the treatment of human insulin-dependent diabetes mellitus.

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“…13,14 Although both are CIs, the incidence of hypertension is lower in patients treated with tacrolimus than with cyclosporine A (CSA). 15,16 No randomized trials in heart transplant recipients are large enough to evaluate the effect of antihypertensive therapy on morbidity, mortality, and graft survival, but it is likely that antihypertensive therapy has similar, if not greater, benefits in the heart transplant recipient than in the general population. One reason is that blood pressure after cardiac transplantation is characterized by a disturbed circadian rhythm without the normal nocturnal blood pressure fall and with a greater 24-hour hypertensive burden.…”

Section: Hypertensionmentioning

confidence: 99%