Artikel
Calcineurin inhibitors but not rapamycin abrogate activation of the immunomodulatory enzyme Indoleamine 2,3-dioxygenase
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Autoren
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G. Brandacher
- Department of General and Transplant Surgery, Univ. Hospital Innsbruck, Austria
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C. Winkler
- Institute for Medical Chemistry and Biochemistry, Medical University Innsbruck, Austria
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S. Schneeberger
- Department of General and Transplant Surgery, Univ. Hospital Innsbruck, Austria
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E.R. Werner
- Institute for Medical Chemistry and Biochemistry, Medical University Innsbruck, Austria
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G. Werner-Felmayer
- Institute for Medical Chemistry and Biochemistry, Medical University Innsbruck, Austria
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R. Margreiter
- Department of General and Transplant Surgery, Univ. Hospital Innsbruck, Austria
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D. Fuchs
- Institute for Medical Chemistry and Biochemistry, Medical University Innsbruck, Austria
| Veröffentlicht: | 15. Juni 2005 |
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Gliederung
Text
Introduction
T-cell costimulatory blockade prevents allograft rejection and can induce peripheral tolerance. However, concomitant use of calcineurin inhibitors but not rapamycin are known to antagonize these effects. Recently, indoleamine 2,3-dioxygenase (IDO) via tryptophan depletion has been demonstrated to be the mediator of CTLA4Ig induced tolerance. An interaction between IDO activity and conventional immunosuppressive agents has not been investigated yet.
Materials
Isolated, human peripheral blood mononuclear cells (PBMC) were stimulated with 10μg/ml phytohaemagglutinin (PHA) and 10mg/ml concanavalin A (ConA) in the absence or presence of 0.01μg/ml - 1μg/ml cyclosporin-A (CsA), tacrolimus (FK506), rapamycin (Rapa), mycophenolate mofetil (MMF) or methylprednisolone (MP). After 48 hours of incubation tryptophan and kynurenin concentrations in cellculture supernatants were analyzed by high performance liquid chromatography (HPLC). Kynurenine to tryptophan ratios (kyn/trp) were calculated as an indirect estimate of functional IDO activity.
Results
PHA and ConA significantly induced IDO activation and thus tryptophan degradation in a dose-dependent manner. CsA, FK506 and MMF revealed profound IDO inhibition in PBMCs as reflected by significantly reduced kyn/trp (all P<0.01) and by increasing tryptophan concentrations. (P<0.01) In sharp contrast Rapa and MP, at identical concentrations, had only marginal effects on IDO enzyme activity and did not decrease tryptophan catabolism when compared to mitogen stimulation alone (P=ns).
Discussion
These data provide first evidence that the differential effects of CsA, FK506 and Rapa on IDO activity may explain their capacity to either inhibit, or synergize with tolerance induction, when used in combination with T-cell costimulatory blocking agents.
