Nephrol Dial Transplant (2004) 19: 702-713
Nephrol Dial Transplant Vol. 19 No. 3 (c) ERA-EDTA 2004; all rights reserved
Original Article
FTY720 exerts differential effects on CD4+ and CD8+ T-lymphocyte subpopulations expressing chemokine and adhesion receptors
Department of Nephrology, Charité, Campus Mitte, Humboldt-University, Berlin, Germany
Correspondence and offprint requests to: Dr Torsten Böhler, Department of Nephrology, Charité, Humboldt-University Berlin, Schumannstrasse 20/21, 10117 Berlin, Germany. Email: torsten.boehler{at}charite.de
Background. FTY720 (FTY), a novel immunomodulator with the potential to improve immunosuppressive therapy after organ transplantation, is currently under clinical investigation. Previous experimental animal studies have shown that FTY has a unique mechanism of action associated with altered lymphocyte recirculation.
Methods. Participating in a phase I clinical trial, we studied the pharmacodynamic effects of FTY in stable renal allograft recipients. We analysed the effect of FTY on surface marker expression on T-cell subpopulations by flow cytometry.
Results. A single oral dose of FTY (0.25–3.5 mg) significantly reduced peripheral lymphocyte counts by 30–70%. FTY reduced all T-lymphocyte subsets, CD4+ cells more than CD8+ cells. However, we observed that lower doses of FTY (0.25–2 mg, n = 11) did not affect peripheral CD4+CCR5+ T-lymphocyte counts, while the highest FTY dose of 3.5 mg (n = 2) exerted a rapid reduction of CD4+CCR5+ cells. Peripheral CD8+CCR5+ T-lymphocyte counts were reduced by either low (0.25–2 mg) or high (3.5 mg) doses of FTY. In contrast to CCR5+ cells, cells expressing CD62L were preferentially reduced after administration of FTY. In particular, CD4+CD62L+ T cells declined after treatment. CD4+ and CD8+ T-lymphocyte subpopulations expressing the other chemokine and adhesion receptors (CXCR4, CD11a and CD49d) were reduced to a similar extent as compared with overall CD4+ or CD8+ T-lymphocyte counts.
Conclusions. Despite the limited number of patients, especially in the placebo (n = 3) and the high-dose groups (n = 2), our observations suggest that FTY exerts differential effects on T-cell subpopulations. FTY predominantly reduces CD4+CD62L+ cells in the peripheral blood suggesting increased migration into lymph nodes. It seems that only FTY doses above 2 mg are able to reduce peripheral CD4+CCR5+ T lymphocytes, which are potentially capable of infiltrating into the allograft during rejection.
Keywords: CCR5; CD62 ligand; FTY; human; lymphocyte subpopulation; renal transplantation
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