FTY720 exerts differential effects on CD4+ and CD8+ T-lymphocyte subpopulations expressing chemokine and adhesion receptors

Abstract

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 (0.25-2mg) or high (3.5mg) 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. © ERA-EDTA 2004; all rights reserved.