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

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.

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.

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.

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.