DOI: 10.1093/ndt/gfg599 Original Article FTY720 exerts differential effects on CD4þ and CD8þ T-lymphocyte subpopulations expressing chemokine and adhesion receptors

Background. FTY720 (FTY), a novel immunomodu-lator with the potential to improve immunosuppres-sive 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 lympho-cyte 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 (0.25–3.5mg) significantly reduced peripheral lymphocyte counts by 30–70%. FTY reduced all T-lymphocyte subsets, CD4þ cells more than CD8þ cells. However, we observed that lower doses of FTY (0.25–2mg, n 11) did not affect peripheral CD4þCCR5þ T-lymphocyte counts, while the highest FTY dose of 3.5mg (n 2) exerted a rapid reduction of CD4þCCR5þ cells. Peripheral CD8þCCR5þ T-lymphocyte counts were reduced by either low (0.25–2mg) or high (3.5mg) doses of FTY. In contrast to CCR5þ cells, cells expressing CD62L were preferentially reduced after administration of FTY. In particular, CD4þCD62Lþ T cells declined after treatment. CD4þ and CD8þ T-lymphocyte subpopulations expressing the other che-mokine and adhesion receptors (CXCR4, CD11a and CD49d) were reduced to a similar extent as compared with overall CD4þ or CD8þ 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 CD4þCD62Lþ cells in the peripheral blood suggesting increased migration into lymph nodes. It seems that only FTY doses above 2mg are able to reduce peripheral CD4þCCR5þ T lym-phocytes, which are potentially capable of infiltrating into the allograft during rejection