FTY720 exerts differential effects on CD4+ and CD8+ T-lymphocyte subpopulations expressing chemokine and adhesion receptors.
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.
Böhler
Torsten
T
Department of Nephrology, Charité, Campus Mitte, Humboldt-University, Berlin, Germany. boehler@charite.de
Waiser
Johannes
J
Schuetz
Manuela
M
Neumayer
Hans H
HH
Budde
Klemens
K
D018929:Cell Culture Techniques; D004311:Double-Blind Method; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000276:immunology; D018655:Lymphocyte Count; D011409:Propylene Glycols / Q000494:pharmacology*; D019707:Receptors, Chemokine / Q000378:metabolism*; D016028:Receptors, Leukocyte-Adhesion / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D019707:Receptors, Chemokine; D016028:Receptors, Leukocyte-Adhesion; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine