FTY 720A mediates reduction of lymphocyte counts in human renal allograft recipients by an apoptosis-independent mechanism.
The novel immunosuppressive compound FTY 720A posseses a mode of action which is different from all other immunosuppressive drugs. The most prominent feature is a reversible decrease in peripheral lymphocyte counts observed in animal experiments. We investigated in the first human trial (phase 1) whether FTY 720A induces apoptosis of peripheral blood mononuclear cells (PBMC) in stable renal allograft recipients. Monitoring of lymphocyte counts revealed a significant and dose-dependent decrease within 6 h post-FTY 720A dose: placebo 5.1%; 0.25 mg 36.4%; 0.5 mg 40.8%; 0.75 mg 39.4%; 1 mg 45.8%; 2 mg 67.2%; 3.5 mg 64.9%. PBMC apoptosis rates did not change, as determined before intake of FTY 720A and 2 h, 6 h, 24 h and 96 h post-FTY 720A dose. We detected no significant difference in apoptosis rates between patients who received placebo or FTY 720A. However, in vitro experiments showed that high concentrations of FTY 720 A induced apoptosis in human PBMC.
Böhler
T
T
Department of Nephrology, Humboldt-University Berlin, Germany. torsten.boehler@charite.de
Waiser
J
J
Schütz
M
M
Friedrich
M
M
Schötschel
R
R
Reinhold
S
S
Schmouder
R
R
Budde
K
K
Neumayer
H H
HH
D017209:Apoptosis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000276:immunology*; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D010919:Placebos; D011409:Propylene Glycols / Q000009:adverse effects / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives
D007166:Immunosuppressive Agents; D010919:Placebos; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine