Immunosuppressive therapy using FTY720 combined with tacrolimus in rat liver transplantation.
BACKGROUND
FTY720 (FTY) exerts its effects through a reduction of peripheral lymphocytes. This unique mechanism allows for a possible combination effect with other immunosuppressants. We investigated therapy with FTY combined with tacrolimus (FK) in rat liver transplantation.


METHODS
Different doses of FK, FTY, or both were orally administered to the recipients for 15 days. Expression of cytokine mRNAs using RT-PCR and appearance of lymphocyte apoptosis by immunohistologic staining were studied in the allografts.


RESULTS
Recipients treated with a low dose of FK (0.3 mg/kg) or FTY (0.03 mg/kg) showed a slightly prolonged survival time, although combination therapy with these drugs prolonged survival time similar to the duration obtained by an optimal dose of each drug alone. A marked suppression of lymphocyte infiltration and decreased levels of mRNAs for IL-2, IFN-gamma, and granzyme B were seen in the grafts with combination therapy. Grafts with combination therapy showed an increased number of cells double-stained with TUNEL and CD2 in infiltrated lymphocytes.


CONCLUSIONS
Allografts that underwent combination therapy demonstrated markedly reduced lymphocyte infiltration; a number of cells had induced apoptosis and an inhibition of IL-2, IFN-gamma, and granzyme B mRNA transcription, but not IL-4 and IL-10 transcripts, accounting for powerful mutual effect of FTY and FK.
Tamura
A
A
Department of Experimental Surgery and Bioengineering, National Children's Medical Research Center, Tokyo, Japan.
Li
X K
XK
Funeshima
N
N
Enosawa
S
S
Amemiya
H
H
Kitajima
M
M
Suzuki
S
S
D000818:Animals; D017209:Apoptosis; D018801:CD2 Antigens / Q000378:metabolism; D004338:Drug Combinations; D000068876:Fingolimod Hydrochloride; D006085:Graft Survival / Q000187:drug effects; D053804:Granzymes; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D007371:Interferon-gamma / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D016031:Liver Transplantation; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D008297:Male; D011409:Propylene Glycols / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D012697:Serine Endopeptidases / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives; D016559:Tacrolimus / Q000627:therapeutic use*
D018801:CD2 Antigens; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011409:Propylene Glycols; D012333:RNA, Messenger; D007371:Interferon-gamma; D053804:Granzymes; C509215:Gzmb protein, rat; D012697:Serine Endopeptidases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D016559:Tacrolimus