Effect of a novel immunosuppressant, FTY720, on allograft survival after renal transplant in rats.
FTY720 was developed by chemical modification of ISP-1 which was purified from culture filtrates of an ascomycete, Isaria sinclairii. We evaluated the effect of FTY720 on allograft survival using a rat renal transplantation model in which Wistar King Aptekman Hokkaido rats (WKAH, RT1(K)) served as the organ donor and Lewis rats (LEW, RT1(l)) as the recipient. WKAH renal allografts were acutely rejected by the untreated LEW recipients at a mean graft survival +/- SD of 7.2 +/- 0.4 days (n = 5). Consecutive oral administration of FTY720 following transplantation significantly prolonged allograft survival in a dose-dependent manner over the range of 0. 05-3 mg/kg/day. The mean allograft survival of the recipients treated with FTY720 at a doses of 0.05, 0.1, 0.5, 1, and 3 mg/kg/day was 12.2 +/- 3.3 (n = 5, p < 0.05, vs. untreated host), 11.2 +/- 2.4 (n = 5, p < 0.05, vs. untreated host), 13.6 +/- 0.9 (n = 5, p < 0.01, vs. untreated host), 14.6 +/- 1.7 (n = 5, p < 0.01, vs. untreated host) and 20.2 +/- 0.8 days (n = 5, p < 0.01, vs. untreated host). In the recipients treated with FTY720 (3 mg/kg/day), the number of peripheral blood lymphocytes significantly decreased. From the results of the flow cytometric study, FTY720 significantly diminished the percentage of interleukin-2 receptor (IL-2R)-positive cells in the allografts (6.34 +/- 0.81% in the untreated recipients vs. 3.10 +/- 0.86% in the recipients treated with FTY720, p < 0.05). As to the CD4/CD8 ratio of splenic cells and graft infiltrate, there was no significant difference between the untreated hosts and the recipients treated with FTY720. In conclusion, FTY720 significantly extended rat renal allograft survival and the immunosuppressive effects of FTY720 may be due to a reduction in not only the number of peripheral lymphocytes but also the percentage of IL-2R-positive cells in the allografts.
Ueda
H
H
Department of Urology, Osaka Medical College, Osaka, Japan.
Takahara
S
S
Azuma
H
H
Kusaka
M
M
Suzuki
S
S
Katsuoka
Y
Y
D000818:Animals; D001772:Blood Cell Count; D001773:Blood Cells / Q000187:drug effects; D016516:CD4-CD8 Ratio; D004305:Dose-Response Relationship, Drug; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D006084:Graft Rejection; D006085:Graft Survival / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D011409:Propylene Glycols / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives; D013154:Spleen / Q000473:pathology; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D015375:Receptors, Interleukin-2; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine