Effect of a New Immunosuppressive Agent, Fty720, on Survival of Islet Allografts

Yamasaki, Toru; Inoue, Kazutomo; Hayashi, Hiroyuki; Gu, Yuanjun; Setoyama, Hiroshi; Ida, Jun; Cui, Wanxing; Kawakami, Yoshiyuki; Kogire, Masafumi; Imamura, Masayuki

doi:10.1177/096368979800700409

Cited by 14 publications

(8 citation statements)

References 13 publications

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“…This drug reaches a maximum concentration at 8 or 9 h, and its metabolites are found in the urine and feces at ratios of 40-50 and 20-50%, respectively [3]. It has been reported that FTY720 exhibits beneficial effects on various kinds of organ transplantations in the rat system; skin, heart, liver, small bowel, and islet grafts [4][5][6][7]. Until now, the mechanism of immunosuppression by this drug has been supposed to be due to induction of apoptosis of the lymphocytes, because FTY720 induced chromatin condensation, formation of apoptotic bodies and DNA fragmentation in lymphocytes [8].…”

Section: Introductionmentioning

confidence: 99%

Effect of a Novel Immunosuppressant, FTY720, on Allograft Survival after Renal Transplant in Rats

et al. 2000

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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.

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Section: Introductionmentioning

confidence: 99%

Effect of a Novel Immunosuppressant, FTY720, on Allograft Survival after Renal Transplant in Rats

et al. 2000

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“…[1][2][3] Upon oral administration, FTY720 prolongs survival of transplanted allografts without noticeable toxicity to the host, 1,[4][5][6][7][8][9] but the original product, ISP-1, causes severe digestive disorders, resulting in death of the animal. 2,3) Administration of a single dose of 10 mg W kg FTY720 to healthy rats reduces the number of peripheral lymphocytes, with a minimum by 3 h after the administration; recovery of the lymphocyte counts to pretreatment levels takes 2 weeks.…”

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confidence: 99%

Elimination of Cell-cycle Regulators during Caspase-3-dependent Apoptosis Caused by an Immunosuppressant, FTY720

Lee

Nakajima

Tsuruga³

et al. 2003

Bioscience, Biotechnology, and Biochemistry

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“…The novel immunosuppressant, FTY720, 2-amino-2-(2-(4-octylphenyl) ethyl)-1,3-propanediol hydrochloride, was screened from synthesized analogs of ISP-1, which is an immunosuppressive metabolite of Isaria sinclairii (28 -31). The oral administration of FTY720 prolongs allograft survival in experimental organ transplantation without producing any noticeable side effects (31)(32)(33)(34)(35). The action mechanism of orally administered FTY720 to suppress graft rejection is regarded as a significant decrease in the number of blood lymphocytes, especially T cells (36).…”

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confidence: 99%

Immunosuppressant FTY720 Induces Apoptosis by Direct Induction of Permeability Transition and Release of Cytochrome c from Mitochondria

Nagahara

Ikekita

Shinomiya³

2000

The Journal of Immunology

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FTY720 has immunosuppressive activity in experimental organ transplantation and shows a prompt and protracted decrease of blood T lymphocytes upon oral administration. The blood lymphocyte decrease in vivo was mainly a result of FTY720-induced apoptosis. However, this apoptotic mechanism is not well understood. We examined the mechanism of FTY720-induced apoptosis in lymphoma. Western blotting and fluorescent caspase-specific substrate revealed that caspase-3 is involved in FTY720-induced apoptosis, whereas caspase-1 is not. Apoptotic cell death was inhibited by the pan-caspase inhibitor, Z-VAD-FMK, suggesting that caspase activation is essential for FTY720-induced apoptosis. FTY720 reduced mitochondrial transmembrane potential and released cytochrome c from the mitochondria of intact cells as well as in a cell-free system even in the presence of Z-VAD-FMK. As these mitochondrial reactions occurred before caspase activation, we concluded that FTY720 directly influences mitochondrial functions. The inhibition of mitochondrial permeability transition by Bcl-2 overexpression or by chemical inhibitors prevented all apoptotic events occurring in intact cells and in a cell-free system. Moreover, using a cell-free system, FTY720 did not directly affect isolated nuclei or cytosol. These results indicate that FTY720 directly affects mitochondria and triggers permeability transition to induce further apoptotic events.

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Effect of a New Immunosuppressive Agent, Fty720, on Survival of Islet Allografts

Cited by 14 publications

References 13 publications

Effect of a Novel Immunosuppressant, FTY720, on Allograft Survival after Renal Transplant in Rats

Effect of a Novel Immunosuppressant, FTY720, on Allograft Survival after Renal Transplant in Rats

Elimination of Cell-cycle Regulators during Caspase-3-dependent Apoptosis Caused by an Immunosuppressant, FTY720

Immunosuppressant FTY720 Induces Apoptosis by Direct Induction of Permeability Transition and Release of Cytochrome c from Mitochondria

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