Immunosuppressive effect of a new drug, FTY720, on lymphocyte responses in vitro and cardiac allograft survival in rats

Suzuki, Seiichi; Enosawa, Shin; Kakefuda, Toshihiro; Li, Xiaokang; Mitsusada, Makoto; Takahara, Shiro; Amemiya, Hiroshi

doi:10.1016/s0966-3274(96)80026-8

Cited by 47 publications

(26 citation statements)

References 14 publications

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“…Both TCR' and CD 45' cells in the peripheral blood were dramatically reduced in number, while polymorphonuclear cells and monocytes were not affected, suggesting that FTY 720-treated animals were relatively resistant to infectious complications. Indeed, none of the rats died of infection or of other complications in our present or previous studies [7,8,11].…”

Section: Discussionsupporting

confidence: 53%

“…Thus, the drug displays bcl-2-associated apoptosis in lymphocytes. We have also shown that the drug has a potent immunosuppressive effect that prolongs graft survival in rat heart and liver recipients and in canine kidney recip-ients [7,8,11]. It is worth noting that FTY 720 has a wide therapeutic window and induces no severe side effects in skin-allografted rats receiving oral doses ranging from 0.1 to 30 mg/kg as well as in heart-allografted rats at doses between 0.05 and 10 mg/kg [l, 71.…”

Section: In Trod Udionmentioning

confidence: 78%

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Prevention of graft rejection and graft-versus-host reaction by a novel immunosuppressant, FTY720, in rat small bowel transplantation

Mitsusada¹,

Suzuki²,

Kobayashi

et al. 1997

Transplant Int

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In the present study, we examined the immunosuppressive effect of a new drug, FTY 720, on small bowel transplantation (SBT) in rats. Grafts from (LEW x BN) F 1-to-LEW rats treated with FTY 720 at 0.5 mg/kg from day 0 to 14 post-SBT survived significantly longer than untreated grafts. In addition, the administration of FTY 720 combined with cyclosporin (CyA; 5 mg/kg per day) had a synergistic effect on allograft survival. The graft-versus-host reaction (GVHR) that occurred in the LEWto-F 1 rats was markedly reduced after the administration of FTY 720. FTY 720 combined with a low dose of CyA completely abrogated GVHR without any adverse reaction. FTY 720 treatment resulted in a significant decrease in the number of lymphocytes in the peripheral blood and the spleen, but the number of peripheral neutrophils was unchanged. Thus, FTY 720 would appear to be an ideal drug to combine with CyA in order to control the immune reaction after SBT.

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Section: Discussionsupporting

confidence: 53%

Section: In Trod Udionmentioning

confidence: 78%

Prevention of graft rejection and graft-versus-host reaction by a novel immunosuppressant, FTY720, in rat small bowel transplantation

Mitsusada¹,

Suzuki²,

Kobayashi

et al. 1997

Transplant Int

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“…The induction of apoptosis seems to occur specifically in the lymphocyte population. The drug also has a potent immunosuppressive effect that prolongs graft survival in recipient rats with heart or liver allografts, and in canine kidney recipients [2,3]. Therefore, FTY720 has unique modes of action and may potentially be used in clinical organ transplants as well as in the treatment of autoimmune diseases.…”

Section: Introductionmentioning

confidence: 99%

The in vivo induction of lymphocyte apoptosis in MRL-lpr/lpr mice treated with FTY720

Suzuki¹,

Li²,

Shinomiya³

et al. 1997

Clinical and Experimental Immunology

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SUMMARYThe in vitro treatment of lpr thymocytes with FTY720 resulted in a dose-dependent reduction in cell viability due to apoptosis. In order to study the effect of FTY720 in vivo, lpr mice received an oral daily dose of 1 mg/kg FTY720 for 14 days, beginning at 16 weeks of age which was when the animals were developing massive lymphoadenopathy. Compared with untreated lpr mice, FTY720-treated lpr mice had significantly prolonged lives. At 24 weeks of age, treated mice demonstrated markedly reduced weights of the spleen and lymph nodes, and the proportion of CD3 + B220 + and CD4 -CD8 -cells in the thymus, spleen and lymph nodes decreased markedly. In addition, in these mice the percentage of CD4 + CD8 + and CD3 -B220 -cells in the thymus and the percentage of CD4 + CD8 -, CD4 -CD8 + , CD3 + B220 -and CD3 -B220 + cells in the spleen returned to almost the normal values observed in wild-type mice. Histological observation 1 day after the final administration of FTY720 revealed a remarkable infiltration of neutrophils in the lymphoid organs. Apoptotic cells were detected in all the lymphoid organs using in situ DNA nick-end labelling. Electron microscopy showed that the apoptotic cells were ingested by phagocytes. FTY720 therapy is thus highly effective in Fas-mutant animals with abnormally expanding lymphocytes.

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“…Also it is not inducing T cell apoptosis at clinically relevant concentrations (7, 9 -12), FTY720 is highly potent in animal models for the treatment of allograft rejection and autoimmunity. Despite ongoing discussions about adverse effects, FTY720 has entered clinical trials and was shown to be beneficial in human kidney transplantation (1,(13)(14)(15)(16)(17).…”

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FTY720 Ameliorates Th1-Mediated Colitis in Mice by Directly Affecting the Functional Activity of CD4+CD25+ Regulatory T Cells

Daniel

Sartory

Zahn

et al. 2007

The Journal of Immunology

155

122

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Following the present concepts, the synthetic sphingosine analog of myriocin FTY720 alters migration and homing of lymphocytes via sphingosine 1-phosphate receptors. However, several studies indicate that the immunosuppressive properties of FTY720 may alternatively be due to tolerogenic activities via modulation of dendritic cell differentiation or based on direct effects on CD4+CD25+ regulatory T cells (Treg). As Treg play an important role for the cure of inflammatory colitis, we used the Th1-mediated 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis model to address the therapeutic potential of FTY720 in vivo. A rectal enema of TNBS was given to BALB/c mice. FTY720 was administered i.p. from days 0 to 3 or 3 to 5. FTY720 substantially reduced all clinical, histopathologic, macroscopic, and microscopic parameters of colitis analyzed. The therapeutic effects of FTY720 were associated with a down-regulation of IL-12p70 and subsequent Th1 cytokines. Importantly, FTY720 treatment resulted in a prominent up-regulation of FoxP3, IL-10, TGFβ, and CTLA4. Supporting the hypothesis that FTY720 directly affects functional activity of CD4+CD25+ Treg, we measured a significant increase of CD25 and FoxP3 expression in isolated lamina propria CD4+ T cells of FTY720-treated mice. The impact of FTY720 on Treg induction was further confirmed by concomitant in vivo blockade of CTLA4 or IL-10R which significantly abrogated its therapeutic activity. In conclusion, our data provide clear evidence that in addition to its well-established effects on migration FTY720 leads to a specific down-regulation of proinflammatory signals while simultaneously inducing functional activity of CD4+CD25+ Treg. Thus, FTY720 may offer a promising new therapeutic strategy for the treatment of IBD.

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Immunosuppressive effect of a new drug, FTY720, on lymphocyte responses in vitro and cardiac allograft survival in rats

Cited by 47 publications

References 14 publications

Prevention of graft rejection and graft-versus-host reaction by a novel immunosuppressant, FTY720, in rat small bowel transplantation

Prevention of graft rejection and graft-versus-host reaction by a novel immunosuppressant, FTY720, in rat small bowel transplantation

The in vivo induction of lymphocyte apoptosis in MRL-lpr/lpr mice treated with FTY720

FTY720 Ameliorates Th1-Mediated Colitis in Mice by Directly Affecting the Functional Activity of CD4+CD25+ Regulatory T Cells

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