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

Mitsusada, Makoto; Suzuki, Seiichi; Kobayashi, Eiji; Enosawa, Shin; Kakefuda, Toshihiro; Miyata, Michio

doi:10.1111/j.1432-2277.1997.tb00927.x

Cited by 26 publications

(34 citation statements)

References 13 publications

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“…؉ T Cells F TY720 is a potent immunomodulator that has been shown to prolong the survival of solid organ allografts, including skin (1-3), heart (4, 5), liver (6 -10), and small bowel (7,11) in animal models. FTY720 has unique modes of action and shows synergy with cyclosporin and sirolimus in these models (7,12).…”

Section: Sphingosine-1-phosphate Receptor Agonism Impairs the Efficiementioning

confidence: 99%

Sphingosine-1-Phosphate Receptor Agonism Impairs the Efficiency of the Local Immune Response by Altering Trafficking of Naive and Antigen-Activated CD4+ T Cells

Xie

Nomura

Koprak

et al. 2003

The Journal of Immunology

116

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FTY720 (2-amino-[2-(4-octylphenyl) ethyl]-1,3-propanediol hydrochloride) is an immunosuppressive agent that inhibits allograft rejection. We recently demonstrated that FTY-phosphate, the active metabolite of FTY720, acts as a full agonist for sphingosine-1-phosphate (S1P) receptors. Furthermore, activation of S1P receptors with their natural ligand, S1P, as well as pharmacological ligands leads to lymphopenia, probably due to sequestration of lymphocytes in secondary lymphoid organs. In the present study we used a local Ag-challenged mouse model to examine the effects of FTY720 on T cell activation in the draining lymph node (DLN) and on the release of activated T cells to the peripheral blood compartment. We showed that the number of Ag-activated CD4+ T cells in the DLN after injection of Ag and CFA into a footpad was dramatically reduced after FTY720 treatment. However, T cell proliferation, both in vitro and in vivo, was not impaired by FTY720. Our results suggest that the reduced efficiency of T cell responses in the DLN in response to a local Ag is probably due to a defective recirculation of naive T cells caused by FTY720 treatment. Furthermore, we found that the numbers of naive and Ag-activated CD4+ T cells in the peripheral blood of Ag-challenged mice were equally reduced with FTY720 treatment, suggesting that both T cell subsets are sequestered in the DLNs. Thus, FTY720 induces immunosuppression through inhibition of both the recirculation of naive T cells and the release of Ag-activated T cells from the DLN to lymph and to the blood compartment.

show abstract

Section: Sphingosine-1-phosphate Receptor Agonism Impairs the Efficiementioning

confidence: 99%

Sphingosine-1-Phosphate Receptor Agonism Impairs the Efficiency of the Local Immune Response by Altering Trafficking of Naive and Antigen-Activated CD4+ T Cells

Xie

Nomura

Koprak

et al. 2003

The Journal of Immunology

116

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“…It has also been tested and has been well tolerated in human phase I and phase II trials (39) as chronic immunosuppressive therapy. FTY has also shown GvHDinhibitory activity in a rat model in which spleen cells were transplanted from a parental strain into F 1 rats treated with 200 mg/kg cyclophosphamide (40) and in a rat small-bowel transplant model (41).…”

mentioning

confidence: 99%

Graft-versus-host disease can be separated from graft-versus-lymphoma effects by control of lymphocyte trafficking with FTY720

Kim

Sachs²,

Asavaroengchai³

et al. 2003

J. Clin. Invest.

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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).…”

mentioning

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

Cited by 26 publications

References 13 publications

Sphingosine-1-Phosphate Receptor Agonism Impairs the Efficiency of the Local Immune Response by Altering Trafficking of Naive and Antigen-Activated CD4+ T Cells

Sphingosine-1-Phosphate Receptor Agonism Impairs the Efficiency of the Local Immune Response by Altering Trafficking of Naive and Antigen-Activated CD4+ T Cells

Graft-versus-host disease can be separated from graft-versus-lymphoma effects by control of lymphocyte trafficking with FTY720

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

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