Immunosuppressive activity of FTY720, sphingosine 1-phosphate receptor agonist: II. Effect of FTY720 and FTY720-phosphate on host-versus-graft and graft-versus-host reaction in mice

Kataoka, Hirotoshi; Ohtsuki, M; Shimano, Kyoko; Mochizuki, Sachiko; Oshita, Koichi; Murata, Mitsuru; Sugahara, Kazuyuki; Sato, Noriko; Hoshino, Yukio; Chiba, Kenji

doi:10.1016/j.transproceed.2004.12.287

Cited by 15 publications

(11 citation statements)

References 7 publications

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“…In line with published data, 9,10 we observed in our patient's peripheral blood an increase in the proportion of naive B cells and effector memory CD4 1 cells (Figure 2B-C). Although most studies 3,[11][12][13] emphasized inhibition of lymphocyte egress as the main mechanism responsible for the anti-GVHD effects of fingolimod, Taylor et al reported contrasting effects of the drug in a murine model of acute GVHD. 14 In this study, fingolimod did not uniformly trap effector T cells in all secondary lymphoid organs.…”

Section: Resultsmentioning

confidence: 99%

Successful treatment with fingolimod of graft-versus-host disease of the central nervous system

Gauthier¹,

Vermersch

Chauvet³

et al. 2018

Blood Advances

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Section: Resultsmentioning

confidence: 99%

Successful treatment with fingolimod of graft-versus-host disease of the central nervous system

Gauthier¹,

Vermersch

Chauvet³

et al. 2018

Blood Advances

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“…The administration of FTY720 causes lymphocyte sequestration in the LN and lymphopenia in the peripheral blood after experimental allogeneic BMT 21, 25. We next examined the fate of donor T cells sequestered in SLO.…”

Section: Resultsmentioning

confidence: 99%

FTY720 enhances the activation‐induced apoptosis of donor T cells and modulates graft‐versus‐host disease

et al. 2006

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FTY720 is a novel immunosuppressant that improves the outcomes after solid organ and bone marrow transplantation (BMT) due to the sequestration of T cells into LN. We tested the hypothesis that the sequestration of donor T cells in LN by FTY720 would enhance their interaction with host APC, thus causing a greater degree of activationinduced apoptosis of alloreactive T cells, and thereby resulting in a reduction of graftvs.-host disease (GVHD). The short-term administration of FTY720 improved the recipient survival after allogeneic BMT. FTY720 treatment facilitated a rapid contraction of the donor T cell pool in association with an increased degree of apoptosis of donor T cells. The donor T cell reactivity to host alloantigens was diminished in host's LN and adoptive transfer of donor T cells isolated from LN of FTY720-treated recipients of allogeneic BMT induced less severe GVHD in secondary recipients than the transfer from controls. Caspase-dependent apoptosis was involved in this mechanism because FTY720-induced protection was abrogated when a pan-caspase inhibitor was administered. These findings thus demonstrate the presence of a novel mechanism by which FTY720 modulates the allogeneic T cell responses: namely, by the induction of activation-induced apoptosis of alloreactive T cells in LN.

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“…[8][9][10][11] Accumulating data in animal studies indicate that FTY is a promising immunosuppressive agent for the treatment of various autoimmunities, promotion of engraftment in several models of solid organ transplantation (reviewed in Brinkmann, 1 Brinkmann and Lynch, 2 Chiba, 3 Yopp et al, 4 and Brinkmann et al 12 ), and inhibition of GVHD. [13][14][15] Although the complete mechanism of FTY is not completely understood, most studies implicate an important role for lymph node (LN) trapping as a mechanism of action. It is generally accepted that sequestration of effector T cells in secondary lymphoid organs is associated with a decrease in T-cell migration and infiltration to sites of inflammation, solid organ grafts, or GVHD target organs, thereby ameliorating autoimmunity, solid organ graft rejection, or GVHD.…”

Section: Introductionmentioning

confidence: 99%

Insights into the mechanism of FTY720 and compatibility with regulatory T cells for the inhibition of graft-versus-host disease (GVHD)

Taylor

Ehrhardt

Lees

et al. 2007

Blood

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The immunomodulator FTY720 (FTY) has been shown to be beneficial in experimental models of organ transplantation and autoimmunity. We show that FTY significantly inhibited but did not prevent graftversus-host disease (GVHD) in lethally irradiated or nonirradiated allogeneic recipients. Although most studies implicate prevention of lymphocyte egress from lymphoid organs as the primary mechanism of action, our data indicate that FTY effects on the host are more likely to be responsible for GVHD inhibition. IntroductionDespite advances in the field, graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality in patients undergoing bone marrow transplantation (BMT). In this study, we examine the effect of FTY720 (FTY), a potent immunomodulator, in a murine model of GVHD.FTY, derived from a metabolite of the fungus Isaria sinclairii, is a high-affinity agonist for 4 of the 5 known sphingosine 1-phosphate receptors (S1PRs). S1P 1 is expressed on all cell types, while S1P 3 is found in endothelial cells, S1P 4 is found primarily on lymphoid cells, and S1P 5 is expressed on the white matter of the central nervous system. [1][2][3][4] These receptors are critically involved in cell survival, cytoskeletal rearrangements, cell motility, and cell migration. [1][2][3][4] FTY induces internalization of the receptor, rendering the cells unresponsive to serum lipid S1P that is produced by platelets. 1,5,6 It is generally accepted that FTY exerts its immunomodulatory effects primarily by sequestering lymphocytes within secondary lymphoid organs, thereby denying them the ability to recirculate to peripheral sites of inflammation. FTY is also thought to act on endothelial cells by enhancing the adherens junction assembly, thereby strengthening the endothelial barrier. 7 More recent data indicate that in addition to exhibiting profound effects on lymphocyte migration and endothelial barrier integrity, FTY also modulates dendritic cell (DC) trafficking and function. [8][9][10][11] Accumulating data in animal studies indicate that FTY is a promising immunosuppressive agent for the treatment of various autoimmunities, promotion of engraftment in several models of solid organ transplantation (reviewed in Brinkmann, 1 Brinkmann and Lynch, 2 Chiba, 3 Yopp et al, 4 and Brinkmann et al 12 ), and inhibition of GVHD. [13][14][15] Although the complete mechanism of FTY is not completely understood, most studies implicate an important role for lymph node (LN) trapping as a mechanism of action. It is generally accepted that sequestration of effector T cells in secondary lymphoid organs is associated with a decrease in T-cell migration and infiltration to sites of inflammation, solid organ grafts, or GVHD target organs, thereby ameliorating autoimmunity, solid organ graft rejection, or GVHD.Our studies indicate that FTY inhibits but does not prevent GVHD. In contrast to other studies, we did not find that FTY sequestered effector T cells to secondary lymphoid organs, thereby reducing their migration to GVHD target or...

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Immunosuppressive activity of FTY720, sphingosine 1-phosphate receptor agonist: II. Effect of FTY720 and FTY720-phosphate on host-versus-graft and graft-versus-host reaction in mice

Cited by 15 publications

References 7 publications

Successful treatment with fingolimod of graft-versus-host disease of the central nervous system

Successful treatment with fingolimod of graft-versus-host disease of the central nervous system

FTY720 enhances the activation‐induced apoptosis of donor T cells and modulates graft‐versus‐host disease

Insights into the mechanism of FTY720 and compatibility with regulatory T cells for the inhibition of graft-versus-host disease (GVHD)

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