FTY720 alters lymphocyte homing and protects allografts without inducing general immunosuppression

Brinkmann, Volker; Chen, S; Li, Feng; Pinschewer, Daniel D.; Nikolova, Zariana; Hof, Robert P.

doi:10.1016/s0041-1345(00)02126-6

Cited by 85 publications

(64 citation statements)

References 10 publications

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“…41,[45][46][47][48][49] Unlike T cells, FTY720p inhibited the TCR-mediated cytokine production of NKT cells through S1P 1 , whereas it did not regulate the S1P-induced migration of NKT cells in vitro. Furthermore, FTY720 attenuated antibody-induced joint inflammation by suppressing cytokine production in NKT cells, whereas FTY720 minimally inhibited NKT cell infiltration into joint tissues.…”

Section: Discussionmentioning

confidence: 99%

FTY720, a sphingosine 1-phosphate receptor modulator, inhibits CD1d-restricted NKT cells by suppressing cytokine production but not migration

Hwang

Kim

et al. 2010

Laboratory Investigation

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FTY720, a sphingosine 1-phosphate (S1P) receptor modulator, suppresses immune responses by inhibiting T-cell migration into target tissues; however, it does not alter T-cell functions. In this study, we investigated the biological effects of FTY720 on NKT cells. Unlike T cells, FTY720 suppressed the production of IL-4, IFN-g, IL-10, and IL-13 by NKT cells through the S1P1 receptor (S1P 1 ). Moreover, FTY720 also inhibited the expression of T-bet and GATA-3 of NKT cells in the presence of TCR engagement. However, it did not inhibit NKT cell migration in vitro or in vivo. In a K/BxN serum transfer arthritis model, FTY720 suppressed arthritis in B6, but not in CD1d À/À mice. Moreover, the adoptive transfer of control NKT cells restored arthritis in CD1d À/À mice, whereas FTY720-pretreated NKT cells did not. The number of NKT cells in the joints of B6 mice given FTY720 was similar to that in the joints of untreated B6 mice, whereas the production of IL-4 and IFN-g was reduced in the FTY720-treated B6 mice. Taken together, these data show that FTY720 suppresses cytokine production in NKT cells through S1P 1 , but not NKT cell migration. Thus, FTY720 may be useful in the treatment of NKT cell-promoted immune diseases.

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Section: Discussionmentioning

confidence: 99%

FTY720, a sphingosine 1-phosphate receptor modulator, inhibits CD1d-restricted NKT cells by suppressing cytokine production but not migration

Hwang

Kim

et al. 2010

Laboratory Investigation

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“…4 Disruption of the S1P gradient therefore negates a major mechanism for stimulating the movement of lymphocytes from lymph nodes to the peripheral blood and results in a marked lymphopenia. [5][6][7] As such, FTY720 has undergone trials for the prevention of graft rejection for renal transplantation [8][9][10][11][12][13] and for the treatment of autoimmune disorders such as multiple sclerosis, although only the latter application remains viable at this point in time.…”

Section: Introductionmentioning

confidence: 99%

FTY720 produces caspase-independent cell death of acute lymphoblastic leukemia cells

Wallington-Beddoe¹,

Hewson²,

Bradstock³

et al. 2011

Autophagy

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“…10 FTY720, in its phosphorylated in vivo form, shares both structural and functional homology to S1P. 20 FTY720-phosphate targets multiple S1P receptors, including S1P 1 and S1P 3 , with an EC 50 almost identical to that of S1P. 20 Recent studies have shown that the predominant S1P receptor on atrial myocytes is S1P 3 and that FTY720-phosphate can efficiently signal this receptor.…”

mentioning

confidence: 99%

“…20 FTY720-phosphate targets multiple S1P receptors, including S1P 1 and S1P 3 , with an EC 50 almost identical to that of S1P. 20 Recent studies have shown that the predominant S1P receptor on atrial myocytes is S1P 3 and that FTY720-phosphate can efficiently signal this receptor. 21,22 Thus, the current understanding of FTY720's capacity to decrease heart rate is that both S1P and FTY720-phosphate are agonists of S1P 3 receptors on atrial myocytes; this agonism results in slowing of the sinoatrial node via activation of inwardly rectifying G-protein-activated potassium channels 1 and 4 (GIRK1/GIRK4) in atrial myocytes.…”

mentioning

confidence: 99%

FTY720: Placebo‐Controlled Study of the Effect on Cardiac Rate and Rhythm in Healthy Subjects

Schmouder

Serra

Wang

et al. 2006

The Journal of Clinical Pharma

107

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895The purpose of this double-blind, placebo-controlled study was to measure the effects of FTY720, a novel immunomodulator, on heart rate and rhythm in healthy volunteers. Subjects (n = 66) FTY720 is a novel immunomodulator that acts as a sphingosine-1-phosphate (S1P) receptor agonist, thereby reducing the recirculation of lymphocytes to blood and peripheral tissues, including inflammatory lesions and graft sites. [1][2][3][4] In contrast to classic immunosuppressants, FTY720 does not impair cellular or humoral immunity to systemic viral infection and does not affect the activation, expansion, or proliferation of T lymphocytes or immunological memory in preclinical models. 5FTY720 was effective in prolonging allograft survival in preclinical models of cardiac, renal, and hepatic transplantation. 4 Furthermore, a synergistic effect was noted when FTY720 was used in combination with subtherapeutic or therapeutic doses of cyclosporine in a number of different allograft models. 4 The results of phase II clinical studies demonstrated that FTY720 can be used effectively and safely in combination with classic immunosuppressive agents, including cyclosporine 6 and everolimus. 7 FTY720 has been well tolerated in comparative studies conducted in renal transplant recipients to date. However, a recurring finding in these trials has been a reduction in heart rate with initiation of FTY720 treatment. [6][7][8][9] This negative chronotropic effect appears to be temporally associated with the first dose of FTY720. A nadir in heart rate is observed within 4 to 12 hours of drug administration, with heart rate recovering close to baseline within 48 hours after a single dose of FTY720.6-9 The mechanism underlying the effect of FTY720 on heart rate appears to be mediated by its capacity to agonize S1P

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FTY720 alters lymphocyte homing and protects allografts without inducing general immunosuppression

Cited by 85 publications

References 10 publications

FTY720, a sphingosine 1-phosphate receptor modulator, inhibits CD1d-restricted NKT cells by suppressing cytokine production but not migration

FTY720, a sphingosine 1-phosphate receptor modulator, inhibits CD1d-restricted NKT cells by suppressing cytokine production but not migration

FTY720 produces caspase-independent cell death of acute lymphoblastic leukemia cells

FTY720: Placebo‐Controlled Study of the Effect on Cardiac Rate and Rhythm in Healthy Subjects

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