Pharmacodynamics of Single Doses of the Novel Immunosuppressant FTY720 in Stable Renal Transplant Patients

Budde, Klemens; Schmouder, Robert; Nashan, Björn; Brunkhorst, Reinhard; Lücker, Peter Wolfgang; Mayer, Thomas; Brookman, L.; Nedelman, Jerry; Skerjanec, Andrej; Böhler, Torsten; Neumayer, Hans‐Hellmut

doi:10.1034/j.1600-6143.2003.00130.x

Cited by 100 publications

(82 citation statements)

References 22 publications

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“…Resolution of specific receptor contribution within the broad family of lipid G-protein-coupled receptors, of which S1P 1-5 are a subset (30), have been limited by the lack of selective agonist or antagonists, and by the essential role of receptors such as S1P 1 in embryogenesis (31). The need to understand selective receptor contributions becomes more acute with a relatively nonspecific S1P receptor agonist (FTY720) in phase III clinical trials showing significant immunosuppression and transient dose-dependent bradycardia (27,32).…”

Section: Discussionmentioning

confidence: 99%

“…S1P 3 Regulates Heart Rate and Is Not Required for the Induction of Lymphopenia-S1P 1 and S1P 3 are coexpressed in some cells, especially endothelium (7,9). The association of a dose-dependent bradycardia with administration of the relatively non-selective receptor FTY720 in humans (27) led us to study the lymphopenic and heart rate responses that associated with S1P 1 and S1P 3 . Induction of lymphopenia (Fig.…”

Section: Freshly Isolated Lymphocytes From Spleen or Lymph Node Do Nomentioning

confidence: 99%

“…Inhibition of lymphocyte egress is associated with clinically useful immunosuppression in both transplantation and autoimmune disease models (24 -26). Pleiotropic responses at low nanomolar plasma concentrations is seen in this system, because FTY720 mediates both lymphopenia and a transient dose-dependent bradycardia on initial dosing in humans (27). The therapeutic window for S1P receptor agonists may therefore depend on the association of single receptors with critical functions.…”

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confidence: 99%

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Sphingosine 1-Phosphate (S1P) Receptor Subtypes S1P1 and S1P3, Respectively, Regulate Lymphocyte Recirculation and Heart Rate

Sanna

Liao

et al. 2004

Journal of Biological Chemistry

572

524

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Sphingosine 1-phosphate (S1P) influences heart rate, coronary artery caliber, endothelial integrity, and lymphocyte recirculation through five related high affinity G-protein-coupled receptors. Inhibition of lymphocyte recirculation by non-selective S1P receptor agonists produces clinical immunosuppression preventing transplant rejection but is associated with transient bradycardia. Understanding the contribution of individual receptors has been limited by the embryonic lethality of the S1P 1 knock-out and the unavailability of selective agonists or antagonists. A potent, S1P 1 -receptor selective agonist structurally unrelated to S1P was found to activate multiple signals triggered by S1P, including guanosine 5 -3-O-(thio)triphosphate binding, calcium flux, Akt and ERK1/2 phosphorylation, and stimulation of migration of S1P 1 -but not S1P 3 -expressing cells in vitro. The agonist also alters lymphocyte trafficking in vivo. Use of selective agonism together with deletant mice lacking S1P 3 receptor reveals that agonism of S1P 1 receptor alone is sufficient to control lymphocyte recirculation. Moreover, S1P 1 receptor agonist plasma levels are causally associated with induction and maintenance of lymphopenia. S1P 3 , and not S1P 1 , is directly implicated in sinus bradycardia. The sustained bradycardia induced by S1P receptor nonselective immunosuppressive agonists in wild-type mice is abolished in S1P 3 ؊/؊ mice, whereas S1P 1 -selective agonist does not produce bradycardia. Separation of receptor subtype usage for control of lymphocyte recirculation and heart rate may allow the identification of selective immunosuppressive S1P 1 receptor agonists with an enhanced therapeutic window. S1P 1 -selective agonists will be of broad utility in understanding cell functions in vitro, and vascular physiology in vivo, and the success of the chemical approach for S1P 1 suggests that selective tools for the resolution of function across this broad lipid receptor family are now possible.Sphingosine 1-phosphate (S1P), 1 through its high affinity G-protein-coupled receptors, is a physiological mediator with widespread effects upon multiple physiological systems (1). It regulates heart rate (2), coronary artery blood flow (3), blood pressure (4), endothelial integrity in lung (5, 6) and most recently has been shown to regulate the recirculation of lymphocytes (7-11). Many of the physiologically relevant functions occur in the low nanomolar range, including activation of endothelial nitric oxide synthase (12, 13), vasorelaxation (14), and inhibition of thymic egress and lymphocyte recirculation (11). Free plasma levels of S1P are tightly regulated by protein binding to albumin and high density lipoprotein to avoid the deleterious effects of systemic S1P receptor subtype activation at high concentrations of ligand, such as bradycardia and coronary artery vasospasm (3, 15). The choice of S1P, through its receptors, as an acute regulator of the number of blood lymphocytes may represent an interesting evolutionary choice by the immun...

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Section: Discussionmentioning

confidence: 99%

Section: Freshly Isolated Lymphocytes From Spleen or Lymph Node Do Nomentioning

confidence: 99%

mentioning

confidence: 99%

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Sphingosine 1-Phosphate (S1P) Receptor Subtypes S1P1 and S1P3, Respectively, Regulate Lymphocyte Recirculation and Heart Rate

Sanna

Liao

et al. 2004

Journal of Biological Chemistry

572

524

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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).…”

mentioning

confidence: 99%

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

153

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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“…Clinically, FTY720 mediates both lymphopenia and transient dose-dependent bradycardia on initial dosing in humans. 22 Because FTY720 acts through multiple S1P receptors, the mechanism of action through one or more of these receptors may account for its side effects. Thus, more selective S1P receptor modulators are needed to evaluate the roles of the different S1P receptors and their therapeutic efficacy.…”

Section: Introductionmentioning

confidence: 99%

The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment

Cheng

Lin

et al. 2014

Cell Mol Immunol

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FTY720, an agonist for four of the five known sphingosine-1-phosphate (S1P) receptors, has been reported to inhibit acute graft-versus-host disease (aGVHD). Because FTY720 functions through multiple S1P receptors, the mechanism of action through one or more of these receptors may account for its side effects. Thus, more selective S1P receptor modulators are needed to evaluate the roles of different S1P receptors and their therapeutic efficacies. In this study, we investigated the effect of an S1P 1 -selective agonist, CYM-5442, on the progression of aGVHD. We showed that CYM-5442 significantly inhibited but did not prevent aGVHD. CYM-5442 did not affect the infiltration of the donor T cells into the target organs, while the number of macrophages in GVHD organs was significantly reduced by CYM-5442 treatment. In vivo proliferation assays showed that the proliferation of macrophages was not suppressed by CYM-5442. Further studies using human endothelial cells demonstrated that CYM-5442 treatment downregulated CCL2 and CCL7 expression in endothelial cells, therefore reducing the migration of monocytes, from which tissue macrophages originate. Our data demonstrate the therapeutic efficacy of an S1P 1 -selective agonist in aGVHD and its possible mechanism of action. The results suggest that further investigations are needed regarding CYM-5442 as a potential therapeutic regimen for aGVHD.

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Pharmacodynamics of Single Doses of the Novel Immunosuppressant FTY720 in Stable Renal Transplant Patients

Cited by 100 publications

References 22 publications

Sphingosine 1-Phosphate (S1P) Receptor Subtypes S1P1 and S1P3, Respectively, Regulate Lymphocyte Recirculation and Heart Rate

Sphingosine 1-Phosphate (S1P) Receptor Subtypes S1P1 and S1P3, Respectively, Regulate Lymphocyte Recirculation and Heart Rate

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

The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment

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