Prevention of autoimmune diabetes by FTY720 in nonobese diabetic mice

Maki, Takashi; Gottschalk, Rita; Monaco, Anthony P.

doi:10.1097/00007890-200212270-00006

Cited by 48 publications

(37 citation statements)

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“…An example of this is FTY720, a sphingosine-like lipid that has been shown to prolong allograft survival (15)(16)(17)(18)(19)(20)(21)(22) and is efficacious in autoimmune disease models such as experimental autoimmune encephalomyelitis (1,23) and the non-obese diabetic mouse (24,25). Recent reports demonstrate that FTY720 is a pro-drug; the immunomodulatory effect associated with its administration requires phosphorylation (1, 2, 26).…”

Section: Discussionmentioning

confidence: 99%

Sphingosine 1-Phosphate Analogs as Receptor Antagonists

Davis

Clemens

Macdonald

et al. 2005

Journal of Biological Chemistry

257

229

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Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator that evokes a variety of cell and tissue responses via a set of cell surface receptors. The recent development of S1P receptor agonists, led by the immunomodulatory pro-drug FTY720, has revealed that S1P signaling is an important regulator of lymphocyte trafficking. With the twin goals of understanding structureactivity relationships of S1P ligands and developing tool compounds to explore S1P biology, we synthesized and tested numerous S1P analogs. We report herein that a subset of our aryl amide-containing compounds are antagonists at the S1P 1 and S1P 3 receptors. The lead compound in the series, VPC23019, was found in broken cell and whole cell assays to behave as a competitive antagonist at the S1P 1 and S1P 3 receptors. The structureactivity relationship of this series is steep; for example, a slight modification of the lead compound resulted in VPC25239, which was one log order more potent at the S1P 3 receptor. These new chemical entities will enable further understanding of S1P signaling and provide leads for further S1P receptor antagonist development. Sphingosine 1-phosphate (S1P)1 is a lysophospholipid mediator that evokes a variety of cellular responses by stimulation of five members of the endothelial cell differentiation gene receptor family. The endothelial cell differentiation gene receptors are G-protein coupled receptors that, upon stimulation, propagate second messenger signals via activation of heterotrimeric G-protein ␣ subunits and ␤-␥ dimers. Ultimately, this S1P-driven signaling results in cell survival, increased cell migration, and, often, mitogenesis. The recent development of agonists targeting S1P receptors has provided insight regarding the role of this signaling system in physiologic homeostasis. For example, the immunomodulator FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol), which is a pan S1P receptor agonist following phosphorylation, revealed that S1P tone influences lymphocyte trafficking (1-4). The utility of an S1P receptor agonist was unexpected; indeed, prior speculation focused on the potential (as yet unrealized) for S1P antagonists as anti-angiogenic agents.Recent findings also suggest a physiological influence for S1P in the vasculature.Although not yet explored in detail, it has been hypothesized that S1P may exert anti-inflammatory actions on endothelial cells through its release from high density lipoprotein (5). A recent study found that S1P inhibited tumor necrosis factor ␣-mediated monocyte-endothelial cell adhesion.2 Furthermore, an S1P 1 receptor antagonist described herein blocked the anti-inflammatory action of S1P, thereby providing evidence that this effect maps to the S1P 1 receptor. If verified, these results would expand the role of the S1P 1 receptor to include influencing monocyte extravasation and would further highlight how the development of S1P receptor-specific compounds is expanding our understanding of the biology of this important signaling system.To further characterize ...

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Section: Discussionmentioning

confidence: 99%

Sphingosine 1-Phosphate Analogs as Receptor Antagonists

Davis

Clemens

Macdonald

et al. 2005

Journal of Biological Chemistry

257

229

View full text Add to dashboard Cite

show abstract

“…Support for the idea that LVs in TLOs serve an efferent function comes from the observation that continual administration of FTY720, an S1P receptor agonist that blocks lymphocyte egress from LNs (52), prevents diabetes in NOD mice (53). This is only effective if the mice have already developed pancreatic TLOs (23).…”

Section: Functions Of Lvs In Tlosmentioning

confidence: 99%

Lymphatic vessels and tertiary lymphoid organs

Ruddle¹

2014

J. Clin. Invest.

158

124

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“…Significantly, CD69 suppresses sphingosine 1-phosophate receptor-1 (S1P1) function [116]. S1P1 plays a critical role in lymphocyte recirculation; its pharmaceutical downmodulation by the agonist fingolimod sequesters lymphocytes in lymph nodes, preventing diabetes in NOD mice [117][118].…”

Section: Cd69mentioning

confidence: 99%

From Markers to Molecular Mechanisms: Type 1 Diabetes in the Post-GWAS Era

Baxter

Jordan²

2012

Rev Diabet Stud

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■ AbstractBy the year 2000, a draft of the human genome sequence was completed. Millions of single-nucleotide polymorphisms (SNPs) had been deposited into public databases, and high throughput technologies were under development for SNP genotyping. At that time, it was predicted that large case control association studies would provide far better resolution and power than genome-wide linkage studies. Type 1 diabetes was one of the first phenotypes to be examined by genome-wide association studies (GWAS), and to date over 50 genomic regions have been associated with the disease.In general, the great majority of these loci individually contribute a relatively small degree of risk, and most loci lie outside of coding sequences. The identification of molecular mechanisms from these genomic data therefore remains a significant challenge. Here, we summarize genetic candidate, linkage, and association studies of type 1 diabetes and discuss a potential strategy to identify mechanisms of disease from genomic data.

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Prevention of autoimmune diabetes by FTY720 in nonobese diabetic mice

Abstract: FTY720 is a safe and benign therapeutic agent that may be used chronically in prediabetic individuals.

Cited by 48 publications

References 0 publications

Sphingosine 1-Phosphate Analogs as Receptor Antagonists

Sphingosine 1-Phosphate Analogs as Receptor Antagonists

Lymphatic vessels and tertiary lymphoid organs

From Markers to Molecular Mechanisms: Type 1 Diabetes in the Post-GWAS Era

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