A Monoselective Sphingosine-1-Phosphate Receptor-1 Agonist Prevents Allograft Rejection in a Stringent Rat Heart Transplantation Model

Pan, Shifeng; Mi, Yuan; Pally, Charles; Chen, Alice; Guerini, Danilo; Hinterding, Klaus; Nuesslein‐Hildesheim, Barbara; Tuntland, Tove; Lefebvre, Sophie; Liu, Yi; Gao, Wenqi; Chu, Alan; Brinkmann, Volker; Berthou, Christian; Streiff, Markus; Cannet, Catherine; Cooke, Nigel G.; Gray, Nathanael S.

doi:10.1016/j.chembiol.2006.09.017

Cited by 115 publications

(105 citation statements)

References 35 publications

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“…6B). In accordance with documented lymphopenic response induced by S1P 1 -specific agonists (Sanna et al, 2004;Pan et al, 2006), a single intraperitoneal injection of CYM-5442 induced lymphopenia for least 18 h (data not shown). Despite systemic effects on naive lymphocyte recirculation, intratracheal delivery of CYM-5442 for up to 2 mg/kg i.t.…”

Section: T Cell Suppression By S1p Analog Modulation Of Dcs 899mentioning

confidence: 58%

Local Not Systemic Modulation of Dendritic Cell S1P Receptors in Lung Blunts Virus-Specific Immune Responses to Influenza

et al. 2008

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The mechanism by which locally delivered sphingosine analogs regulate host response to localized viral infection has never been addressed. In this report, we show that intratracheal delivery of the chiral sphingosine analog (R)-2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol (AAL-R) or its phosphate ester inhibits the T-cell response to influenza virus infection. In contrast, neither intraperitoneal delivery of AAL-R nor intratracheal instillation of the nonphosphorylatable stereoisomer AAL-S suppressed virus-specific T-cell response, indicating that in vivo phosphorylation of AAL-R and sphingosine 1-phosphate (S1P) receptor modulation in lungs is essential for immunomodulation. Intratracheal delivery of water-soluble S1P 1 receptor agonist at doses sufficient to induce systemic lymphopenia did not inhibit virus-specific T-cell response, indicating that S1P 1 is not involved in the immunosuppressive activities of AAL-R and that immunosuppression acts independently of naive lymphocyte recirculation. Accumulation of dendritic cells (DCs) in draining lymph nodes was inhibited by intratracheal but not intraperitoneal delivery of AAL-R. Direct modulation of DCs is demonstrated by the impaired ability of virus-infected bone marrow-derived DCs treated in vitro with AAL-R to trigger in vivo T-cell response after adoptive transfer to the airways. Thus, our results suggest that locally delivered sphingosine analogs induce immunosuppression by modulating S1P receptors other than S1P 1 or S1P 2 on dendritic cells in the lungs after influenza virus infection.

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Section: T Cell Suppression By S1p Analog Modulation Of Dcs 899mentioning

confidence: 58%

Local Not Systemic Modulation of Dendritic Cell S1P Receptors in Lung Blunts Virus-Specific Immune Responses to Influenza

et al. 2008

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“…To test this hypothesis, we have examined the clinical efficacy of a small molecule agonist that specifically targets S1P1 receptor activity (AUY954) in the context of SJL/J relapsing-remitting EAE. AUY954 has previously been shown to prevent acute allograft rejection (11), to modulate allergic responses (12), and to reduce neuroinflammation in acute and chronic settings (13,14). We found that AUY954 treatment ameliorated the clinical symptoms of relapsing-remitting EAE in SJL/J mice, concomitant with reduced appearance of cytokine-producing lymphocytes in the CNS.…”

supporting

confidence: 48%

A Sphingosine-1-Phosphate Receptor 1-Directed Agonist Reduces Central Nervous System Inflammation in a Plasmacytoid Dendritic Cell-Dependent Manner

Galicia

Pikor

Schwartz

et al. 2012

The Journal of Immunology

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Gradients of the sphingolipid sphingosine-1-phosphate (S1P) are responsible for the egress of lymphocytes from lymph nodes by activating the S1P1 receptor expressed on the surface of lymphocytes. Small molecule drugs that downregulate S1P receptors induce the sequestration of lymphocytes within lymph nodes, thus preventing lymphocytes from accessing sites of inflammation. In particular, FTY720, a pan-S1P receptor agonist, has been efficacious in the treatment of multiple sclerosis as well as its animal model, experimental autoimmune encephalomyelitis (EAE), by virtue of its ability to restrain lymphocytes within the lymph nodes, thus precluding their migration into the CNS. However, multiple leukocyte subsets express S1P receptors of varying types, and although it is beneficial to prevent transmigration of proinflammatory lymphocytes into the CNS, allowing access of regulatory leukocyte subsets to the CNS is desirable. In this study, we show that an S1P1-specific agonist (AUY954) is clinically efficacious in ameliorating pre-established EAE in SJL/J mice. Efficacy of AUY954 correlated with a reduction of lymphocytes in the CNS, but access of plasmacytoid dendritic cells (pDCs) to the CNS was unimpaired, and the presence of pDCs was found to be an important cofactor in mediating the clinical efficacy of AUY954. These results indicate that pDCs are important in quieting autoimmune responses during EAE, and that trafficking inhibitors that are permissive for pDC accumulation in the CNS may be of therapeutic value for the treatment of multiple sclerosis.

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“…PAR1 antagonist RWJ58259 (5 mg kg -1 ), S1P1/S1P3 agonist AAL(R) (2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol) (0.5 mg kg -1 ) 28 , S1P1 agonist AUY (AUY954) (1 mg kg -1 ) 29 or thrombin inhibitor hirudin (120 mg kg -1 lepirudin, 1 mg kg -1 PEG hirudin) were bolus-injected intravenously. For CLP, mice were anaesthetized (ketamine/xylazine, 100/ 8 mg kg -1 ) to ligate 1 cm of caecum for two punctures (21G needles), confirmed to be patent by extrusion of stool.…”

Section: Methods Summarymentioning

confidence: 99%

Dendritic cell PAR1–S1P3 signalling couples coagulation and inflammation

Niessen¹,

Schaffner²,

Furlan-Freguia³

et al. 2008

Nature

260

257

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Defining critical points of modulation across heterogeneous clinical syndromes may provide insight into new therapeutic approaches. Coagulation initiated by the cytokine-receptor family member known as tissue factor is a hallmark of systemic inflammatory response syndromes in bacterial sepsis and viral haemorrhagic fevers 1,2 , and anticoagulants can be effective in severe sepsis with disseminated intravascular coagulation 3 . The precise mechanism coupling coagulation and inflammation remains unresolved 4-7 . Here we show that protease-activated receptor 1 (PAR1) signalling sustains a lethal inflammatory response that can be interrupted by inhibition of either thrombin or PAR1 signalling. The sphingosine 1-phosphate (S1P) axis is a downstream component of PAR1 signalling, and by combining chemical and genetic probes for S1P receptor 3 (S1P3) we show a critical role for dendritic cell PAR1-S1P3 cross-talk in regulating amplification of inflammation in sepsis syndrome. Conversely, dendritic cells sustain escalated systemic coagulation and are the primary hub at which coagulation and inflammation intersect within the lymphatic compartment. Loss of dendritic cell PAR1-S1P3 signalling sequesters dendritic cells and inflammation into draining lymph nodes, and attenuates dissemination of interleukin-1b to the lungs. Thus, activation of dendritic cells by coagulation in the lymphatics emerges as a previously unknown mechanism that promotes systemic inflammation and lethality in decompensated innate immune responses.Disseminated intravascular coagulation and systemic inflammation are signs of excessive activation of the innate immune system. Both are attenuated by genetic reduction of tissue factor and its protease ligand coagulation factor VIIa, leading to improved survival in endotoxaemia 6,8 . In a model of severe, but not completely lethal lipopolysaccharide (LPS) challenge 9 , we show that PAR1 deficiency protects mice from lethality (Fig. 1a). PAR1 2/2 mice initially developed elevated inflammation and coagulation markers indistinguishable from the wild type (Fig. 1b, c). Unlike the wild type, PAR1 2/2 mice progressively resolved systemic inflammation beginning at 12 h. To address whether coagulation amplifies inflammation signalling. a, Survival advantage of PAR1 2/2 mice in 90% lethal LPS challenge induced by intraperitoneal injection of 8 mg kg -1 LPS (summary of three independent experiments, n $ 28 per genotype, PAR1 2/2 survival advantage for each individual experiment, P , 0.05). b, Reduced late-stage inflammation in PAR1 2/2 mice documented by IL-6 and IL-1b levels (mean 6 s.d., n 5 18 per group, asterisks indicate groups that are different from the wild type (WT), P , 0.05). c, TAT levels in wild-type and PAR1 2/2 mice, or wild-type mice treated at 10 h with PAR1 antagonist RWJ58259 (P1ant) or the thrombin inhibitor hirudin (Hir). d, Intervention with PAR1 antagonist or hirudin improves survival, similarly to PAR1 deficiency (n 5 8 per group, P , 0.02 relative to wild-type control). e, Intervention with P...

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A Monoselective Sphingosine-1-Phosphate Receptor-1 Agonist Prevents Allograft Rejection in a Stringent Rat Heart Transplantation Model

Cited by 115 publications

References 35 publications

Local Not Systemic Modulation of Dendritic Cell S1P Receptors in Lung Blunts Virus-Specific Immune Responses to Influenza

Local Not Systemic Modulation of Dendritic Cell S1P Receptors in Lung Blunts Virus-Specific Immune Responses to Influenza

A Sphingosine-1-Phosphate Receptor 1-Directed Agonist Reduces Central Nervous System Inflammation in a Plasmacytoid Dendritic Cell-Dependent Manner

Dendritic cell PAR1–S1P3 signalling couples coagulation and inflammation

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