Prevention and Cure of Autoimmune Diabetes in Nonobese Diabetic Mice by Continuous Administration of FTY720

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

doi:10.1097/01.tp.0000161220.87548.ee

Cited by 67 publications

(64 citation statements)

References 13 publications

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“…This is only effective if the mice have already developed pancreatic TLOs (23). Treatment results in additional accumulation of lymphocytes in the pancreatic TLOs, which is reversed upon cessation, resulting in rapid islet destruction and diabetes (23,54). These data suggest that lymphocyte trafficking through LVs in TLOs in NOD mice occurs under the control of the lymph S1P gradient and re-expression of its receptor by T cells, as occurs in LNs.…”

Section: Functions Of Lvs In Tlosmentioning

confidence: 93%

Lymphatic vessels and tertiary lymphoid organs

Ruddle¹

2014

J. Clin. Invest.

158

124

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Section: Functions Of Lvs In Tlosmentioning

confidence: 93%

Lymphatic vessels and tertiary lymphoid organs

Ruddle¹

2014

J. Clin. Invest.

158

124

View full text Add to dashboard Cite

“…At high concentrations, FTY720 (fingolimod) also affects S1PL (17), but its main target is S1P receptor 1 (S1P1) (18). FTY720 administration has proved beneficial in experimental disease models (19)(20)(21)(22)(23), and recently in human clinical trials of relapsing multiple sclerosis (24). Both S1P and FTY720 result in S1P1 internalization and recycling (25,26), FTY720 being a more efficient inducer of receptor degradation (27).…”

Section: Introductionmentioning

confidence: 99%

S1P Is Associated with Protection in Human and Experimental Cerebral Malaria

Finney

Hawkes

Kain

et al. 2011

Mol Med

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Cerebral malaria (CM) is associated with excessive inflammatory responses and endothelial activation. Sphingosine 1-phosphate (S1P) is a signaling sphingolipid implicated in regulating vascular integrity, inflammation and T-cell migration. We hypothesized that altered S1P signaling during malaria contributes to endothelial activation and inflammation, and show that plasma S1P levels were decreased in Ugandan children with CM compared with children with uncomplicated malaria. Using the Plasmodium berghei ANKA (PbA) model of experimental CM (ECM), we demonstrate that humanized S1P lyase (hS1PL) -/-mice with reduced S1P lyase activity (resulting in increased bio-available S1P) had improved survival compared with wild-type littermates. Prophylactic and therapeutic treatment of infected mice with compounds that modulate the S1P pathway and are in human trials for other conditions (FTY720 or LX2931) significantly improved survival in ECM. FTY720 treatment improved vascular integrity as indicated by reduced levels of soluble intercellular adhesion molecule (sICAM), increased angiopoietin 1 (Ang1) (regulator of endothelial quiescence) levels, and decreased Evans blue dye leakage into brain parenchyma. Furthermore, treatment with FTY720 decreased IFNγ levels in plasma as well as CD4 + and CD8 + T-cell infiltration into the brain. Finally, when administered during infection in combination with artesunate, FTY720 treatment resulted in increased survival to ECM. These findings implicate dysregulation of the S1P pathway in the pathogenesis of human and murine CM and suggest a novel therapeutic strategy to improve clinical outcome in severe malaria.

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“…This impairs the ability of lymphocytes to respond to the proposed S1P gradient (Gonzalez-Cabrera et al, 2007;Oo et al, 2007). S1P receptor modulating compounds such as FTY-P have found application in a wide variety of experimental settings, which include immunosuppression during organ transplant (Pan et al, 2006;Brinkmann, 2007), treatment of autoimmune conditions (Fujino et al, 2003;Maki et al, 2005), recovery after ischemia/reperfusion injury (Hofmann et al, 2009), and as a means of increasing endothelial barrier function (Sanna et al, 2006). In the clinic, there have been trials of FTY720 in patients undergoing kidney transplant and patients with multiple sclerosis (Brinkmann, 2007).…”

Section: Introductionmentioning

confidence: 99%

Elimination of a Hydroxyl Group in FTY720 Dramatically Improves the Phosphorylation Rate

et al. 2010

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The new immunosuppressant FTY720 (fingolimod), an analog of the endogenous lipid sphingosine, induces transient lymphopenia through the sequestration of lymphocytes in secondary lymphoid organs. Phosphorylation of FTY720 by sphingosine kinase 2 (SphK2) yields the active metabolite FTY720-phosphate (FTY-P), which induces lymphopenia through agonism of the sphingosine 1-phosphate receptor S1P 1 on endothelial cells and lymphocytes. Dephosphorylation of circulating FTY-P creates an equilibrium between FTY720 and its phosphate, and results with human patients indicate that phosphorylation of FTY720 could be rate limiting for efficacy. We report that the FTY720 derivative 2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol [AAL(R)] is phosphorylated much more rapidly than FTY720 in cultured human cells and whole blood. The K cat for AAL(R) with recombinant SphK2 is 8-fold higher than for FTY720, whereas the K m for the two substrates is very similar, indicating that the increased rate of phosphorylation results from faster turnover by SphK2 rather than a higher binding affinity. Consequently, treating cells with AAL(R), but not FTY720, triggers an apoptotic pathway that is dependent on excessive intracellular accumulation of long-chain base phosphates. In agreement with the in vitro results, phosphorylation of AAL(R) is more complete than that of FTY720 in vivo (mice), and AAL(R) is a more potent inducer of lymphopenia. These differences may be magnified in humans, because phosphorylation of FTY720 is much less efficient in humans compared with rodents. Our results suggest that AAL(R) is a better tool than FTY720 for in vivo studies with S1P analogs and would probably be a more effective immunosuppressant than FTY720.

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Prevention and Cure of Autoimmune Diabetes in Nonobese Diabetic Mice by Continuous Administration of FTY720

Abstract: FTY720, which does not cause generalized immunosuppression, may be a safe and benign therapeutic agent for chronic use to prevent or cure type 1 diabetes.

Cited by 67 publications

References 13 publications

Lymphatic vessels and tertiary lymphoid organs

Lymphatic vessels and tertiary lymphoid organs

S1P Is Associated with Protection in Human and Experimental Cerebral Malaria

Elimination of a Hydroxyl Group in FTY720 Dramatically Improves the Phosphorylation Rate

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