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FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system.
Br J Pharmacol. 2009 Nov; 158(5):1173-82.BJ

Abstract

FTY720 (fingolimod) is a first-in-class sphingosine 1-phosphate (S1P) receptor modulator that was highly effective in Phase II clinical trials for Multiple Sclerosis (MS). FTY720 is phosphorylated in vivo by sphingosine kinase-2 to form the active moiety FTY720-phosphate that binds to four of the five G protein-coupled S1P receptor subtypes. Studies using conditional S1P1 receptor-deficient and sphingosine kinase-deficient mice showed that the egress of lymphocytes from lymph nodes requires signalling of lymphocytic S1P1 receptors by the endogenous ligand S1P. The S1P mimetic FTY720-phosphate causes internalization and degradation of cell membrane-expressed S1P1, thereby antagonizing S1P action at the receptor. In models of human MS and demyelinating polyneuropathies, functional antagonism of lymphocytic S1P1 slows S1P-driven egress of lymphocytes from lymph nodes, thereby reducing the numbers of autoaggressive TH17 cells that recirculate via lymph and blood to the central nervous system and the sciatic/ischiatic nerves. Based on its lipophilic nature, FTY720 crosses the blood-brain barrier, and ongoing experiments suggest that the drug also down-modulates S1P1 in neural cells/astrocytes to reduce astrogliosis, a phenomenon associated with neurodegeneration in MS. This may help restore gap-junctional communication of astrocytes with neurons and cells of the blood-brain barrier. Additional effects may result from (down-) modulation of S1P3 in astrocytes and of S1P1 and S1P5 in oligodendrocytes. In conclusion, FTY720 may act through immune-based and central mechanisms to reduce inflammation and support structural restoration of the central nervous system parenchyma. Beyond the autoimmune indications, very recent studies suggest that short-term, low-dose administration of FTY720 could help treat chronic (viral) infections. Differential effects of the drug on the trafficking of naïve, central memory and effector memory T cell subsets are discussed.

Authors+Show Affiliations

Autoimmunity, Transplantation & Inflammation, Novartis Institutes for BioMedical Research, Basel, Switzerland. volker.brinkmann@novartis.com

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

19814729

Citation

Brinkmann, Volker. "FTY720 (fingolimod) in Multiple Sclerosis: Therapeutic Effects in the Immune and the Central Nervous System." British Journal of Pharmacology, vol. 158, no. 5, 2009, pp. 1173-82.
Brinkmann V. FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharmacol. 2009;158(5):1173-82.
Brinkmann, V. (2009). FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system. British Journal of Pharmacology, 158(5), 1173-82. https://doi.org/10.1111/j.1476-5381.2009.00451.x
Brinkmann V. FTY720 (fingolimod) in Multiple Sclerosis: Therapeutic Effects in the Immune and the Central Nervous System. Br J Pharmacol. 2009;158(5):1173-82. PubMed PMID: 19814729.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system. A1 - Brinkmann,Volker, Y1 - 2009/10/08/ PY - 2009/10/10/entrez PY - 2009/10/10/pubmed PY - 2010/2/13/medline SP - 1173 EP - 82 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 158 IS - 5 N2 - FTY720 (fingolimod) is a first-in-class sphingosine 1-phosphate (S1P) receptor modulator that was highly effective in Phase II clinical trials for Multiple Sclerosis (MS). FTY720 is phosphorylated in vivo by sphingosine kinase-2 to form the active moiety FTY720-phosphate that binds to four of the five G protein-coupled S1P receptor subtypes. Studies using conditional S1P1 receptor-deficient and sphingosine kinase-deficient mice showed that the egress of lymphocytes from lymph nodes requires signalling of lymphocytic S1P1 receptors by the endogenous ligand S1P. The S1P mimetic FTY720-phosphate causes internalization and degradation of cell membrane-expressed S1P1, thereby antagonizing S1P action at the receptor. In models of human MS and demyelinating polyneuropathies, functional antagonism of lymphocytic S1P1 slows S1P-driven egress of lymphocytes from lymph nodes, thereby reducing the numbers of autoaggressive TH17 cells that recirculate via lymph and blood to the central nervous system and the sciatic/ischiatic nerves. Based on its lipophilic nature, FTY720 crosses the blood-brain barrier, and ongoing experiments suggest that the drug also down-modulates S1P1 in neural cells/astrocytes to reduce astrogliosis, a phenomenon associated with neurodegeneration in MS. This may help restore gap-junctional communication of astrocytes with neurons and cells of the blood-brain barrier. Additional effects may result from (down-) modulation of S1P3 in astrocytes and of S1P1 and S1P5 in oligodendrocytes. In conclusion, FTY720 may act through immune-based and central mechanisms to reduce inflammation and support structural restoration of the central nervous system parenchyma. Beyond the autoimmune indications, very recent studies suggest that short-term, low-dose administration of FTY720 could help treat chronic (viral) infections. Differential effects of the drug on the trafficking of naïve, central memory and effector memory T cell subsets are discussed. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/19814729/FTY720__fingolimod__in_Multiple_Sclerosis:_therapeutic_effects_in_the_immune_and_the_central_nervous_system_ L2 - https://doi.org/10.1111/j.1476-5381.2009.00451.x DB - PRIME DP - Unbound Medicine ER -