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February 21, 2011

Sphingosine 1-phosphate (S1P)
Physiology and the effects of S1P receptor modulation

February 22, 2011 issue
76 (8_supplement_3) S3-S8

Abstract

Sphingosine 1-phosphate (S1P) and 5 specific high-affinity S1P receptor (S1PR) subtypes, S1P1–5, have important regulatory functions in normal physiology and disease processes, particularly involving the immune, central nervous, and cardiovascular systems. Within the immune system, downmodulation of S1P1 prevents the egress of B and T cells from lymph nodes (LN) into the lymphatic circulation. This is especially relevant in certain autoimmune diseases, including multiple sclerosis (MS), in which demyelination and brain atrophy occur due to the presence of autoreactive lymphocytes within the CNS. Accordingly, S1P1-directed pharmacologic interventions that aim to retain these autoreactive lymphocytes in the LN and thus prevent their recirculation and subsequent infiltration into the CNS have been investigated as a means of preventing disease progression in patients with MS. Fingolimod (FTY720), a structural analog of sphingosine, is phosphorylated in vivo into fingolimod phosphate by sphingosine kinase-2. Fingolimod phosphate, which binds to S1PRs, has been shown to modulate the activity of S1P1 in patients with MS and to reduce immune cell infiltration into the CNS, consistent with its previously established effects in animal models of the disease. Preclinical studies also suggest that fingolimod has beneficial effects within the CNS that are independent of its immune cell trafficking activity. This review highlights the normal physiologic processes modulated by S1P and S1PRs, and the therapeutic effects of S1PR modulation in the immune, central nervous, and cardiovascular systems.

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Information & Authors

Information

Published In

Neurology®
Volume 76Number 8_supplement_3February 22, 2011
Pages: S3-S8
PubMed: 21339489

Publication History

Published online: February 21, 2011
Published in print: February 22, 2011

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Disclosure

Dr. Hla has served as a paid consultant for Novartis, Allozyne Inc., Connecticut Children's Medical Center, Wilmer Hale LLC, and Sidley Austin LLC; has served as Editor-in-Chief of Prostaglandins & Other Lipid Mediators; has patents on methods for inhibiting vascular permeability and apoptosis, sphingosine phosphate receptors in abnormal angiogenesis of the eye, and sphingosine 1-phosphate receptors in atherosclerosis; and has received research support from the NIH. Dr. Brinkmann is an employee of Novartis Institutes for Biological Research. Dr. Hla holds a Professorship at Weill Cornell Medical College.

Authors

Affiliations & Disclosures

Timothy Hla, PhD
From the Center for Vascular Biology (T.H.), Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, NY; and Autoimmunity, Transplantation & Inflammation (V.B.), Novartis Institutes for BioMedical Research, Basel, Switzerland.
Volker Brinkmann, PhD
From the Center for Vascular Biology (T.H.), Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, NY; and Autoimmunity, Transplantation & Inflammation (V.B.), Novartis Institutes for BioMedical Research, Basel, Switzerland.

Notes

Address correspondence to Dr. Timothy Hla, Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065 [email protected]
Study funding: Supported by NIH grants HL67330, HL70694, and HL89934.
This Neurology® supplement is not peer-reviewed. Information contained in this Neurology® supplement represents the opinions of the authors. These opinions are not endorsed by nor do they reflect the views of the American Academy of Neurology, Editor-in-Chief, or Associate Editors of Neurology®.

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