Abstract

Sphingosine 1-phosphate (S1P), a multi-functional phospholipid mediator, is generated from sphingosine by sphingosine kinases and binds to five known G protein-coupled S1P receptors (S1P<sub>1</sub>, S1P<sub>2</sub>, S1P<sub>3</sub>, S1P<sub>4</sub>, and S1P<sub>5</sub>). It is widely accepted that S1P receptor 1 (S1P<sub>1</sub>) plays an essential role in lymphocyte egress from the secondary lymphoid organs (SLO) and thymus, because lymphocyte egress from these organs to periphery is at extremely low levels in mice lacking lymphocytic S1P<sub>1</sub>. Fingolimod hydrochloride (FTY720) is a first-in-class, orally active S1P<sub>1</sub> functional antagonist which was discovered by chemical modification of a natural product, myriocin. Since FTY720 has a structure closely related to sphingosine, the phosphorylated FTY720 (FTY720-P) is converted by sphingosine kinases and binds 4 types of S1P receptors. FTY720-P strongly induces down-regulation of S1P<sub>1</sub> by internalization and degradation of this receptor and acts as a functional antagonist at S1P<sub>1</sub>. Consequently, FTY720 inhibits S1P<sub>1</sub>-dependent lymphocyte egress from the SLO and thymus to reduce circulating lymphocytes including autoreactive Th17 cells, and is highly effective in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In relapsing remitting MS patients, oral FTY720 shows a superior efficacy when compared to intramuscular interferon-β-1a. Based on these data, it is presumed that modulation of the S1P-S1P<sub>1</sub> axis provides an effective therapy for autoimmune diseases including MS.

Highlights

  • An immunosuppressive natural product, (2S,3R,4R)-(E)-2-amino-3,4-dihydroxy-2-(hydroxymethyl)-14-oxoeicos-6-enoic acid, (Figure 1) was isolated from cultures of Isaria sinclairii, a type of entomopathogenic fungus that is an "eternal youth" nostrum in traditional Chinese medicine [1]

  • The development of EAE induced by myelin proteolipid protein (PLP) in SJL/J mice is almost completely prevented by prophylactic treatment with FTY720 or FTY720-P; and infiltration of CD4 T cells into the spinal cord is decreased [61,62]

  • FTY720 is a first-in-class S1P receptor 1 (S1P1) functional antagonist which was discovered by chemical modification of a natural product

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Summary

AIMS Molecular Science

Received date 29 July 2014, Accepted date 19 November 2014, Published date 25 November 2014. S1P receptor 1 functional antagonist in lymphocyte circulation and autoimmune diseases. Kenji Chiba *, Yasuhiro Maeda, Noriyasu Seki, Hirotoshi Kataoka, and Kunio Sugahara. Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan

Introduction
S1P and S1P receptors in lymphocyte circulation
FTY720 acts as a functional antagonist at S1P1
Role of the S1P-S1P1 axis in the thymic egress
Role of the S1P-S1P1 axis in mature lymphocyte egress from bone marrow
Therapeutic effects of FTY720 on EAE
Role of the S1P-S1P1 axis in trafficking of Th17 and Th1 cells in EAE
Role of the S1P-S1P1 axis in astrocytes activation in EAE
Therapeutic effects of FTY720 on other autoimmune disease models
Phase 1 studies of FTY720
Phase 2 clinical trials of FTY720 in relapsing MS patients
Phase 3 clinical studies of FTY720 in relapsing remitting MS patients
Therapeutic potentials of S1P1 functional antagonists in autoimmune diseases
Findings
Conclusions
Full Text
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