S1P1 Receptor Modulation with Cyclical Recovery from Lymphopenia Ameliorates Mouse Model of Multiple Sclerosis
- Pedro J. Gonzalez-Cabrera,
- Stuart M. Cahalan,
- Nhan Nguyen,
- Gor Sarkisyan,
- Nora B. Leaf,
- Michael D. Cameron,
- Tomoyuki Kago1 and
- Hugh Rosen
- Departments of Chemical Physiology (P.J.G.C., S.M.C., N.N., G.S., N.B.L., T.K., H.R.) and Immunology (S.M.C.), The Scripps Research Institute, La Jolla, California; and Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida (M.D.C.)
- Address correspondence to:
Dr Hugh Rosen, Department of Chemical Physiology, Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. E-mail: hrosen{at}scripps.edu
-
P.J.G.C. and S.M.C. contributed equally to this work.
Abstract
Multiple sclerosis (MS) therapies modulate T-cell autoimmunity in the central nervous system (CNS) but may exacerbate latent infections. Fingolimod, a nonselective sphingosine-1-phosphate (S1P) receptor agonist that induces sustained lymphopenia and accumulates in the CNS, represents a new treatment modality for MS. We hypothesized that sustained lymphopenia would not be required for efficacy and that a selective, CNS-penetrant, peripherally short-acting, S1P1 agonist would show full efficacy in a mouse MS model. Using daily treatment with 10 mg/kg 2-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl amino)ethanol (CYM-5442) at the onset of clinical signs in myelin oligodendrocyte glycoprotein MOG35–55- induced experimental allergic encephalomyelitis (EAE), we assessed clinical scores, CNS cellular infiltration, demyelination, and gliosis for 12 days with CYM-5442, vehicle, or fingolimod. CYM-5442 levels in CNS and plasma were determined at experiment termination, and blood lymphopenia was measured 3 and 24 h after the last injection. Plasma levels of cytokines were assayed at the end of the protocol. Changes in S1P1-enhanced green fluorescent protein expression on neurons and astrocytes during active EAE and upon CYM-5442 treatment were quantified with flow cytometry and Western blotting by using native-locus enhanced green fluorescent protein-tagged S1P1 mice. S1P1 agonism alone reduced pathological features as did fingolimod (maximally lymphopenic throughout), despite full reversal of lymphopenia within each dosing interval. CYM-5442 levels in CNS but not in plasma were sustained. Neuronal and astrocytic S1P1 expression in EAE was suppressed by CYM-5442 treatment, relative to vehicle, and levels of key cytokines, such as interleukin 17A, were also significantly reduced in drug-treated mice. S1P1-selective agonists that induce reversible lymphopenia while persisting in the CNS may be effective MS treatments.
Footnotes
-
H.R. is a cofounder of Receptos, Inc.
-
↵
The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
-
This work was supported by the National Institutes of Health National Institute of Allergy and Infectious Diseases [Grants U01-AI074564, R01-AI055509] and the National Institutes of Health National Institute of Mental Health [Grant U54-MH084512].
-
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
-
ABBREVIATIONS:
- MS
- multiple sclerosis
- CNS
- central nervous system
- PBS
- phosphate-buffered saline
- PE
- phycoerythrin
- APC
- antigen-presenting cell
- S1P
- sphingosine-1-phosphate
- MOG
- myelin oligodendrocyte glycoprotein
- EAE
- experimental allergic encephalomyelitis
- eGFP
- enhanced green fluorescent protein
- PTX
- pertussis toxin
- LFB
- Luxol fast blue
- CYM-5442
- 2-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl amino)ethanol
- RP-001
- N-[4-[5-[3-cyano-4-(1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-iden-1-yl]-β-alanine.
- Received September 27, 2011.
- Accepted October 26, 2011.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
