PT  - JOURNAL ARTICLE
AU  - Pedro J Gonzalez-Cabrera
AU  - Stuart M Cahalan
AU  - Nhan Nguyen
AU  - Gor Sarkisyan
AU  - Nora B Leaf
AU  - Michael Cameron
AU  - Tomoyuki Kago
AU  - Hugh Rosen
TI  - S1P<sub>1</sub> Receptor Modulation with Cyclical Recovery from Lymphopenia Ameliorates Mouse Model of Multiple Sclerosis
AID  - 10.1124/mol.111.076109
DP  - 2011 Oct 26
TA  - Molecular Pharmacology
PG  - mol.111.076109
4099  - http://molpharm.aspetjournals.org/content/early/2011/10/26/mol.111.076109.short
4100  - http://molpharm.aspetjournals.org/content/early/2011/10/26/mol.111.076109.full
AB  - Multiple sclerosis therapies modulate T cell autoimmune pathology in the CNS but may exacerbate latent infections. Fingolimod, a non-selective S1P receptor agonist that induces sustained lymphopenia and accumulates in CNS represents a new modality of MS therapy. We hypothesized that sustained lymphopenia is not required for efficacy and that a selective, CNS-penetrant, but peripherally short-acting S1P1 agonist would show full efficacy in a mouse model of MS. Using daily treatment with 10 mg/kg CYM-5442, at onset of clinical signs in MOG35-55- induced EAE, we assessed clinical scores, CNS cellular infiltration, demyelination and gliosis for 12 days for CYM-5442, vehicle and fingolimod. CYM-5442 levels in CNS and plasma were determined at experiment termination and blood lymphopenia was measured at 3- and 24 h following last injection. Plasma levels of cytokines were assayed at protocol end. Changes in S1P1-eGFP expression on neurons and astrocytes during active EAE and upon CYM-5442 treatment were directly quantified by flow cytometry and Westerns using native-locus-eGFP tagged S1P1 mice. S1P1 agonism alone reduced pathology equivalent to fingolimod (maximally lymphopenic throughout) despite full reversal of lymphopenia within each dosing interval. CYM-5442 levels in CNS were sustained, but not in plasma. Neuronal and astrocytic S1P1 expression in EAE was suppressed by CYM-5442 treatment relative to vehicle mice, whereas key cytokine levels such as IL-17A were also significantly reduced in drug treated mice. S1P1-selective agonists inducing reversible lymphopenia while persisting in CNS may be effective MS treatments while limiting adverse consequences of long-term lymphopenia.