Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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, S1P(1) 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 MOG(35-55)- 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 S1P(1)-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 S1P(1) mice. S1P(1) 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 S1P(1) 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. S1P(1)-selective agonists that induce reversible lymphopenia while persisting in the CNS may be effective MS treatments.
 ...
PMID:S1P(1) receptor modulation with cyclical recovery from lymphopenia ameliorates mouse model of multiple sclerosis. 2203 73

Fingolimod, a sphingosine-1-phosphate receptor modulator, inhibits the egress of CCR7-positive lymphocytes, including encephalitogenic lymphocytes, from lymph nodes and may sometimes cause lymphopenia. A recent study reported that varicella zoster virus reactivation occurred in the saliva of 20% of multiple sclerosis (MS) patients treated with fingolimod. I compared the risk of developing herpes zoster between 32 MS patients treated with fingolimod (FTY-MS) and 45 patients, including those with neuromyelitis optica spectrum disorder, horizontal hemianopsia without anti-aquaporin-4 antibodies, and myelitis with anti-myelin oligodendrocyte glycoprotein antibodies, treated with tacrolimus (TCR-NMO). The risk of developing herpes zoster in FTY-MS (40/1,000 patient-years) was significantly higher than that in TCR-NMO (6/1,000 patient-years) (P < 0.0001, odds ratio: 6.90). The incidence of herpes zoster of patients with rheumatoid arthritis treated with Tofacitinib in Asian countries has been shown to be higher than those of patients in the United States or European countries. It may be better to pay more attention to develop herpes zoster in Japanese MS patients treated with fingolimod.
 ...
PMID:The risk of varicella zoster virus infection in multiple sclerosis patients treated with fingolimod. 2701 95