Abstract
Multiple sclerosis is a demyelinating disease affecting the central nervous system. T cells are known to contribute to this immune-mediated condition. Fingolimod modulates sphingosine-1-phosphate receptors, thereby preventing the egress of lymphocytes, especially CCR7-expressing CD8+ and CD4+ T cells, from lymphoid tissues. Using Affymetrix Human Transcriptome Arrays (HTA 2.0), we performed a transcriptome profiling analysis of CD4+ cells obtained from the peripheral blood of patients with highly active relapsing-remitting multiple sclerosis. The samples were drawn before the first administration of fingolimod as well as 24 hours and 3 months after the start of therapy. Three months after treatment initiation, 890 genes were found to be differentially expressed with fold-change >2.0 and t-test p-value < 0.001, among them several microRNA precursors. A subset of 272 genes were expressed at lower levels, including CCR7 as expected, while 618 genes showed an increase in expression, e.g., CCR2, CX3CR1, CD39, CD58 as well as LYN, PAK1 and TLR2. To conclude, we studied the gene expression of CD4+ cells to evaluate the effects of fingolimod treatment, and we identified 890 genes to be altered in expression after continuous drug administration. T helper cells circulating in the blood during fingolimod therapy present a distinct gene expression signature.
Highlights
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) affecting more than 2.3 million people worldwide
The aim of the present study was the evaluation of differential gene expression in response to fingolimod in CD4+cells obtained from blood samples of remitting form of MS (RRMS) patients in order to achieve a better understanding of MS and the drug’s molecular mechanisms of action
Most RRMS patients showed a benefit from fingolimod treatment
Summary
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) affecting more than 2.3 million people worldwide. It is a common cause of chronic neurological disability in young adults[1,2]. Several disease-modifying therapies with proven clinical benefits are available for the treatment of RRMS. They allow to reduce the rate and severity of relapses and the number of new brain lesions seen in magnetic resonance imaging (MRI)[18,19]. As a structural analogue of natural sphingosine, fingolimod can be phosphorylated to produce fingolimod-phosphate, which binds to S1P receptors expressed on lymphocytes. In the absence of S1P1, CCR7+lymphocytes are unable to override the retention signals in lymphoid tissues[23]
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