Immunophenotype and Transcriptome Profile of Patients With Multiple Sclerosis Treated With Fingolimod: Setting Up a Model for Prediction of Response in a 2-Year Translational Study

作者：Irene Moreno‐Torres, Coral González‐García, M. Marconi, Aránzazu García‐Grande, Luis Rodríguez‐Esparragoza, V́ıctor Elvira, Elvira Ramil, Lucía Campos-Ruíz, Ruth García-Hernández, Fátima Al‐Shahrour, Coral Fustero‐Torre, Alicia Sánchez-Sanz, Antonio García‐Merino, Antonio José Sánchez López · 发表于：Frontiers in Immunology · 年份：2018 · DOI：10.3389/fimmu.2018.01693 · 被引用次数：41 · 研究领域：Multiple Sclerosis Research Studies、Sphingolipid Metabolism and Signaling、Immune Response and Inflammation

BACKGROUND: Fingolimod is a functional sphingosine-1-phosphate antagonist approved for the treatment of multiple sclerosis (MS). Fingolimod affects lymphocyte subpopulations and regulates gene expression in the lymphocyte transcriptome. Translational studies are necessary to identify cellular and molecular biomarkers that might be used to predict the clinical response to the drug. In MS patients, we aimed to clarify the differential effects of fingolimod on T, B, and natural killer (NK) cell subsets and to identify differentially expressed genes in responders and non-responders (NRs) to treatment. MATERIALS AND METHODS: Samples were obtained from relapsing-remitting multiple sclerosis patients before and 6 months after starting fingolimod. Forty-eight lymphocyte subpopulations were measured by flow cytometry based on surface and intracellular marker analysis. Transcriptome sequencing by next-generation technologies was used to define the gene expression profiling in lymphocytes at the same time points. NEDA-3 (no evidence of disease activity) and NEDA-4 scores were measured for all patients at 1 and 2 years after beginning fingolimod treatment to investigate an association with cellular and molecular characteristics. RESULTS: Fingolimod affects practically all lymphocyte subpopulations and exerts a strong effect on genetic transcription switching toward an anti-inflammatory and antioxidant response. Fingolimod induces a differential effect in lymphocyte subpopulations after 6...