Abstract
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. 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. 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 months of treatment in responder and NR patients. Patients who achieved a good response to the drug compared to NR patients exhibited higher percentages of NK bright cells and plasmablasts, higher levels of FOXP3, glucose phosphate isomerase, lower levels of FCRL1, and lower Expanded Disability Status Scale at baseline. The combination of these possible markers enabled us to build a probabilistic linear model to predict the clinical response to fingolimod. MS patients responsive to fingolimod exhibit a recognizable distribution of lymphocyte subpopulations and a different pretreatment gene expression signature that might be useful as a biomarker.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS)
A transitory increase in the annualized relapse rate (ARR) and the number of gadolinium-enhanced T1 lesions (GdE) lesions in the NTZ group was observed through the first year, but at 2 years these variables were decreased with no differences between the subgroups
When the gene expression profile was compared at 6 months between subgroups to determine the differential effect of fingolimod according to the clinical response, we found 6 differentially expressed genes (DEGs) in responder vs NR patients at 1 year and 51 DEGs at 2 years
Summary
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). It is known that MS patients have a higher number of autoreactive T and B cells as well as fewer regulatory T cells (Tregs) [2] and B1 cells [3] than healthy controls (HC) in peripheral blood Such therapies as fingolimod (Gilenya®), a functional sphingosine-1-phosphate (S1P) antagonist, have been developed to retain the autoreactive lymphocytes within the lymph nodes [4, 5]. 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
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