Abstract
Biomarkers predicting fingolimod (FTY) treatment response in relapsing-remitting multiple sclerosis (RRMS) are lacking. Here, we performed extensive functional immunophenotyping using multiparametric flow cytometry to examine peripheral immune changes under FTY treatment and explore biomarkers of FTY treatment response. From among 135 RRMS patients who initiated FTY in a 2-year multicentre observational study, 36 were classified as ‘Active’ or ‘Stable’ based on clinical and/or radiological activity on-treatment. Flow cytometric analysis of immune cell subsets was performed on pre- and on-treatment peripheral blood mononuclear cells (PBMC) samples. Decreased absolute counts of B cells and most T-cell subsets were seen on-treatment. Senescent CD8 + T cells, CD56 + T cells, CD56dim natural killer cells, monocytes and dendritic cells were not reduced in number and hence relatively increased in frequency on-treatment. An unbiased multiparametric and traditional manual analysis of T-cell subsets suggested a higher pre-treatment frequency of CD4 + central memory T cells (TCM) in patients who were subsequently Active versus Stable on-treatment. Lower pre-treatment terminally differentiated effector memory (TEMRA) cell frequencies were also seen in the subsequently Active cohort. Together, our data highlight differential effects of FTY on peripheral immune cell subsets and suggest that pre-treatment T-cell subset frequencies may have value in predicting FTY treatment response.
Highlights
Biomarkers predicting fingolimod (FTY) treatment response in relapsing-remitting multiple sclerosis (RRMS) are lacking
This sequestration is believed to reduce the migration of pathogenic T cells into the central nervous system (CNS) of MS patients[2,3], the degree of FTY treatment response has not been found to correlate with the degree of overall lymphopenia induced by treatment
In this prospective study we examined FTY’s effects on a range of immune cell subsets and explored potential immune biomarkers of treatment response
Summary
Biomarkers predicting fingolimod (FTY) treatment response in relapsing-remitting multiple sclerosis (RRMS) are lacking. Our data highlight differential effects of FTY on peripheral immune cell subsets and suggest that pre-treatment T-cell subset frequencies may have value in predicting FTY treatment response. FTY causes internalization of the S1P1 receptor resulting in immune cell sequestration within LNs2 This sequestration is believed to reduce the migration of pathogenic T cells into the central nervous system (CNS) of MS patients[2,3], the degree of FTY treatment response has not been found to correlate with the degree of overall lymphopenia (total lymphocyte counts; TLC) induced by treatment. Rare but serious drug-related adverse events have emerged over time with the use of FTY in MS patients, including cases of cryptococcal meningitis, progressive multifocal leukoencephalopathy and immune thrombocytopenic purpura[7,8,9] Biomarkers predicting such adverse events or distinguishing patients who respond well or poorly to FTY would be of great clinical value but are yet to be discovered. Heterogeneity in baseline type I interferon (IFN) and Th17 activity may explain variability in IFN-β responsiveness[10,11]
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