Peripheral Blood T Cell Dynamics Predict Relapse in Multiple Sclerosis Patients on Fingolimod

BACKGROUND: Fingolimod efficiently reduces multiple sclerosis (MS) relapse by inhibiting lymphocyte egress from lymph nodes through down-modulation of sphingosine 1-phosphate (S1P) receptors. We aimed to clarify the alterations in peripheral blood T cell subsets associated with MS relapse on fingolimod. METHODS/PRINCIPAL FINDINGS: Blood samples successively collected from 23 relapsing-remitting MS patients before and during fingolimod therapy (0.5 mg/day) for 12 months and 18 healthy controls (HCs) were analysed for T cell subsets by flow cytometry. In MS patients, the percentages of central memory T (CCR7(+)CD45RO(+)) cells (TCM) and naïve T (CCR7(+)CD45RO(-)) cells decreased significantly, while those of effector memory T (CCR7(-)CD45RA(-)) and suppressor precursor T (CD28(-)) cells increased in both CD4(+)T and CD8(+)T cells from 2 weeks to 12 months during fingolimod therapy. The percentages of regulatory T (CD4(+)CD25(high)CD127(low)) cells in CD4(+)T cells and CCR7(-)CD45RA(+)T cells in CD8(+)T cells also increased significantly. Eight relapsed patients demonstrated greater percentages of CD4(+)TCM than 15 non-relapsed patients at 3 and 6 months (p=0.0051 and p=0.0088, respectively). The IL17-, IL9-, and IL4-producing CD4(+)T cell percentages were significantly higher at pre-treatment in MS patients compared with HCs (p<0.01 for all), while the IL17-producing CD4(+)T cell percentages tended to show a transient increase at 2 weeks of fingolimod therapy (p(corr)=0.0834). CONCLUSIONS: The CD4(+)TCM percentages at 2 weeks to 12 months during fingolimod therapy are related to relapse.