| Result |
In this study, fingolimod significantly reduced the mean ARR in 47.2 and 88.6% at 1 and 2 years, respectively, and the percentage of relapse-free patients was ~75% at the end of the study without differences between the subgroups.In lymphocyte populations, no significant differences between HC and patients were observed before treatment, except for the percentage of LB1 cells composed mostly of CD11b+ cells, which was smaller in patients.We could verify that fingolimod affected practically all lymphocyte populations and subpopulations of B, T, and NK cells.As expected, a reduction of the percentages of CD3+, CD4+, CD20+, CD19+, TCM and TN, memory B (switched and no-switched), regulatory B, NK bright, and cytokine-producing cells (IFN, IL-17, and IL-2) was observed after treatment, with a relative increase in effector memory T (TEM), terminally differentiated effector T (TEMRA), NK, NK dim, NKT, Tregs, nave B, immature B, transitional B, CD5+ B, LB1, and plasmablast cells.Patients who achieved NEDA-3 and NEDA-4 status at 1 year had a significantly higher percentage of NK bright and plasmablast cells and a lower proportion of NK dim and IL-2-producing cells at baseline than NR patients.These patients were significantly more resistant to decreases in percentages of NK bright and LB1 cells and showed a greater decline of CD8 nave T and CD8+ CCR4+ CCR6+ cells than NR patients after 6 months of treatment.Fingolimod exerts powerful transcriptional effects on PBMCs of MS patients.A total of 16,818 filtered probes were used for the differential analyses, resulting in the identification of 3,805 upregulated and 3,741 downregulated genes in response to fingolimod.
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| Mechanism/pathway |
Such therapies as fingolimod (Gilenya), a functional sphingosine-1-phosphate (S1P) antagonist, have been developed to retain the autoreactive lymphocytes within the lymph nodes. The phosphorylated form of fingolimod binds to four of five S1P-receptors (S1P1 and S1P3–5), resulting in aberrant internalization and degradation of the receptor on the cell surface and blockade of the egress and recirculation of activated CCR7+ and CD62+ lymphocytes from lymph nodes, such as central memory (TCM) and nave T (TN) cells.In addition, S1P receptors are differentially expressed in several tissues and have significant roles in a variety of cellular responses, including survival, inhibition of apoptosis, cardioprotection, activation of innate and adaptive immune systems, Treg differentiation, and promoting Th1 and Th17 differentiation in vitro and in vivo.
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