FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system

Abstract

FTY720 (fingolimod) is a first-in-class sphingosine 1-phosphate (S1P) receptor modulator that was highly effective in Phase II clinical trials for Multiple Sclerosis (MS). FTY720 is phosphorylated in vivo by sphingosine kinase-2 to form the active moiety FTY720-phosphate that binds to four of the five G protein-coupled S1P receptor subtypes. Studies using conditional S1P1 receptor-deficient and sphingosine kinase-deficient mice showed that the egress of lymphocytes from lymph nodes requires signalling of lymphocytic S1P1 receptors by the endogenous ligand S1P. The S1P mimetic FTY720-phosphate causes internalization and degradation of cell membrane-expressed S1P1, thereby antagonizing S1P action at the receptor. In models of human MS and demyelinating polyneuropathies, functional antagonism of lymphocytic S1P1 slows S1P-driven egress of lymphocytes from lymph nodes, thereby reducing the numbers of autoaggressive TH17 cells that recirculate via lymph and blood to the central nervous system and the sciatic/ischiatic nerves. Based on its lipophilic nature, FTY720 crosses the blood-brain barrier, and ongoing experiments suggest that the drug also down-modulates S1P1 in neural cells/astrocytes to reduce astrogliosis, a phenomenon associated with neurodegeneration in MS. This may help restore gap-junctional communication of astrocytes with neurons and cells of the blood-brain barrier. Additional effects may result from (down-) modulation of S1P3 in astrocytes and of S1P1 and S1P5 in oligodendrocytes. In conclusion, FTY720 may act through immune-based and central mechanisms to reduce inflammation and support structural restoration of the central nervous system parenchyma. Beyond the autoimmune indications, very recent studies suggest that short-term, low-dose administration of FTY720 could help treat chronic (viral) infections. Differential effects of the drug on the trafficking of naïve, central memory and effector memory T cell subsets are discussed.

Figure 1

FTY720 inhibits the egress of lymphoytes from lymph nodes. T cells recirculate between blood and lymph nodes (LNs) in search for foreign antigen, entering LNs either from blood via high endothelial venules or from tissues via afferent lymphatics. Once in the LNs, the cells up-regulate sphingosine 1-phosphate (S1P)1 on cell membranes as a consequence of the S1P^low environment. To egress from LNs, T cells transmigrate through the sinus-lining endothelium into the S1P^high cortical sinus. Imaging studies showed that this process depends on lymphocytic S1P1, as only wild type but not S1P1-deficient T cells transmigrate through the endothelium. In the cortical sinuses, T cells are captured in a region of flow, passaged to medullary sinuses and flushed into the subcapsular space and the efferent lymph. Treatment with FTY720 causes internalization of lymphocytic S1P1 on T cells, thereby inhibiting the egress from LNs.

Figure 2

Redistribution of naive, memory and TH17 T cell subsets in FTY720-treated Multiple Sclerosis (MS) patients. (A) The percentage of naive and memory T cell subsets within blood CD4⁺ and CD8⁺populations was determined by flow cytometry. The characterized subsets are CCR7⁺ CD45RA⁺naive T cells (naive), CCR7⁺ CD45RA⁻ central memory T cells (TCM), CCR7⁻ CD45RA⁻ effector memory T cells (TEM) and CCR7⁻ CD45RA⁺ effector memory T cells (TEMRA). The subsets were determined in healthy controls (HD, n= 7), drug-untreated MS patients (MS, n= 3), IFNβ-treated MS patients (MS-IFNβ, n= 3) and FTY720-treated MS patients (MS-FTY720, n= 5). (B) The production of IL-17 by equal numbers of anti-CD3/anti-CD28-stimulated CD3⁺ T cells isolated from indicated donor populations was determined by ELISA (HD, n= 5; MS, n= 4; MS FTY720, n= 6; MS-IFNβ, n= 6). Data represent means ± SD.

Figure 3

Proposed mode of action of FTY720 in Multiple Sclerosis. The model is based on experiments using conditional sphingosine 1-phosphate (S1P)1 receptor-deficient and sphingosine kinase-deficient mice, and in vivo analysis of FTY720 and S1P. The data suggest that FTY720 functionally antagonizes S1P-S1P1-dependent immune and central processes. This reduces: (i) the egress of TH17 cells from lymphoid organs and their recirculation to the central nervous system (CNS); and (ii) the astrogliosis associated with Multiple Sclerosis, to restore gap-junctional communication between CNS cells. It remains to be determined whether (down-) modulation of S1P3 in astrocytes and of S1P1 and/or S1P5 in oligodendrocytes further contributes to the therapeutic effects.