Fingolimod Therapy for Multiple Sclerosis
Fingolimod, a derivate of the fungal metabolite myriocin, is structurally similar to sphingosine, an important component of cell membranes. Phosphorylation by sphingosine kinase leads to formation of sphingosine 1-phosphate (S1P), which functions as a soluble regulator of a wide range of cellular processes, including lymphocyte recirculation, cardiac rate, neural cell proliferation and function, and endothelial permeability. These functions are mediated by interaction with a family of five G-protein-coupled SIP receptors. Sphingosine kinase also phosphorylates fingolimod into the active form, fingolimod-phosphate, which binds four of five S1P receptors with high affinity, acting as a functional antagonist. The therapeutic effects of fingolimod may involve S1P receptor modulation in both the immune system and the CNS.
Lymphocytes, including T cells and B cells, predominantly express S1P-type-1 receptor (S1P1), which directs lymphocyte egress from lymphoid tissues and recirculation in the periphery. Fingolimod-phosphate binds lymphocyte S1P1 with high affinity resulting in receptor internalization and degradation. Levels of S1P1 mRNA are also reduced. The loss of surface expression of S1P1 results in functional antagonism, loss of responsiveness to the S1P gradient necessary for egress with resultant lymphocyte retention in secondary lymphoid tissue.
The percentages of both CD4+ and CD8+ T cells are reduced in fingolimod-treated patients. The predominant effect is on CC-chemokine receptor-7-positive naïve T cells, central memory T cells, and T cells producing interleukin-17. These subpopulations include autoreactive lymphocytes that are thought to mediate CNS inflammation in MS. Peripheral effector memory T cells, thought to be important in defense against local pathogen invasion, are relatively spared.
Fingolimod also binds S1P receptors outside of the immune system. S1P receptors expressed by oligodendrocytes, astrocytes, microglia, and other neural cells influence neurogenesis, neural cell function, and migration. Fingolimod crosses the blood-brain barrier and is phosphorylated in situ. Functional antagonism of S1P receptors in the CNS may result in reduced secretion of proinflammatory cytokines, enhanced remyelination, and protection of oligodendrocytes from cell death. The direct effects of fingolimod in the CNS are suggested by preclinical evidence. Additional studies are needed to investigate the potential reparative and neuroprotective actions of fingolimod in MS.
Mechanism of Action
Fingolimod, a derivate of the fungal metabolite myriocin, is structurally similar to sphingosine, an important component of cell membranes. Phosphorylation by sphingosine kinase leads to formation of sphingosine 1-phosphate (S1P), which functions as a soluble regulator of a wide range of cellular processes, including lymphocyte recirculation, cardiac rate, neural cell proliferation and function, and endothelial permeability. These functions are mediated by interaction with a family of five G-protein-coupled SIP receptors. Sphingosine kinase also phosphorylates fingolimod into the active form, fingolimod-phosphate, which binds four of five S1P receptors with high affinity, acting as a functional antagonist. The therapeutic effects of fingolimod may involve S1P receptor modulation in both the immune system and the CNS.
Lymphocytes, including T cells and B cells, predominantly express S1P-type-1 receptor (S1P1), which directs lymphocyte egress from lymphoid tissues and recirculation in the periphery. Fingolimod-phosphate binds lymphocyte S1P1 with high affinity resulting in receptor internalization and degradation. Levels of S1P1 mRNA are also reduced. The loss of surface expression of S1P1 results in functional antagonism, loss of responsiveness to the S1P gradient necessary for egress with resultant lymphocyte retention in secondary lymphoid tissue.
The percentages of both CD4+ and CD8+ T cells are reduced in fingolimod-treated patients. The predominant effect is on CC-chemokine receptor-7-positive naïve T cells, central memory T cells, and T cells producing interleukin-17. These subpopulations include autoreactive lymphocytes that are thought to mediate CNS inflammation in MS. Peripheral effector memory T cells, thought to be important in defense against local pathogen invasion, are relatively spared.
Fingolimod also binds S1P receptors outside of the immune system. S1P receptors expressed by oligodendrocytes, astrocytes, microglia, and other neural cells influence neurogenesis, neural cell function, and migration. Fingolimod crosses the blood-brain barrier and is phosphorylated in situ. Functional antagonism of S1P receptors in the CNS may result in reduced secretion of proinflammatory cytokines, enhanced remyelination, and protection of oligodendrocytes from cell death. The direct effects of fingolimod in the CNS are suggested by preclinical evidence. Additional studies are needed to investigate the potential reparative and neuroprotective actions of fingolimod in MS.
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