Clinical immunology of the sphingosine 1-phosphate receptor modulator fingolimod (FTY720) in multiple sclerosis

Abstract

The oral sphingosine 1-phosphate (S1P) receptor (S1PR) modulator fingolimod has been shown to be effective in the treatment of patients with relapsing multiple sclerosis (MS). The drug binds with high affinity to 4 of the 5 G-protein-coupled S1P receptors (S1P(1-5)). After binding, the receptors are internalized, degraded, and thus functionally antagonized by fingolimod. Under physiologic conditions, S1P(1) mediates the egress of lymphocytes from secondary lymphoid organs to the peripheral circulation. Functional antagonism of S1P(1) by fingolimod results in a reduction in peripheral lymphocyte counts by inhibiting egress of lymphocytes, including potentially encephalitogenic T cells and their naïve progenitors that would otherwise be present within the circulation. Despite the fingolimod-mediated reduction of lymphocyte counts, fingolimod-treated patients with MS have been shown to have few infections and related complications and were able to mount antigen-specific immune responses in vaccination studies.

FTY720 (Gilenya) Phosphate Selectivity of Sphingosine 1-Phosphate Receptor Subtype 1 (S1P1) G Protein-coupled Receptor Requires Motifs in Intracellular Loop 1 and Transmembrane Domain 2

“…The S1P receptor modulator FTY720 (Gilenya) has been approved as frontline treatment for relapsing/remitting multiple sclerosis (8,9). FTY720 is phosphorylated in vivo by sphingosine kinase 2 to form the active metabolite FTY720 phosphate (FTY720P), which is a high affinity agonist of all the endothelial differentiation gene family S1P receptors except S1P 2 (10 -12).…”

Plasma Lipoproteins in Brain Inflammatory and Neurodegenerative Diseases

“…Because low plasma HDL-cholesterol is associated with a predominance of proinflammatory phenotype of monocyte-derived macrophage [48], these findings suggest an immunosuppressive role of HDL in the development of MS lesions. This interpretation is further supported by the beneficial therapeutical effects of fingolimod in the disease [49].…”

“…SP1 receptors are widespread in CNS cells and a defect of sphingolipid and phospholipid metabolism is observed early in normal appearing white and grey matter in MS patients. Moreover, S1P is reduced in affected white matter and is increased in CSF of these patients [49]. Importantly, FTY720 treatment has been shown to have neuroprotective effects independent of immunomodulatory mechanisms [50].…”

Therapeutic Approach to Steroid-Resistant Dermatitis Using Novel Immunomodulator FTY720 (Fingolimod) in Combination with Betamethasone Ointment in NC/Nga Mice

“…4 (c)). Mehling et al 25) reported that the reductions in circulating T lymphocytes are predominantly in naïve T cells and central memory T cells (TCM) subsets. This may be related to the fact that naïve T cells and TCM express high levels of CCR7.…”