Sphingosine-1-phosphate receptor (S1PR) modulators have entered clinical
practice as immune-modulators for the treatment of multiple sclerosis (MS). Pharmacologic
modulation of S1PR expression on lymphocytes inhibits these cells capacity
to respond to the S1P gradient within regional lymph nodes (LNs) (and thymus) that
promotes their exit into peripheral circulation. The resultant peripheral blood restricted
lymphopenia is considered to underlie the capacity of S1PR modulators to reduce
new inflammatory lesion formation in MS in the absence of global immune suppression.
These modulators also regulate entry of selective lymphocyte populations
and dendritic cells (DCs) into LNs and modulate sphingosine-1-phosphate (S1P) cell
signaling networks that govern the generation of specific cell subsets within LNs.
S1PR modulators that access the CNS can also have functional effects within this compartment since
S1PRs are expressed by cells comprising the blood brain barrier (BBB) and by those within the parenchyma,
including neurons, astrocytes, oligodendrocytes and microglia. Absence of S1P1 receptor
(S1PR1) on astrocytes reduces disease severity in experimental autoimmune encephalomyelitis (EAE).
Even under conditions that inhibit cell responses to the natural ligand, S1PR modulators can continue to
induce active signaling responses; such responses may be relevant for promoting neuroprotection and
augmenting tissue repair within the CNS.
Keywords: FTY720, GPCR, immune-modulators, sphingosine-1-phosphate receptor, lymphopenia, multiple sclerosis.
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