**5.2.1 S1P receptor agonists, FTY-720**

The immunosuppressant drug FTY-720 (fingolimod) was originally described as a sphingosine analogue that is phosphorylated *in vivo* by SphK2 to a S1P agonist for all S1P receptors except S1P2 (Brinkmann et al., 2002; Mandala et al., 2002). Further studies revealed that FTY-720-P not only activates S1P receptors, it also down-regulates them and consequently renders cells unresponsive to S1P (Matloubian et al., 2004). FTY-720 has been suggested to play a major role in autoimmune disease, such as multiple sclerosis [reviewed in (Nicholas et al., 2011)]. Multiple sclerosis is a common neurological disability, in which autoreactive T-cells migrate across the blood–brain barrier and attack myelin sheaths, leading to demyelination and axonal damage. FTY-720 deprives thymocytes and lymphocytes by downregulating S1P receptors and interfering with S1P signalling necessary for their egress from secondary lymphoid tissues (Cyster, 2005; Graler and Goetzl, 2004; Kappos et al., 2006; Matloubian et al., 2004). The results of a Phase II clinical trial evaluating the efficacy and safety of FTY-720 for treating relapsing multiple sclerosis showed that the annualized relapse rate of the FTY-720 group was significantly decreased (Kappos et al., 2006). FTY-720 was recently FDA-approved for the treatment of multiple sclerosis (Strader et al., 2011).

The effects of FTY-720 have been examined in several animal models of arthritis (Matsuura et al., 2000; Tsunemi et al., 2010; Wang et al., 2007). In the study of Wang et al. (2007), CIA rats were treated daily with FTY-720 for 28 days and the arthritis index was measured. Radiological analysis revealed that FTY-720-treated CIA rats had less joint damage in comparison to untreated CIA rats. Moreover, while histological assessment showed that CIA rats suffered from inflammatory cell infiltration and synovial hyperplasia in their joints, FTY-720 treatment clearly reduced these pathological parameters. Similarly, Matsuura et al. (2000) compared FTY-720 with two other anti-rheumatic compounds, mizoribine and prednisolone, in the rat models of CIA and AIA. FTY-720 completely suppressed the increase in hind paw volume and bone destruction to normal control levels by inhibiting leukocyte accumulation in the arthritic joint. Moreover, FTY-720 was shown to possess antiarthritic activity with a wider margin of safety in AIA and CIA models as compared to mizoribine and prednisolone. A recent study by Tsunmi et al. (2010) revealed that FTY-720 administration suppressed the progression of laminarin-induced arthritis in SKG mice. FTY-720 treatment decreased IL-6 and TNF- expression by synovial fibroblasts, diminished the number of inflammatory cells migrating into the�joints, and suppressed bone destruction.
