Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis

Abstract

Background: There has been poor translation for the use of immunosuppressive agents from experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), into the treatment of MS. This may be due to the fact that most EAE studies examine prophylactic, pre-treatment regimes that prove to be therapeutically-ineffective in long-established, often progressive, MS. FTY720 (fingolimod/Gilenya) is a sphingosine-1-phosphate receptor modulator. This is a new oral agent that markedly reduces the number of relapses in people with MS, compared with currently licensed injectable agents such as the beta interferons. FTY720 has activity against lymphocytes but may also influence oligodendroglia and could therefore have the potential to influence progressive MS, by promoting remyelination. Methods: The effect of FTY720 was assessed in relapsing-progressive EAE in mice. Results: Early intervention during relapsing EAE could completely inhibit subsequent relapses, inhibited the accumulation of neurodegeneration, and facilitated motor recovery. However, when examined in secondary progressive EAE, that develops after the accumulation of deficit from relapsing disease, long-term treatment with FTY720 failed to slow deterioration when initiated late (4 months) into the disease course. Conclusions: This study indicates that early intervention with immunosuppressive agents may inhibit the generation of the neurodegenerative microenvironment, which is no longer responsive to potent immunosuppression. However, if treatment is initiated too late, progressive, neurological-disease continues unabated. This suggests that immunosuppression is insufficient to control secondary progression in animals, as has been found so far to be the case in MS, and may warrant early intervention with FTY720 for optimal treatment benefit.