Fingolimod is a sphingosine 1 phosphate receptor (S1P1) agonist approved for oral treatment of patients with relapsing-remitting multiple sclerosis (MS). Its principal mechanisms of action is supposed to be to prevent the encephalitogenic attack by sequestering autoreactive lymphocytes in secondary lymphoid organs via downregulation of their S1P1.

Unexpectedly, clinicians have recently found that patients on fingolimod that discontinue the treatment are at risk of extremely severe MS rebound. Although the immunological basis of this rebound is unexplored, elucidating its molecular mechanisms might be of remarkable clinical relevance.

In the present study, we developed the first mouse model of postfingolimod MS rebound. We found that upon fingolimod withdrawal S1P1 overexpression occurs in lymph node-entrapped lymphocytes, and confers them the ability to massively egress form lymphoid organs and bring about a severe CNS infiltration. We also found that S1P1 overexpression that follows fingolimod discontinuation impairs, in a Akt-dependent manner, the ability of regulatory lymphocytes (Tregs) to counteract CNS autoimmunity.

Overall, data disclose the first molecular and cellular mechanisms that may concur to the pathogenesis of postfingolimod rebound in MS patients, and can be targeted for therapeutic interventions. We believe that these novel findings are of importance to those working in the fields of immunological disorders of the CNS and MS therapy.