Unexpected consequences arise from our incomplete knowledge of the immune system. Who, for example, would have predicted that natalizumab, a monoclonal antibody targeting α4 integrin on leukocytes, would dramatically increase the risk of developing progressive multifocal leukoencephalopathy without causing notable immunosuppression? Thus, any new immunomodulatory therapy in humans must be approached with caution.

Fingolimod, the first oral drug to treat multiple sclerosis (MS), is a sphingosine 1-phosphate (S1P) receptor modulator. 1 By modulating S1P receptors on lymphocytes, fingolimod inhibits egress of naive and central memory lymphocytes, but not effector memory T cells, from lymph nodes. How the resultant relative increase in effector memory T cells in blood translates to an amelioration of a putative immunopathologic response in brain is unknown. Furthermore, fingolimod may directly affect astrocytes, oligodendrocytes, microglia, endothelial cells, and neurons, since they all express sphingolipids and S1P receptors and the effect of fingolimod on these cells is uncertain.