Therapeutic interference with leukocyte recirculation in multiple sclerosis

Multiple sclerosis (MS) is an immune-mediated disease where T cells are thought to initiate an inflammatory reaction in the brain and spinal cord, resulting in demyelination and axonal pathology. Interfering with the activation and recruitment of immune cells reduces disease activity in MS. We review the mechanism of action and treatment effects of natalizumab and fingolimod, which interfere with the recruitment of pathogenic immune cells in MS. Fingolimod blocks the egress of activated lymphocytes from lymph nodes by binding to the sphingosine-1-phosphate (S1P) receptor 1, but may also have effects on S1P receptor-expressing cells within the central nervous system (CNS). Natalizumab reduces the migration of lymphocytes to the CNS by binding to the α4 integrin very late antigen 4. Fingolimod and natalizumab also have other effects, but these are less well understood. Both treatments are efficacious in reducing relapses, accumulation of persisting disability and magnetic resonance imaging disease activity. Both treatments are safe and well tolerated in the majority of patients, but due to a potential for serious side effects they are licensed as second line therapies or for treatment of highly active MS in most European countries. We conclude that fingolimod and natalizumab have well known effects on the migration of immune cells in MS and have substantial effects on disease activity in relapsing-remitting MS. Additional effects on disease progression, potential effects within the CNS and other effects on immune cells are still being clarified.