[Basic mechanisms of action of fingolimod in relation to multiple sclerosis].
BACKGROUND
Fingolimod has recently been approved for the therapy of relapsing multiple sclerosis. This drug binds to different sphingosine-1-phosphate receptors.


OBJECTIVE
To analyze basic mechanisms of action that can account for the efficacy of this drug in multiple sclerosis.


METHODS
Fingolimod acts as an inverse agonist on sphingosine-1-phosphate receptors, inducing degradation of receptors. On lymphoid circulation, this effect causes retention in lymph nodes of naive and central memory T cells, including Th17 T lymphocytes, bearing CCR7 and CD62L receptors. As a result, the level of circulating T cells is markedly decreased. B ell circulation is impaired and complex effects on other immune cells are also induced. Fingolimod enters the central nervous system and binds to receptors on glial cells and neurons. In experimental autoimmune encephalomyelitis, the therapeutic efficacy of fingolimod is not only associated with a reduced entry of inflammatory cells into the nervous system, but also with a direct effect mostly on astroglial cells.


CONCLUSIONS
In multiple sclerosis patients, the available evidence indicates that fingolimod efficacy is directly associated with impairment of circulation of several T cell subsets and possibly B cells. Animal studies raise the possibility that an additional effect on glial cells might also contribute to the clinical efficacy.
Unidad y Laboratorio de Neuroinmunología, Servicio de Neurología, Hospital Universitario Puerta de Hierro-Majadahonda, 28035 Majadahonda, Espana. jgarciam.hpth@salud.madrid.org
J Antonio
JA
García-Merino
Antonio J
AJ
Sánchez
D000818:Animals; D001284:Atrophy; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D001921:Brain / Q000276:immunology / Q000473:pathology; D002465:Cell Movement; D004353:Drug Evaluation, Preclinical; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D019041:L-Selectin / Q000032:analysis; D008246:Lysophospholipids / Q000502:physiology; D051379:Mice; D015394:Molecular Structure; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D009457:Neuroglia / Q000187:drug effects / Q000276:immunology; D011409:Propylene Glycols / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D054400:Receptors, CCR7 / Q000032:analysis; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use; D016176:T-Lymphocyte Subsets / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology
C515370:CCR7 protein, human; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D011409:Propylene Glycols; D054400:Receptors, CCR7; D049349:Receptors, Lysosphingolipid; D019041:L-Selectin; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine