title: FTY720 (fingolimod) modulates the severity of viral-induced encephalomyelitis and demyelination.
abstract: BACKGROUND
  FTY720 (fingolimod) is the first oral drug approved by the Food and Drug Administration for treatment of patients with the relapsing-remitting form of the human demyelinating disease multiple sclerosis. Evidence suggests that the therapeutic benefit of FTY720 occurs by preventing the egress of lymphocytes from lymph nodes thereby inhibiting the infiltration of disease-causing lymphocytes into the central nervous system (CNS). We hypothesized that FTY720 treatment would affect lymphocyte migration to the CNS and influence disease severity in a mouse model of viral-induced neurologic disease.
  
  
  METHODS
  Mice were infected intracranially with the neurotropic JHM strain of mouse hepatitis virus. Infected animals were treated with increasing doses (1, 3 and 10 mg/kg) of FTY720 and morbidity and mortality recorded. Infiltration of inflammatory virus-specific T cells (tetramer staining) into the CNS of FTY720-treated mice was determined using flow cytometry. The effects of FTY720 treatment on virus-specific T cell proliferation, cytokine production and cytolytic activity were also determined. The severity of neuroinflammation and demyelination in FTY720-treated mice was examined by flow cytometry and histopathologically, respectively, in the spinal cords of the mice.
  
  
  RESULTS
  Administration of FTY720 to JHMV-infected mice resulted in increased clinical disease severity and mortality. These results correlated with impaired ability to control viral replication (P < 0.05) within the CNS at days 7 and 14 post-infection, which was associated with diminished accumulation of virus-specific CD4+ and CD8+ T cells (P < 0.05) into the CNS. Reduced neuroinflammation in FTY720-treated mice correlated with increased retention of T lymphocytes within draining cervical lymph nodes (P < 0.05). Treatment with FTY720 did not affect virus-specific T cell proliferation, expression of IFN-γ, TNF-α or cytolytic activity. FTY720-treated mice exhibited a reduction in the severity of demyelination associated with dampened neuroinflammation.
  
  
  CONCLUSIONS
  These findings indicate that FTY720 mutes effective anti-viral immune responses through impacting migration and accumulation of virus-specific T cells within the CNS during acute viral-induced encephalomyelitis. FTY720 treatment reduces the severity of neuroinflammatory-mediated demyelination by restricting the access of disease-causing lymphocytes into the CNS but is not associated with viral recrudescence in this model.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Blanc
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Lane
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes; D002478:Cells, Cultured; D002490:Central Nervous System / Q000473:pathology; D003711:Demyelinating Diseases / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000821:virology*; D004195:Disease Models, Animal; D018792:Encephalitis, Viral / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000068876:Fingolimod Hydrochloride; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D006517:Murine hepatitis virus / Q000472:pathogenicity; D009419:Nerve Tissue Proteins / Q000235:genetics; D011409:Propylene Glycols / Q000627:therapeutic use*; D012720:Severity of Illness Index; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000473:pathology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D007166:Immunosuppressive Agents; D009419:Nerve Tissue Proteins; D011409:Propylene Glycols; C491561:Sip1 protein, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine