Abstract
BackgroundFTY720 (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.MethodsMice 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.ResultsAdministration 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.ConclusionThese 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.
Highlights
FTY720 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
FTY720 treatment of JHM strain of mouse hepatitis virus (JHMV)-infected mice increases clinical disease severity and impairs control of viral replication S1P1 eGFP knock-in mice C57BL/6 mice [36] were infected i.c. with JHMV (150 plaque forming units (PFU)) and subsequently treated with increasing concentrations (1, 3 or 10 mg/kg) of FTY720 via i.p. injection administered daily starting at day 5 p.i
These findings indicated that the increase in mortality following administration of FTY720 correlated with impaired ability to control viral replication within the central nervous system (CNS) and argues that either trafficking of virus-specific lymphocytes is impaired and/or anti-viral effector functions are negatively affected
Summary
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. 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. FTY720, called Gilenya/fingolimod, is an oral drug recently approved by the Food and Drug Administration (FDA) for treatment of patients with the relapsing-remitting form of MS [3,4,5,6,7,8]. FTY720 treatment mutes effective anti-viral immune responses following infection with a neurotropic virus by dampening trafficking of virus-specific T cells to the CNS.
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