title: Neurodegeneration progresses despite complete elimination of clinical relapses in a mouse model of multiple sclerosis.
abstract: BACKGROUND
  [corrected] Multiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression. In contrast to the increasing number of effective anti-inflammatory disease modifying treatments for relapse-remitting disease, the absence of therapies for progressive disease represents a major unmet clinical need. This raises the unanswered question of whether elimination of clinical relapses will prevent subsequent progression and if so how early in the disease course should treatment be initiated. Experimental autoimmune encephalomyelitis in the Biozzi ABH mouse recapitulates the clinical and pathological features of multiple sclerosis including relapse-remitting episodes with inflammatory mediated demyelination and progressive disability with neurodegeneration. To address the relationship between inflammation and neurodegeneration we used an auto-immune tolerance strategy to eliminate clinical relapses in EAE in a manner analogous to the clinical effect of disease modifying treatments.
  
  
  RESULTS
  By arresting clinical relapses in EAE at two distinct stages, early and late disease, we demonstrate that halting immune driven demyelination even after the first major clinical event is insufficient to prevent long-term neurodegeneration and associated gliosis. Nonetheless, early intervention is partially neuroprotective, whereas later interventions are not. Furthermore early tolerisation is also associated with increased remyelination.
  
  
  CONCLUSIONS
  These findings are consistent with both a partial uncoupling of inflammation and neurodegeneration and that the regenerative response of remyelination is negatively correlated with inflammation. These findings strongly support the need for early combinatorial treatment of immunomodulatory therapies and neuroprotective treatments to prevent long-term neurodegeneration in multiple sclerosis.
authors.affiliation: Centre for Clinical Brain Sciences, MS Centre, University of Edinburgh Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK. dhampton@staffmail.ed.ac.uk.
authors.forename: David W
authors.initials: DW
authors.lastname: Hampton
authors.forename: Andrea
authors.initials: A
authors.lastname: Serio
authors.forename: Gareth
authors.initials: G
authors.lastname: Pryce
authors.forename: Sarah
authors.initials: S
authors.lastname: Al-Izki
authors.forename: Robin Jm
authors.initials: RJ
authors.lastname: Franklin
authors.forename: Gavin
authors.initials: G
authors.lastname: Giovannoni
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.forename: Siddharthan
authors.initials: S
authors.lastname: Chandran
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology / Q000502:physiology; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000503:physiopathology* / Q000628:therapy; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000503:physiopathology / Q000628:therapy; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy; D038602:Mice, Biozzi; D017628:Microglia / Q000473:pathology / Q000502:physiology; D018613:Microscopy, Confocal; D009046:Motor Neurons / Q000502:physiology; D009410:Nerve Degeneration / Q000503:physiopathology* / Q000628:therapy; D015213:Neuroimmunomodulation / Q000502:physiology*; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology
chemical_list: D005904:Glial Fibrillary Acidic Protein