Neuroimmunological characterization of a mouse model of primary progressive experimental autoimmune encephalomyelitis and effects of immunosuppressive or neuroprotective strategies on disease evolution

Abstract Progressive multiple sclerosis (PMS) is a devastating disorder sustained by neuroimmune interactions still wait to be identified. Recently, immune-independent, neural bioenergeticderangements have been hypothesized as causative of neurodegenerationin PMS patients. To gather information on the immune and neurodegenerative components during PMS, in the present study we investigated the molecular and cellular events occurring in a Non-obese diabetic ( NOD) mouse model of experimental autoimmune encephalomyelitis(EAE). In these mice, we also evaluated the effects of clinically-relevant immunosuppressive (dexamethasone) or bioenergeticdrugs ( bezafibrateand biotin) on functional, immune and neuropathological parameters. We found that immunized NOD miceprogressively accumulated disability and severe neurodegenerationin the spinal cord. Unexpectedly, although CD4 and CD8 lymphocytes but not B or NK cells infiltrate the spinal cord linearly with time, their suppression by different dexamethasone treatment schedules did not affect disease progression. Also, the spreading of the autoimmune response towards additional immunogenic myelin antigen occurred neither in the periphery nor in the CNS of EAE mice. Conversely, we found that altered mitochondrial morphology, reduced contents of mtDNA and decreased transcript levels for respiratory complex subunits occurred at early disease stages and preceded axonal degeneration within spinal cord columns. However, the mitochondria boosting drugs, bezafibrateand biotin, were unable to reduce disability progression. Data suggest that EAE NOD micerecapitulate some features of PMS. Also, by showing that bezafibrateor biotindo not affect progression in NOD mice, our study suggests that this model can be harnessed to anticipate experimental information of relevance to innovative treatments of PMS.