Determining Immune System Suppression versus CNS Protection for Pharmacological Interventions in Autoimmune Demyelination

Evonuk, Kirsten S.; Moseley, Carson E.; Doyle, Ryan E.; Weaver, Casey T.; DeSilva, Tara M.

Multiple sclerosis (MS) is characterized by inflammatory lesions predominantly in white matter regions of the brain early in disease. After longterm progression, gray matter atrophy is detected by MRI imaging and marks the neurodegenerative phase of the disease. Reactive gliosis, demyelination, and axonal damage in the white matter are attributed to CNS-infiltrating immune cells. None of the treatments currently used in MS reverse or directly prevent neurodegeneration in the CNS -instead, they reduce inflammation by attenuating T cell activation and/or infiltration into the CNS. Because there is no cure for MS and patients using current treatments continue to experience disease progression, discoveries of drugs that prevent demyelination and neuronal loss are critically important. However, differentiating between effects on immune cells and those on the CNS can be difficult experimentally, as the outcome -i.e., reduced damage to the CNS -looks the same regardless of the mechanisms through which it occurs. Therefore, assessment of CNS protection must be partnered with assessments of CNS-infiltrating immune cells and proliferation of immune cells in the periphery to determine how pharmacological agents affect disease mechanisms.