Johns Hopkins School of Medicine

ENDOGENOUS REMYELINATION IN THE CNS

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS and is the most common cause of neurological disability in young adults after trauma. In MS, infiltrating immune cells from the periphery activate glial cells and mediate demyelination and neurodegeneration, but the molecular mechanisms of injury are poorly understood. An area of special interest is the observation that endogenous remyelination can occur as a result of mobilization and differentiation of oligodendrocyte precursor cells (OPC). Despite extensive indirect or observational evidence that immune cells may suppress remyelination, there is remarkably little known regarding the cellular signaling pathways by which these processes occur. The Calabresi laboratory uses the animal models experimental autoimmune encephalomyelitis (EAE) and cuprizone to model the inflammatory and demyelinating aspects of the disease. We recently developed a novel model capitalizing on aspects of both EAE and cuprizone, which we refer to as adoptive transfer (AT)-cuprizone in which antigen specific TEffector cells are injected into mice after 4 weeks of cuprizone feeding and the mice are sacrificed 2 weeks later (Baxi et al J Neurosci 2015). We have shown that myelin reactive T cells secreting both IFNγ and IL-17 inhibit the endogenous remyelination that normally occurs in the cuprizone model. In order to examine the molecular mechanisms underlying the effects of T cell secreted cytokines on OPCs we have developed in vitro and in vivo (lineage fate mapping in PDGFαR_CreER; Rosa26_YFP mice) systems to transcriptionally profile OPCs inhibited by immune cells.