Mechanisms by which effector T cells modulate endogenous remyelination

Project Summary:
The project addresses an important problem - multiple sclerosis (MS), which is the most common cause of
neurological disability in young adults after trauma. While the approval of numerous immunotherapies has had
an impact on reducing inflammatory disease activity in relapsing remitting MS, there are no therapies to date
that enhance repair of the myelin or markedly influence the progressive stage of the disease. Although
non-inflammatory mechanisms may contribute to progressive MS, several recent papers highlight a critical role
for ongoing inflammation within the brain at or next to sites of tissue injury. A direct pathogenic role for T
cells in progressive MS has been suggested by the presence of lymphoid meningeal follicles, which are
associated with cortical demyelination and thinning. A more detailed understanding of how immune cells
inhibit remyelination is critical for developing therapies to enhance remyelination and halt progressive MS.
Despite observational evidence that immune cells may suppress or promote
remyelination, there is remarkably little known regarding the specific mechanisms by which these processes
occur. This project addresses a barrier to progress in the field because our understanding
of why remyelination fails in disease is presently limited because we have not elucidated the
pathways involved in failed oligodendrocyte precursor cell (OPC) differentiation. We plan to pursue an exciting
novel observation that not only do OPCs fail to differentiate into myelin producing cells, but in an
inflammatory environment they adopt an immune phenotype (iOPCs) and can prime CD8 T cells, as
well as become targets of the cytotoxic lymphocytes (CTL). This represents a paradigm shift in thinking
about OPC biology and remyelination.
We will characterize the profile, fate and function of iOPC. We seek to understand the mechanisms by
which they activate CD8 T cells that in turn kill a subset of the iOPC as target cells. We will track iOPC using
fate mapping strategies and two-photon intravital microscopy through cranial windows. We aim to develop drug
therapies that target the NFkB signaling pathway involved in MHC expression using several novel therapeutic
approaches including the type 2 diabetes mellitus drug exenatide and an agonist of the NLRX-1 signaling
molecule that normally regulates NFkB expression.

Grant Number: 5R01NS041435-24
NIH Institute/Center: NIH
Principal Investigator: PETER CALABRESI