Transcript: Inflammatory Oligodendrocyte Precursor Cells and Remyelination in MS

Peter Calabresi, MD: Hello, I'm Dr Peter Calabresi. I'm a professor of neurology at Johns Hopkins University. Today, I'm going to tell you about our studies of oligodendrocyte precursor cells in the context of remyelination for multiple sclerosis.

My laboratory has been working on understanding how oligodendrocyte precursor cells, or what are called OPCs, may be able to differentiate into myelin-producing oligodendrocytes. The hope here is that we can tap into these cells to facilitate remyelination in human diseases like multiple sclerosis.

There are already several clinical trials that have been performed with putative remyelinating agents. These target signals that are already wired into OPCs to facilitate developmental myelination. Unfortunately, the results from these studies have been disappointing in that we have not seen marked improvements in the behavioral outcomes that we would hope would come along with facilitating remyelination.

So, the question arises, why are these strategies not working? And, one potential explanation is that, within the brain and within the MS plaque, there are inhibitory factors that may be blocking the OPCs from differentiating and turning into myelinating cells. Of course, there's several possibilities here. One is that there are not enough of these OPCs, and that may be somewhat true with age, but that doesn't appear to be a primary factor early on in the disease process.

A second problem might be that the cells are not able to wrap myelin because the axons are actually no longer intact, and of course, in severe injury, this is a real problem that might inhibit remyelination.

A final possibility is that the inflammation within the MS plaque or microenvironment is inhibitory to OPC differentiation. And in fact, several groups have already shown that inflammatory cytokines, such as interferon-γ, may inhibit this differentiation process. So, we developed a model in which we demyelinate animals using cuprizone and then add back myelin-reactive T cells, which are secreting these inflammatory cytokines. And, we were able to show that this not only inhibits the remyelination process in the corpus callosum, but to our surprise, we found that it reprograms the OPCs to become a different cell type. In fact, these OPCs now take on an inflammatory phenotype with a process and present exogenous antigen through a known immunological pathway called antigen cross presentation, and present the antigens on MHC class I molecules, which can then activate CD8 T cells, and those CD8 T cells in turn mediate cytotoxic death of the OPCs.

So, the big picture here is that OPCs now become an immune cell, they further propagate the inflammation, and thereby actually become targeted for cell death. And so, we think this can explain several features of what's happening in MS. First, it may explain why there are so many CD8s in MS brain tissue, which has been known for decades, but never fully explained. And second, it may explain why, over years, the OPCs become depleted, suggesting that they are actually being targeted as part of this secondary immune response within the brain. And of course, all of this has important implications because, by dissecting the signaling pathway of these OPCs that are now part of the inflammatory process, we think that we can develop rational strategies to intervene in this process and hopefully reprogram them to stop their inflammatory response and to facilitate myelin repair.

We and other groups around the world–they're calling these iOPCs, or inflammatory OPCs, and we think, just like many other immune cells and CNS-resident glia, that these cells can add different phenotypes, which are important to understand biologically and, of course, for therapeutic purposes.

We're extremely excited about exploring the phenotype of these inflammatory OPCs. We think that this is a very novel understanding of what's happening within the MS plaque, and we think that this will eventually lead to strategies that can truly facilitate myelin repair and also to block the inflammation, not just in the peripheral blood, but the CNS-compartmentalized inflammation that may mediate the slow progression of the disease.

Clinically, we desperately need therapies that actually work for progressive MS. We have many peripherally acting immune therapies for relapsing-remitting MS, but we think by understanding mechanisms that underlie inflamed glia, including these oligodendroglia, that we can better target what's happening within the MS plaque and facilitate repair and hopefully improve function for patients who are suffering with this terrible disease.