marcstck, thanks for pointing this out to us. I have to share my favorite part of the report, given it's investigation into the role of the immune system.
Section IV – How is the immune response involved in damaging myelin or preventing its repair?
Section leader – Steve Miller
In earlier reports we showed that one critical component of the inflammatory immune response, interferon-gamma, appears to prevent myelin repair by triggering the endoplasmic reticulum (ER) stress response in oligodendrocytes. Ordinarily this ER stress response protects cells from damage but when the oligodendrocytes begin to produce massive quantities of myelin proteins, even a little additional stress is sufficient to kill them. Therefore we have been investigating ways to protect oligodendrocytes from anything that triggers the adverse effects of the ER stress response. Additionally, we have found that in adults the ER stress response can actually provide protection to oligodendrocytes against subsequent stresses through the activation of the integrated stress response (ISR), which is a general stress response. We have demonstrated this in mice by controlling a key gene necessary for ISR activation, and we have used brain tissue sections from mice to show that an experimental drug compound that prolongs the effects of the ISR can provide protection to oligodendrocytes against the adverse effects of interferon gamma. This project has now advanced to the point where a high throughput drug screen is being conducted at the National Drug Discovery Laboratory at the Harvard Center for Neurodegeneration and Repair to look for possible drug candidates that will have similar effects.
Previous MRF research progress reports discuss how dendritic cells have been found to penetrate the CNS in animal models of MS. These cells, along with memory and naïve T cells from the circulating blood that enter the inflamed CNS, result in the local activation of T cells specific for released fragments of myelin proteins called epitopes. This process is called epitope spreading and plays a major role in disease progression. Continued efforts have shown that myeloid dendritic cells are the primary subset present within demyelinated lesions and are responsible for activation of pro-inflammatory T cells that secret interferon gamma. Before we begin investigations into possible therapeutic approaches for targeting this critical antigen- presenting cell type, our animal studies are being expanded to include examination of human tissue from the Rocky Mountain MS Center to see if a similar pattern of myeloid dendritic cells is present in, or around, MS lesions. This study could provide considerable insight into the nature of the immune response in MS. Furthermore, selectively controlling their generation or migration, or their ability to stimulate a localized immune response, offers a new therapeutic approach to MS.
Continued investigations into combinatorial therapeutic approaches targeting both the underlying autoimmune response (using specific immunotherapeutic approaches) and promoting myelin repair for the treatment of established EAE have shown great promise. Combined short-term therapy using antibody fragments to block delivery of critical costimulatory signals required for T cell activation, along with a gamma secretase inhibitor which has been shown to promote myelination In Vitro, have demonstrated an ability to work synergistically to prevent disease relapses and promote recovery in mice with relapsing-remitting EAE.