Promising New Molecular Target Identified in MS

All of the recent treatment advances in MS have been linked to basic scientific discoveries about how the immune system in MS and attacks a person’s healthy nerve tissue (in the brain and elsewhere). For instance, we know that interferons (contained in medications like Avonex) play an important role in controlling the activity of the immune system and can increase levels of the immune system protein interleukin-10 (IL-10, for short), which is an called an anti-inflammatory cytokine and helps stop or inhibit inflammation. Many teams of scientist from around the world are currently hard at work trying to gain insights about immune system function that will enable development of new and more effective MS treatments.

A team of scientists led by Nathalie Arbour, PhD, of the Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), has made an exciting discovery that may have implications for the development of future treatments for MS. Results were reported by Zaguia and colleagues in the Journal of Immunology in an article that was named as one of the top 10% most interesting to be published by the journal.

The authors of the article, which appeared in the March 15 issue of the journal, reported that they had found increased amounts of a certain type of white blood cell called a CD4 T cell that includes a molecule called the NKG2C membrane protein in patients with MS. This NKG2C molecule has been shown to be highly toxic and harmful to brain tissues (specifically oligodendrocytes, types of brain cells that are involved in insulating and supporting axons). The discovery may lead to the development of improved treatments for MS that reduce disease progression and improve symptoms, while decreasing risk of side effects (principally infections) and improving patient quality of life.1,2

What did the researchers find? (Warning: this is a bit technical!)

The experiments that eventually led to the discovery of NKG2C started with CD4 T cells, which have long been recognized as key players in the inflammatory process that causes myelin damage in MS. However, the specific molecule associated with these CD4 T cells that allows them to target brain cells had not been identified. Dr. Arbour’s team, which included clinicians from the University of Montreal Hospital and the Montreal Neurological Institute of McGill University, compared brain tissue from patients with MS with tissue from healthy subjects. They found that CD4 T cells that attacked myelin in patients with MS contained the NKG2C molecule, which served as the activating receptor for another important immune system molecule called HLA-E. These CD4 T cells also produced a range of cytotoxic molecules (molecules that cause the destruction of cells), while CD4 T cells that did not contain the NKG2C molecule did not produce these molecules. Experiments showed that NKG2C-containing CD4 T cells can cause the destruction of human oligodendrocytes. Furthermore, brain tissues from patients with MS displayed evidence that they had been attacked by NKG2C-positive CD4 T cells. Additionally, a significantly greater percentage of CD4 T cells with the NKG2C molecule were present in the peripheral blood of MS patients compared with healthy controls.2

What this discovery may mean for future treatments

Findings from this research hold promise for the development of treatments more narrowly targeted to a specific cell or molecule that promotes nerve damage in MS. Current MS treatments target molecules expressed by immune cells, but these treatments often exert effects that are too broad. For instance, when an MS medications impairs immune system function, it may decrease the damage that occurs in MS, but it also decreases the ability of the immune system to keep the body safe and increases risk for serious infections, such as progressive multifocal leukoencephalopathy.

Because NKG2C is expressed only in a subset of CD4 T cells that exist only in patients with MS, treatments that target NKG2C-positive CD4 T cells would address the pathologic mechanism involved in MS, while sparing other important immune cells and leaving the immune system in tact. "These results are very encouraging,” noted Dr. Arbour, “since they provide us with a much more refined picture of how the brain cells of MS patients are targeted by the immune system and provide us with a clearer understanding of how to go about blocking their action."1

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