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Axons covered with myelin

Advanced cell-labeling technology identifies suspect cell type, possible new therapeutic approach to multiple sclerosis

Researchers have identified an immune cell type with an apparently critical role in multiple sclerosis, and a way to block its entry into the brain.

There's no known cure for multiple sclerosis. But Stanford neuroimmunologist Larry Steinman, MD, has been working on it for decades.

Steinman has a long, illustrious history of pioneering new approaches to understanding and treating MS: an unpredictable, often disabling autoimmune disease in which white matter – the insulation that coats, and speeds transmission in, nerve tracts in the brain – gets attacked and, in places, destroyed by the body's immune system. MS is often characterized by alternating bouts of initially localized but increasingly severe paralysis, followed by remissions and subsequent relapses.

Steinman's research was directly responsible for the development of a powerful multiple-sclerosis treatment, natalizumab (marketed as Tysabri). But powerful drugs can have powerful side effects. Natalizumab, approved in 2004, was withdrawn from the market not long afterward when three suspicious cases of a sometimes fatal, but normally rare, neurological condition surfaced. Restored in 2006, natalizumab remains on the market and continues to see wide use because its effectiveness in treating MS outweighs its risk profile. However, its indisputable therapeutic benefit is marred by the continued occurrence, at low rates, of the neurological disorder.

Natalizumab's target (that's what the drug binds to and disables) is a molecule on the surfaces of certain types of immune cells. This molecule is required in order for these cells to get out of the bloodstream and into the brain, where at least some of them are responsible for the damage inflicted on white matter in MS. By preventing their entry, natalizumab counters MS symptoms.

The problem is, some of the immune cells prevented from leaving the blood stream by natalizumab – innocent parties with respect to MS – can no longer carry out their legitimate tasks. This is undoubtedly the source of the drug's troubling side effects.

So, in a study published in Nature Neuroscience, Steinman and his colleagues found a new target. They did it by using an advanced cell-labeling technology pioneered by Stanford immunologist, serial inventor and study co-author Garry Nolan, PhD. With this technology, it's now possible to draw ever finer distinctions between subtly differing types and subtypes of cells previously thought to be more or less identical.

In a classic mouse model of MS, the study's lead author, Bahareh Ajami, PhD, was able to distinguish among several different types and subtypes of immune cells present in the blood and brain at various phases of the MS-like syndrome characterizing both the mouse model and the human version of the disease: pre-symptomatic, onset, peak, chronic and recovered. She also identified a new target molecule on the surface on a particular type of immune cell whose activity tracks the rise and fall of MS-like symptoms in the mice. The same marker turns up in close association with MS lesions, particularly around blood vessels.

A drug that specifically blocked this surface molecule prevented cells of that type from crossing the blood-brain barrier and entering the brain. It also substantially reduced disease severity in the experimental mice.

The surface molecule in question, unlike the one that's a target of natalizumab, is absent on the surfaces of T cells and B cells – the workhorses of the adaptive immune system. Steinman told me he thinks it could prove to be a superior target for MS therapy.

Image of myelinated axons by Tom Deerinck and Mark Ellisman, National Center for Microscopy and Imaging Research

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