Animal studies by University of Michigan scientists suggest that people who
experience the same clinical signs of multiple sclerosis (MS) may have different
forms of the disease that require different kinds of treatment.
results, if borne out in further studies, point to a time when doctors will be
able to target specific inflammatory processes in the body and more effectively
help MS patients, using available drugs and new ones in the
Since the 1990s, the treatment picture has brightened for
people with multiple sclerosis in its most common form, relapsing-remitting MS.
Beta interferon drugs and glatiramer acetate (marketed as Copaxone) have proved
effective at decreasing the attack rate and suppressing inflammatory plaque
development in many patients with MS. Yet why the drugs help some patients, but
not others, has remained a mystery.
The U-M research team conducted the
studies in mice that have a disease similar to MS: experimental autoimmune
encephalomyelitis or EAE. The team found that different inflammatory chemicals,
whose activity is linked to two different types of immune system T cells, could
bring on the same paralysis and other MS-like signs. They also showed that drugs
that block one of the inflammation pathways were not effective at blocking the
other. The results, published online ahead of print, will appear in the July 7
issue of the Journal of Experimental Medicine
"These two forms of
disease differ in the specific anti-inflammatory agents that they are responsive
to," says Benjamin Segal, M.D., the study's senior author and the director of
the Multiple Sclerosis Center at the U-M Health System.
"We already know
that some people respond better to the drugs beta interferon or Copaxone
than others. Now we've shown proof that you can cause MS-like syndrome in mice
due to qualitatively different types of inflammatory damage. As a result, these
two kinds of inflammation likely require different approaches to treatment,"
says Segal. He directs the Holtom-Garrett Program in Neuroimmunology and is the
Holtom-Garrett Family Professor of Neurology at the U-M Medical
MS is an inflammatory disease of the
central nervous system believed to be autoimmune in nature. Certain cells in the
body's immune system mount an inappropriate response against proteins in the
nervous system, in particular myelin, the fatty substance that covers nerve
axons. MS affects an estimated 2.5 million people worldwide. Symptoms, which
vary widely, include numbness and weakness, incontinence, double vision, tremor,
imbalance and pain.
In 85 percent of MS cases, patients begin with what
is called a relapsing-remitting form of the disease. Initially, they have
attacks in which they experience symptoms for a time, return to normal, then
have attacks again. In the last 15 years, several beta interferon drugs and
Copaxone have been effective in many patients at limiting the number of attacks.
These drugs also can also decrease damage in the brain as visualized on MRI
Segal's research team injected one
group of mice with an immune system T helper cell, Th1, long believed to play a
role in MS, and another group with a T helper cell, Th17, whose potential role
in MS has recently come to light. They measured the activity of specific
inflammatory agents that are induced by each type of T cell as the immune system
mounts its misguided attack on the myelin sheaths of nerve cells.
groups of mice developed similarly severe and rapid paralysis. But the
researchers found clear differences in the inflammatory agents involved, called
cytokines and chemokines, and in the resulting damage to the central nervous
Mice injected with Th1 cells showed a pattern of central nervous
system inflammation that resembled that of common MS, with lesions filled with
macrophages, a type of immune system defender cell. Mice injected with Th17
cells, however, had lesions filled with another immune cell type, neutrophils.
In these mice, inflammation reached deep in central nervous system tissues and
in the optic nerve.
In both groups of mice, the scientists tested the
effects of neutralizing antibody drugs similar to drugs being developed against
autoimmune diseases in humans. Some of the drugs inhibited disease in the Th17
mice, but not in the mice receiving Th1 cells. Other drugs were effective
against both types of disease.
"That's our proof that these really are
different mechanisms of disease," says Mark Kroenke, the study's first author
and a Ph.D. student in immunology at
It's not yet known whether the same
differences will prove true in people with MS. But the study suggests the need
to develop drugs tailored to affect distinct inflammation pathways that might
drive different forms of relapsing-remitting MS.
"We speculate at some
point being able to identify and measure active inflammatory agents in patients,
and to develop customized profiles that would help predict what treatments will
be effective," Segal says.
In addition, Segal says, the findings may aid
the search for effective drugs for two difficult-to-treat diseases closely
related to MS: neuromyelitis optica, which affects the optic nerve and spinal
cord, and opticospinal MS, most common in Asia. The pattern of inflammation the
team saw in the Th17-injected mice resembled the pattern in these variants of
Other authors include: Anuska V. Andjelkovic, Ph.D., U-M Department
of Pathology; and Thaddeus J. Carlson, Ph.D., University of Rochester School of
Medicine and Dentistry.
Segal is on the scientific advisory board of the
National MS Society, http://www.nationalmssociety.org/index.aspx
was supported by grants from the National Multiple Sclerosis Society and the
National Institutes of Health.
Citation: Journal of Experimental
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