There may be two distinct versions of multiple sclerosis, a study in
both animal models and human blood samples suggests. What's more, a
patient's responsiveness to the most popular first-line drug for this
episodic and all-too-often recurring autoimmune condition seems to
depend on which version that patient has.
“I think
this has the potential to transform the way we take care of people with
multiple sclerosis.”
If these findings are confirmed in larger human studies and by other
laboratories, people with multiple sclerosis might someday be able to
take a simple blood test to see whether they are likely to respond to
treatment with the standard multiple-sclerosis therapy, said senior
study author Lawrence Steinman, MD, the George A. Zimmerman Professor of
Neurology and Neurological Sciences at the Stanford University School of
Medicine.
Public health may benefit, too, Steinman said, as the cost savings from
being able to predict in advance which patients will benefit from
beta-interferon, a costly bioengineered drug whose global sales come to
some $4 billion a year, could be considerable.
Beta-interferon's overall efficacy is only fair, he said, with perhaps
half of all multiple-sclerosis patients experiencing an average
one-third reduction in recurrences. Plus, its discomfiting side effects
— flulike symptoms — can make compliance an issue for patients,
especially given the drug's iffy efficacy.
In a study to be published online March 28 in Nature Medicine,
Steinman and his colleagues used an established animal model of multiple
sclerosis called experimental autoimmune encephalitis, or EAE, which
they induced by injecting the animals with myelin in a way that caused
the immune system to inappropriately attack the animals' own myelin
nerve-cell coatings.
Many nerve cells in mammalian brains and peripheral tissues must convey
electrochemical impulses over great distances, and quickly. Long,
wirelike projections that transmit these cells' signals to other nerve
or muscle cells are coated by myelin, a natural substance whose
insulating properties sustain the impulses' strength and increase their
speed.
Multiple sclerosis is triggered when, for reasons that are not yet
clear, immune cells called T cells attack the myelin sheathing, causing
symptoms including paralysis and blindness. The condition affects
400,000 people in the United States, according to the National Multiple
Sclerosis Society.
A few years ago while still a PhD student at the University of Alabama,
the study's first author, Robert Axtell, had shown that, as in people
with multiple sclerosis, beta-interferon can reverse paralysis in mice
with EAE. But it turns out that EAE can be induced by two different
autoimmune pathways, characterized by different patterns of secretion by
T cells.
Like nerve cells, immune cells also communicate with one another across
long distances, but they accomplish this through various chemicals
called cytokines that they secrete into the blood. Immune cells on the
receiving end of a cytokine "signal" may respond quite differently,
depending on the particular type of cytokine to which they are exposed.
Two cytokines called gamma-interferon and IL-17, for example, tend to
induce the kinds of inflammatory immune-system arousal that can trigger
multiple sclerosis.
Axtell (now a postdoctoral scholar in Steinman's lab), Steinman and
their colleagues were able to induce two superficially similar forms of
EAE in mice by directing the myelin-attacking T cells to predominantly
secrete either gamma-interferon or IL-17, respectively. The researchers
found that beta-interferon improved the condition of animals whose EAE
had been induced by gamma-interferon-secreting T cells, but exacerbated
symptoms in those whose EAE had been induced by IL-17-secreting T cells.
Intrigued, the investigators turned to humans. Another postdoctoral
scholar in the Steinman lab, Brigit deJong, MD, the study's second
author, had previously been involved in research in Amsterdam in which
multiple-sclerosis patients were treated with beta-interferon and
meticulously followed up. The Stanford group obtained blood samples
taken from 26 of these patients both before and about two years after
the initiation of treatment. Without knowing which samples came from
patients who had responded well or poorly to beta-interferon treatment,
they went about measuring IL-17 levels in those samples.
Eventually, patients' follow-up histories were revealed to the
researchers and their measured IL-17 levels were paired with their
post-treatment progress. A clear pattern emerged. Measurements of a
particular variety of IL-17, called IL-17F, clustered at either very
high or very low levels in individual patients' blood. Those with very
low detectable blood levels of IL-17F responded well to beta-interferon
treatment, experiencing no relapses or instances of required steroids
(to quickly shut down a malfunctioning immune system). But patients with
very high IL-17F levels — about one out of three subjects — responded
poorly by the same criteria. In fact, said Steinman, there is some
evidence that beta-interferon actually worsened these patients'
conditions.
Steinman cautioned that the results need to be confirmed in larger
patient groups, in his lab as well as in others. But, he said, "I think
this has the potential to transform the way we take care of people with
multiple sclerosis." He said a simple, already available blood test
could spare many patients the inconvenience and side effects — and spare
the health-care system the expense — of a drug that most likely won't do
any good. "The other side of the coin is that beta-interferon, if it's
given only to those who are predisposed to respond to it, could turn out
to be a far better drug than we ever imagined."
Although Steinman and his colleagues do not stand to benefit in any
direct way from this work, Stanford University's Office of Technology
Licensing has filed a patent application on the use of the blood test.
Earlier work by Steinman, proceeding from animal models to clinical
trials, led to the development of another blockbuster multiple-sclerosis
drug, natalizumab, marketed under the trade name Tysabri.