A new therapy effectively treats a disease similar to multiple sclerosis
(MS) in monkeys, and the approach could soon be tested against MS and other
autoimmune diseases in humans. The therapy's promising results, reported by
scientists at the National Institute of Allergy and Infectious Diseases (NIAID),
will be published in the February 1 issue of the Journal of Immunology.
"Current treatments for MS broadly suppress the immune system and can cause
toxic side effects," says senior study author Michael Lenardo, M.D., of NIAID's
Laboratory of Immunology. "This treatment, called antigen-specific immunotherapy,
specifically targets the immune system's T cells that cause the disease. Presumably,
it would not lead to such side effects."
Autoimmune diseases such as rheumatoid arthritis, type 1 diabetes and MS
affect approximately 5 percent of the US population. Directly and indirectly,
they cost the US economy more than $100 billion per year. "Immune-mediated
diseases are a major cornerstone of the NIAID research effort," says Anthony
S. Fauci, M.D., director of NIAID. "Efforts such as Dr. Lenardo's hold great
promise for developing new treatments for individuals with autoimmune diseases."
MS is a paralyzing disease that affects nerves in the brain and spinal cord,
disturbing speech, vision and movement. MS primarily strikes young adults,
most often women who live in northern latitudes. The disease is caused by
a malfunction in the immune system: certain white blood cells called T cells
mistakenly attack myelin sheaths, protective coverings that surround the signal-carrying
fibers of nerve cells.
Antigen-specific immunotherapy is based on a discovery by Dr. Lenardo and
his colleagues that T cells exposed to small amounts of the proteins making
up the myelin sheaths are stimulated to attack the sheaths. But T cells exposed
to large amounts of the same proteins will undergo a pre-programmed "self-destruct"
sequence. (In fact, T cells exposed to large amounts of any antigen — a substance
that provokes them to attack — will self-destruct.) Therefore, introducing
large amounts of myelin proteins into the body should remove the problematic
T cells and halt the disease, Dr. Lenardo explains.
"The therapy is counter-intuitive; one might think it would be like pouring
gasoline on a fire," Dr. Lenardo says. But the self-destruct sequence actually
protects the body from having too many active T cells, which can themselves
be toxic. "Like any potent weapon, you want to control how much is deployed,"
Dr. Lenardo explains. "The immune system doesn't let your T cells grow uncontrolled
and kill you. In this case, adding more antigen smothers the fire."
Dr. Lenardo and his colleagues first injected nine male marmoset monkeys
with just enough myelin proteins to stimulate their T cells to attack myelin
sheaths, inducing a disease very similar to MS in humans. Three monkeys then
received additional large doses of myelin proteins, three received moderate
doses, and three received nothing. The monkeys were observed for 105 days.
All three of the untreated monkeys showed clinical symptoms of the disease.
In contrast, none of the monkeys in the large-dose group showed symptoms.
In the moderate-dose group, two of the three showed symptoms, but those symptoms
were significantly delayed.
Magnetic resonance images of the animals' brains revealed severe damage to
the myelin sheaths in two of the untreated monkeys and one of the moderate-dose
monkeys. Minor damage did occur in the large-dose group, indicating the disease
process had not been completely thwarted although it had been greatly suppressed.
The treatment appeared to cause no adverse side effects. Researchers at the
National Institute of Neurological Disorders and Stroke assisted with the
Dr. Lenardo and his colleagues are investigating how the therapy works against
other autoimmune diseases in laboratory mice. One such disease under investigation
is myasthenia gravis, a paralyzing condition affecting children that is caused
when the immune system mistakenly attacks the receptors on muscle cells that
receive nerve impulses.