Jefferson: Multiple sclerosis (MS) is caused by immune cells that activate a
cascade of chemicals in the brain, attacking and degrading the
insulation that keeps neuronal signals moving. These chemicals, called
cytokines, drive the inflammation in the brain, attracting more immune
cells, and causing the debilitating disease marked by loss of
neurological function. Researchers have long debated which cytokines
drive the disease and which are merely accessory. Now, a study published
online April 27th, in the Journal of Immunology, confirms that
the cytokine GM-CSF (Granulocyte macrophage colony-stimulating factor)
likely plays an important role in human disease and offers a new
explanation for why the MS treatment interferon-Beta (INF-β) is often
effective at reducing MS attacks.
“After our animal studies showed that GM-CSF was important in the
development of an MS-like disease, we were excited to see these results
confirmed using samples from MS patients in the current study,” says
Abdolmohamad Rostami, M.D., Ph.D., Chair of the Department of Neurology
at Thomas Jefferson University and director of its neuroimmunology laboratory.
A few years ago, MS researchers were focused on a new type of immune
cell called the Th-17 cell, which appeared to be a key player in driving
the neuronal damage in MS. Because Th-17 cells produce the cytokine
IL-17, researchers likewise thought this chemical was essential to the
disease. IL-17, however, turned out to be something of a red herring.
In a paper published in Nature Immunology in 2011, Dr. Rostami
and colleagues showed that the Th-17 cells also produced another
cytokine called GM-CSF, which created a chain reaction with another cell
type ultimately increasing the GM-CSF levels in the brain of mouse
models significantly. In addition, the researchers showed that in
experimental models of MS, mice that were unable to produce GM-CSF never
developed the disease, whereas mice lacking IL-17 did develop the
disease, though generally developed a milder form.
In the new study, to test whether the same observation was true in
humans, Dr. Rostami and colleagues tested blood samples of patients with
MS who had not yet received therapy, and those currently being treated
with INF-β, a commonly used therapy. On average, untreated patients had
two to three times as many immune cells producing GM-CSF as did
patients being treated with INF-β, or normal subjects. In addition, the
researchers looked at brain samples of deceased patients with MS and
found increased numbers of GM-CSF-producing cells in comparison to
normal brain samples. “The study demonstrates a new mechanism of action
for INF-β therapies,” says Dr. Rostami.
In addition, a recent Phase 1 clinical trial of an antibody that
blocks GM-CSF showed early signs of effect. Phase 1 trials are
typically only designed to determine if a new drug is safe, and can’t
answer whether a new drug works. However, these results together with
the work from the Rostami lab suggest that GM-CSF is a target worth
pursuing for the treatment of MS.
“We hope that this research showing GM-CSF is an important target
will lead us toward therapies that more effectively block the damaging
immune reaction in the central nervous system of MS patients,” says Dr.
Rostami.