Scientists at the Johns Hopkins Kimmel
Cancer Center have found that a
gene pathway linked to a deadly form
of leukemia may provide a new way to treat
autoimmune diseases, including multiple
sclerosis. Their tests in cell cultures and
mice suggest that blocking the pathway by
interfering with a blood cell growth gene
known as FLT3 targets an immune system
cell often ignored in favor of T cell targets
in standard therapies.
FLT3, which controls the development of
healthy blood cells, was identified as a treatment
target in patients with acute myeloid
leukemia, a blood cell cancer, several years
ago by the same Johns Hopkins investigators.
In the current work, the team has confirmed
that the gene is activated in dendritic
cells, whose role is to distribute "look here"
information about unwanted foreign invaders
to soldiering T cells.
"Someday, using a drug to block FLT3
gene signaling could stop dendritic cells
from triggering harmful responses against
a patientís own body," said Donald Small,
professor of pediatric oncology, whose findings
appear in the Nov. 15 issue of the Proceedings
of the National Academy of Sciences.
Preliminary clinical tests in people with
autoimmune diseases with just such a drug
could begin in the next year, Small said.
A characteristic of autoimmune diseases is
that patientsí immune T cells mistake normal
cells in the body for foreign ones. Current
therapies, such as steroids, are designed
to suppress T cell responses. But the Hopkins
investigators believe that targeting dendritic
cells may stop the faulty immune response
at a higher "upstream" level since T cells
frequently receive their information from
Testing their idea, Small and Katherine
Whartenby, an assistant professor of oncology,
used an experimental compound called
CEP 701, already known to block actions
of the growth-promoting FLT3 gene, on
human dendritic cells and in mice engineered
to mimic multiple sclerosis, a disease
that causes T cells to destroy the myelin protein
sheath around nerves in the central nervous
system. The drug had a similar effect on
dendritic cells, causing most of them to die.
In the mouse model, investigators found that
more of the myelin sheath was preserved in
mice treated with CEP 701 than those not
Small cautions that massive die-off of dendritic
cells poses a possible risk of immune
system suppression, a condition that could
leave patients vulnerable to infections or
other diseases. "But our studies show that
though many dendritic cells were destroyed,
some still remained," he said.
The tests also revealed that mice infected
with a potent bacterium survived after treatment
with CEP 701.
This research was funded by the National
Institutes of Health. Additional authors are
Peter A. Calabresi, Erin McCadden, Bao
Nguyen, David Kardian, Tianhong Wang,
Claudio Mosse and Drew M. Pardoll, all of