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The newspaper of The Johns Hopkins University February 13, 2006 | Vol. 35 No. 21
 
Dendritic cells offer new target for treating autoimmune diseases

By Vanessa Wasta
Johns Hopkins Medicine

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 dendritic cells.

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 treated.

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 Johns Hopkins.

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