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Dendritic cells offer new therapeutic target for drugs to treat MS and other autoimmune disease

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 Hopkins 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 patient's own body," says Donald Small, M.D., Ph.D., professor at the Johns Hopkins Kimmel Cancer Center, whose findings appear in the November 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 patients' 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 his Hopkins colleague Katherine Whartenby 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 m ultiple 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.

Their tests also revealed that mice infected with a potent bacterium survived after treatment with CEP-701.

Additional authors include Peter A. Calabresi, Erin McCadden, Bao Nguyen, David Kardian, Tianhong Wang, Claudio Mosse and Drew M. Pardoll from Johns Hopkins.


Source:Johns Hopkins Medical Institutions

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