By Lisa Seachrist

Washington Editor

WASHINGTON — It all began nearly 50 years ago with a mouse named "scurfy."

Make that a strain of mice that researchers at the Oak Ridge National Lab, in Oak Ridge, Tenn., developed and dubbed scurfy. Females of the scurfy type are uniformly unremarkable, but approximately half of all scurfy males come down with extensive autoimmune trouble that kills them within three weeks of being born.

Tucked away on the animals' X chromosome is a mutation in a gene that allows the immune system to launch a relentless attack on the animal's own tissues.

From those mice, Chiroscience Group plc, of London and Seattle, has isolated the culprit gene and learned the product of that gene serves as an on/off switch for immune responses. Company researchers have found a similar gene residing on the X chromosome of humans.

"This is a novel gene that was not known previously," said Fred Ramsdell, director of discovery biology for Chiroscience. "It also resides in a novel pathway for controlling the immune system. It's an exciting and important discovery."

Chiroscience has filed patents for the gene as a novel, proprietary drug target in a number of autoimmune and inflammatory diseases, as well as in cancer. The gene could ultimately play a role in rheumatoid arthritis, diabetes, psoriasis, Crohn's disease, ulcerative colitis and allergy as well as cancer and AIDS.

The gene product appears to regulate the activity of CD4 T-cells, the cell type that dwindles as a result of infection with HIV. Ramsdell said the company has determined the function of the gene, but the information will remain proprietary while the company works on characterizing the pathway by which it regulates CD4 T-cells.

Male mice carrying the mutation experience uncontrolled growth of CD 4 cells, and have massive amounts of cytokines in their bloodstreams. When the animals die, their lymph nodes and spleens are enlarged to five to 10 times the normal size.

Ramsdell said Chiroscience has no idea if a similar mutation occurs in humans, because there is no human disease that mimics what happens to the mice. However, he also said that it is possible that any male fetus carrying such a mutation wouldn't survive to birth.

Discovering ways to dampen the growth of T-cells would provide an effective means to treat autoimmune diseases, while enhancing proliferation of the cells could offer ways to combat cancer and AIDS. Chiroscience will focus on developing small-molecule drugs aimed at various steps in this new pathway.

"We want to be able to modulate the immune system," Ramsdell said. "In order to do that, we need to know how this gene product works. So, we are dissecting the biochemistry of the pathway to see where it intersects with the pathways we already know about."

The scurfy mice project grew from a collaboration between Darwin Molecular Corp., of Seattle, and the Oak Ridge National Lab. In November 1996, Chiroscience bought most of Darwin — mainly, Ramsdell said, because of the ongoing research there. *