The Search for Anti-Adhesion Therapy

In the mid-1980s, UW Medical Center treated a boy with a rare condition. His white blood cells didn’t accumulate at the site of a local infection to fight off invasive microbes. Routine infections became life threatening. He died some years later.

The boy’s case sparked research on the fundamental process that had gone awry: the adhesion of white blood cells at an infection site and their movement from the bloodstream into the infected tissue. Dr. John Harlan, professor of medicine and head of the Division of Hematology, pioneered the field of adhesion biology.

“We helped identify in white blood cells a key adhesion molecule that the boy lacked,” said Harlan. “This molecule acts like glue. It enables a white blood cell to stick to the blood vessel lining at the infection site.”

Although the boy’s rare problem had been too little adhesion, many diseases occur because of too much. Harlan realized that drugs to inhibit adhesion could potentially offer a new form of therapy for inflammatory and immune diseases. The ultimate goal of his work, now spanning 20 years, is anti-adhesion therapy.

The movement of white blood cells (or leukocytes) across the blood vessel wall from bloodstream to tissue is part of the body’s normal defense against infection. Once in the tissue, leukocytes ingest and kill bacteria.

Many diseases are thought to be due to an excessive immune response, when the leukocytes overload and cause tissue inflammation. Autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, and inflammatory diseases could in theory be prevented if cell adhesion were inhibited. Leukocytes, failing to stick to the blood vessel lining, would stream by in the blood.

Harlan’s work confirmed, first in cell cultures and then in animal models, that antibodies blocking the adhesion molecules could prevent tissue damage. Today almost 20 adhesion molecules have been identified. Pharmaceutical and biotech companies are pursuing anti-adhesion therapy. In clinical trials, the results for stroke and heart attack have been disappointing to date, but the efficacy of anti-adhesion therapy has been demonstrated for inflammatory bowel disease, multiple sclerosis, and psoriasis. FDA approval is pending for several drugs.

In the late 1990s, Harlan studied leukocyte adhesion deficiency in a second patient. That work, in collaboration with a team at the Technion in Haifa, Israel, helped identify a treatment for the disorder as well as potential drug targets.

Harlan is delving deeper into the adhesion process by investigating the biochemical signaling pathways within leukocytes that switch adhesion on and off to make them stick at a site of infection but not stick elsewhere. In 2002, he identified a key molecule regulating leukocyte adhesion.

In June of 2002, Harlan was named Clement A. Finch, M.D., Endowed Professor of Hematology.