New Way to Block Rush of Immune Cells
Researchers have found a way to selectively block the ability of white blood cells to “crawl” toward the sites of injury and infection when such mobility drives disease, according to a study published in The Journal of Experimental Medicine. The results suggest a new treatment approach for autoimmune diseases like rheumatoid arthritis, lupus and multiple sclerosis, and for conditions made worse by misplaced inflammation, like atherosclerosis, stroke and transplant rejection, researchers said.
Disease-fighting cells move toward bacteria and cells infected with viruses, which they target for destruction. Unfortunately, the same cells can mistakenly attack the body’s own cells or drive inflammation too far, worsening the problem they rushed in to solve.
A team of researchers at the University of Rochester Medical Center has been studying proteins called integrins that enable T cells, a major subset of immune cells, to migrate. These scientists described for the first time a way to shut down only those T cells currently in the act of disease-related migration, while leaving in place reserves needed in the likely event that another infection occurs during treatment.
“There are many cases where it would be incredibly useful to precisely block integrin activation, and thus T cell migration,” said Minsoo Kim, PhD, lead author of the article. “Good examples include when our immune system attacks our own cells, or rejects a lifesaving transplant or clogs our blood vessels by mistake. The problem is that past, system-wide attempts that block all integrin activation … shut down not only unwanted inflammation in one locale, but also vital immune defenses elsewhere, leaving patients vulnerable to infection.”
The Great Migration
Two mechanisms make cell migration, possible. The first, called chemotaxis, tells the cell which direction to move in. Cell surface proteins sense and follow chemicals and molecules they are attracted to toward wherever those attractants are most concentrated. T cells move toward the byproducts of bacteria and viruses.
The second migratory mechanism is propulsion. In between infections and injuries, inactive T cells ride along with the bloodstream. T cells “realize” when they pass by part of a blood vessel wall close to the site of an injury or infection. Integrins on their surfaces unfold and grab onto key proteins on the surface of blood vessel wall cells (e.g., ICAM), resisting the surrounding blood flow. The T cells then pass through the vessel wall, and once outside the bloodstream, crawl along the tissue scaffolding toward the site of injury.
In a T cell at rest, integrins are distributed evenly over the entire surface of the T cell. When the cell gets ready to move, however, activated integrins cluster on the leading edge of the cell in the direction the cell wants to move. They bind to their counterpart adhesion proteins (like ICAM) on the surface that the T cell is moving across. The T cell then contracts to pull itself along. The integrins on the front end “grab hold” in a new spot and trailing edge integrins let go. Without precise biochemical changes that enable the front end to gain traction, and the tail to let go, the cell cannot migrate.
Kim’s team was able to figure out the chemical changes that allow the integrins to grab and let go, enabling movement. They also were able to prevent specific chemical interactions, reducing the ability of the T cells to crawl.
In the next phase, the team will seek to develop better-targeted, anti-integrin therapies to regulate T cell migration.
“Initial clinical studies on T cell migration focused on overall blocking of migration, but general inhibition is a blunt tool,” said Tim Mosmann, PhD, director of the Vaccine Biology and Immunology center at University of Rochester. “As studies such as Dr. Kim’s help us to understand the process more precisely, we should be able to design much more precise methods to block migration in the selected circumstances that cause problems, without crippling the essential immune responses to infections.”
This article was adapted from a press release issued by the University of Rochester.