Discovery of T-cell "traffic control" boosts new drug promise

July 2005 cover of Nature Reviews Immunology -----

Scientists have begun to clarify how one of the body’s molecules controls the trafficking of T cells through the blood, lymph nodes and on to tissues to fight infection—a crucial response that sometimes goes awry, attacking the body’s own tissues and causing autoimmune diseases.

The traffic control system—composed of a fat-like compound called S1P and its receptor on T cells—usually prevents T cells from launching harmful reactions. But when the S1P traffic cop reacts incorrectly, T cells can swamp healthy tissue. The new research explains how a promising experimental drug treats the autoimmune disease multiple sclerosis by blocking excess S1P action. The research also shows the promise of similar strategies to prevent rejection of transplanted organs and tissues without compromising essential immune defenses.

The emerging view brings together research findings on S1P’s effect on both the immune system and the blood-circulating vascular system, showing how the two systems interact to regulate T cell circulation and prevent a constant and potentially dangerous release of T cells, or lymphocytes.

The research is presented this month in a special issue of Nature Reviews Immunology. Authors are Edward Goetzl, MD, at UCSF and Hugh Rosen, MD, PhD, at the Scripps Research Institute, scientists who have pioneered the new understanding. Goetzl is the Robert L. Kroc Professor of Medicine and Immunology at UCSF. Rosen is a professor of immunology at Scripps.

Goetzl and Rosen participated in the discovery of S1P’s role in T cell trafficking. Goetzl has also shown that S1P regulates T cell trafficking by occupying a receptor on the T cell surface that suppresses the cells’ normal response to a “forward march” signal.

T cells respond by chemotaxis—moving from areas of lower to higher concentration of a signaling molecule known as a chemokine.  Studies by the two scientists have shown that S1P and its T cell receptors block this signaling.
They slow the flood of T cells “called into” lymph nodes by chemokines.

The scientists made a second discovery about T cell movement: S1P, like chemokines, can also act as a chemotactic attractant to T cells. Once T cells enter lymph nodes—the sites where they encounter antigens for microbes and other infectious agents—they sense S1P in the outflowing blood and so migrate into the blood and onto tissues where they are needed to fight infection.

In a key experiment, Goetzl’s and Rosen’s labs showed that by chemically displacing S1P, its natural braking effect is released, stimulating T cell traffic into lymph nodes. Because this also blocks S1P’s chemotactic influence, migration of T cells out of the lymph nodes is greatly reduced.  T cells are essentially sequestered in the nodes.  Such an effect would prevent T cells from swamping newly transplanted organs or launching a harmful autoimmune reaction, the scientists suggest in the paper.

They think this mechanism underlies the promising clinical trial results of a new drug against multiple sclerosis (MS) recently reported by other researchers. That study showed that the experimental drug, FTY720, significantly reduced the destructive autoimmune process in patients with MS, a debilitating disease in which the body’s T cells attack the myelin coating of nerve cells and disrupt their function.  Neither Goetzl nor Rosen is involved in the on-going clinical trials of the new drugs and neither has financial ties to the companies that manufacture them.

Controlling this process with drugs offers “enormous potential” against devastating immune reactions, Goetzl says.

“Transplanting organs or even cells, such as insulin-producing Beta cells, into a patient triggers immune reactions that reject the transplant, but a drug such as FTY720 controls S1P function and slows the rush of T cells to the transplantation site without blocking normal immune response against bacteria and other infectious agents,” he says. Similarly, such a drug should slow the autoimmune response that occurs in MS, a hypothesis recently confirmed in phase 2 clinical trials, he says.

Such drugs do not interfere with essential protective immune function since bacterial proteins that normally trigger immune defense do so when they enter lymph nodes—“where the T cells are essentially trapped by the drug for a few days, but still are working fine and allowing new antibody formation,” he explains.

Treatment using this drug strategy does not come without risks, Goetzl cautions. Current drugs that affect one type of S1P receptor affect all others as well, and some of these control heart rate and muscle development. In clinical trials of some of these kinds of drugs, a number of patients have tired easily, experienced lower blood flow and a tendency for airways to constrict as muscle walls develop abnormally, Goetzl says.

“Fully exploiting this approach for treatment of autoimmune diseases and transplant rejection will depend on developing new drugs that block only the immune type of S1P receptor,” he adds. “But early studies by a number of researchers are quite promising.”

Progress will also come from finding “uniquely effective combinations of these agents with other immunosuppressive drugs,” he says.

In animal studies and clinical research with patients over more than a decade, scientists have come to understand that millions of T cells and B cells are “called” into lymph nodes by other immune molecules called chemokines.

“But we began to wonder why T cells don’t always swarm into lymph nodes and flood on into blood vessels that lead to all parts of the body,” Goetzl says.
“We asked ourselves, ‘What is the brake?’”

In research with mice that have T cells that lack S1P receptors or have over-expressed receptors, the Goetzl and Rosen labs and others determined that T cells have on their surfaces what are known as G protein-coupled receptors, which when occupied by chemokines—their natural binding partners—prompt the T cells to rush into lymph nodes. But S1P, they found, can act through its own G-coupled receptors to prevent chemokines from triggering T cell movement. In ways not yet fully understood, this process is reversible, providing the body with a crucial control over when and how much of the potent T cell soldiers to release into the blood stream.

Research support for both Goetzl and Rosen comes from the National Institutes of Health.

NOTE: S1P is an abbreviation for Sphingosine1-phosphate, one of a family of fat-like molecules that affect proliferation and diverse functions of many cell types.