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.