T-cell control discovery boosts new drug research
research after the process of T-cell trafficking through the blood
and lymph nodes to fight infection was discovered. Controlling this
process with drugs offers "enormous potential" against devastating
immune reactions.
The researchers said that the mechanism, which formed the basis of ongoing clinical trial results, might eventually result in a new drug against multiple sclerosis (MS) Swiss drug company, Novartis, showed that 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.
The new approach centres on the traffic control system, composed of a fat-like compound called S1P and its receptor on T cells, which usually prevents T cells from launching harmful reactions.
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. Similarly, such a drug should slow the autoimmune response that occurs in MS, a hypothesis recently confirmed in phase 2 clinical trials.
The researchers, from the Scripps Research Institute and the University of California at San Francisco (UCSF), said that such drugs do not interfere with immune function since bacterial proteins that normally trigger immune defence do so when they enter lymph nodes.
"The T cells are essentially trapped by the drug for a few days, but still are working fine and allow new antibody formation," explained Edward Goetzl, professor of Medicine and Immunology at UCSF.
However, treatment using this drug strategy does not come without risks, Goetzl added. 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.
"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 said.
Goetzl participated in the discovery of S1P's role in T cell trafficking along with Hugh Rosen, professor of immunology at Scripps Research Institute, 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 signalling molecule known as a chemokine. Studies by the two scientists have shown that S1P and its T cell receptors block this signalling. 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.
The research is presented this month in a special issue of Nature Reviews Immunology.
