NEWS: Discovery of T-cell 'traffic control' boosts new drug promise

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Discovery of T-cell 'traffic control' boosts new drug promise

15 Jul 2005

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 Goetzl, MD, at UCSF and Hugh

Rosen, MD, PhD, at the Scripps Research Institute, scientists who have

pioneered the new understanding. Goetzl is the 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.

Wallace Ravven

wravven@...

415-476-2557

University of California - San Francisco

http://www.ucsf.edu

http://www.medicalnewstoday.com/medicalnews.php?newsid=27449