New Tool Can Boost or Block the Body’s Protective Inner Barriers

A team of experts funded by the National Institutes of Health (NIH) has developed a chemical tool that allows scientists to manipulate control of the passage of substances through the barriers between blood and the tissues of every organ — from the brain, lungs, and heart to the organs of the immune system. The passage of substances, such as immune cells, water, and other fluids that occurs through these barriers maintains a healthy balance between the blood and tissues; however, serious illness may result when the balance is disrupted. Fluid may accumulate in the lungs, for example, or lymph organs may inappropriately release immune cells that attack the body’s own tissues, as in multiple sclerosis and other autoimmune diseases.

The study, conducted in living mice, focused on the S1P1 receptor system, a mechanism that opens and closes molecular “gates” on biological barriers, such as the lining of blood vessels and barriers in the tissues of lymph organs. Researchers showed that they could manipulate the mechanism with selective chemical compounds, raising the possibility of finding ways to alter the mechanism for prevention and treatment of illnesses. Together, the compounds act as a pair of chemical probes that interact with the receptor in ways that enable researchers to explore the receptor system’s actions.

The probes will enable scientists to define medically important functions of the S1P1 receptor system by seeing how biological barriers change — and the physiological effects of those changes — when researchers alter the “set point” at which the receptor goes into action. Results of the study will be published on-line July 9, 2006, and in the August issue of Nature Chemical Biology.

The probe is among the first developed by scientists working within the Molecular Libraries Screening Centers Network (MLSCN) initiative, part of the NIH Roadmap, an enterprise designed to answer fundamental questions that are shared by many fields of research and whose answers will lead to major progress in virtually all of them. The MLSCN initiative, which was established in 2004, is guided by two NIH institutes, the National Institute of Mental Health and the National Human Genome Research Institute. Other chemical probes are likely to follow from the initiative’s efforts, since its purpose is to develop such tools for the scientific community.

“This chemical tool has implications for research on the brain, the lungs, the heart; anywhere in the body that there are biological barriers which must be crossed and whose dysfunction can result in illness,” said NIH Director Elias Zerhouni, M.D. “This is exactly the kind of fundamental finding the NIH Roadmap was designed to generate, which scientists from here to academia to industry can use to accelerate their research toward practical applications,” he added.

Led by Hugh Rosen, MB.ChB., D. Phil., of The Scripps Research Institute, a team of investigators focused on two different biological barriers, among the many on which S1P1 receptors are found: capillary walls, where exchange of substances between the blood and tissues occurs; and lymph organs, which produce and regulate passage of lymphocytes, the main cells of the immune system, into the bloodstream.

The integrity of the lymph barrier is important because lymphocytes must be retained in lymph organs long enough to mature so they will be effective in fighting infection, for example, when they are released across the barrier into the bloodstream and travel to tissues where they are needed. In some cases, even properly matured lymphocytes sent across the barrier can cause problems, as when the immune system “sees” a transplanted liver as a foreign invader and releases lymphocytes to destroy it.

“In cases like autoimmune disease or rejection of organ transplants, or when the lungs are filling up with dangerous levels of fluid because of leaky capillaries, being able to reversibly manipulate the mechanisms that control what gets across biological barriers would be helpful to patients,” said Rosen. “This probe helps us learn how to do that safely,” he added.

Rosen and his team used a chemical compound to block the S1P1 receptor, to promote passage of substances through the barriers of the vascular and immune systems. They then used selective activators of the S1P1 receptor to reverse these effects. Having thus established these probes, the team found that vascular and immune-system tissues differ in the “set points” at which their S1P1 receptors go into action. The barrier in blood vessels remained intact at naturally occurring “resting” levels of receptor activity, but to strengthen the barrier in immune organs to levels that would prevent lymphocytes from being released, the scientists had to boost the receptor’s activity.

The team began by searching published studies on compounds to find those likely to be useful for showing that the S1P1 receptor is a crucial part of the molecular gating system and for manipulating the receptor. From these leads, they synthesized two receptor blockers that were mirror images of each other. Much as only a person’s right hand fits into a right-handed glove, the shape of one or the other of the compounds was likely to fit better into the shape of the S1P1 receptor, to interact with it. The “right-handed” compound was about 100-fold more potent at interacting with the receptor than was the left-handed compound, and it alone proved to be a valuable tool for manipulating the receptor in mice.

Rosen was joined in this research by Chi-Huey Wong, of The Scripps Research Institute (TSRI); Michael Cahalan and Ian Parker, University of California, Irvine (UC, I); M. Germana Sanna and Sheng-Kai Wang (TSRI); Pedro J. Gonzalez-Cabrera (TSRI and Novartis Foundation); Anthony Don (TSRI); David Marsolais (TSRI); Melanie P. Matheu (UC,I); Sindy H. Wei (UCI); Euging Jo (TSRI); and Wei-Chieh Cheng (TSRI).

NIMH is part of the National Institutes of Health (NIH), the Federal Government’s primary agency for biomedical and behavioral research. NIH is a component of the U.S. Department of Health and Human Services.

The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Reference: Sanna MG, Wang SK, Gonzalez-Cabrera PJ, Don A, Marsolais D, Matheu MP, Wei SH, Parker I, Euijung J, Cheng WC, Cahalan MD, Wong CH, Rosen H. Enhancement of Capillary Leakage and Restoration of Lymphocyte Egress by a Chiral S1P1 Antagonist In Vivo. Nature Chemical Biology, online ahead of print, July 9, 2006.

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National Institute of Mental Health (NIMH)

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