Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Marine sponge leads researchers to immune system regulator

12.11.2004


A Japanese brewery, an Okinawan sea sponge and some clever detective work have enabled an international research team based at the University of Chicago to solve a biological mystery, and the solution suggests a novel way to boost the body’s defenses against cancer.



In Science Express, the online early-publication version of the journal Science, the researchers provide evidence that a sugary lipid known as iGb3 plays a key role in regulating the response of natural killer T cells, a component of the immune system that plays an important role in preventing cancer, fighting infections and perhaps triggering or avoiding autoimmune diseases.

Discovered less than ten years ago, natural killer (NK) T cells are unusual because they target lipids, often bound to carbohydrates, rather than proteins. When presented with a lipid that may signal a threat, they pump out chemical signals, such interferon-gamma and interleukin-4, which tell other components of the immune system to rid the body of these invaders.


Mice with defects in this system are prone to cancer and susceptible to infections. On the other hand, misdirected NKT cells may play a role in autoimmune diseases, such as type-1 diabetes. "Until now we had no idea what activated NKT cells except for one curious compound, a glycosphingolipid derived from a marine sponge," said study author Albert Bendelac, "but once we learned that this compound could prevent the spread of cancer in mice, a lot of people became very interested."

Bendelac, M.D., Ph.D., a professor of pathology at the University of Chicago, is one of only a handful of immunologists who concentrate on NKT cells. Scientists know a great deal about how the immune system recognizes proteins, but comparatively little about this type of cell or the mechanisms the immune system uses to sort out lipids.

NKT cells are also odd in that they fall somewhere between the brute force of innate immunity and the flexible sophistication of adaptive immunity. They appear to have an ingrained ability to recognize some bacterial lipids. At the same time, they express less-variable versions of T-cell receptors. These stripped-down receptors enable NKT cells to respond to a limited array of lipid or carbohydrate antigens when presented in certain ways.

The only substance known to fully activate NKT cells through these receptors was the glycosphingolipid derived from an Okinawan sea sponge Agelas mauritianus. In the 1990s, researchers at the Kirin Brewery in Japan found this molecule alpha-Galactosyl-ceramide, by performing a pharmaceutical screen for natural compounds with anti-tumor activity. While this compound exhibited potent anti-cancer activity in vivo, there was no clue about the mechanism of action until researchers discovered that it was recognized by NKT cells.

A purified synthetic version, known as a-GalCer or KRN 7000, is now in phase-2 human clinical trials for several tumor types. One problem with a-GalCer, however, is that it can over-stimulate NKT cells. After a burst of activity and rapid secretion of interferon-gamma, NKT cells driven by a-GalCer essentially "burn out," disappearing from the circulation for weeks. "This sponge glycolipid, a-GalCer, is not a substance seen in mammals," said Bendelac. "But it pointed us toward similar molecules in our hunt for the natural substance that activates NKT cells."

Finding the natural activator -- what immunologist call the endogenous ligand -- for these cells is crucial to understanding their biology, he added, and might provide a gentler and more enduring way to get them to fight tumors.

Bendelac’s team developed several approaches to identify the endogenous ligand. One crucial clue came from the discovery of genetically deficient mice that have almost no NKT cells. Bendelac’s team found that these mice are unable to make an enzyme required to produce iGb3. Mice that lack this enzyme have a severe NKT cell deficiency, and are cancer prone. "We don’t yet know the real function of iGb3, how it works or even how to find and measure it in the body," Bendelac said, "but we suspect is serves as an alarm of some kind. It may be produced by cells that are stressed -- damaged by an infection or transformed into cancer cells. Then it alerts the immune system to the presence of cells in trouble."

Activating NKT cells may be particularly valuable for preventing or treating cancers that spread to the liver, where NKT cells are most common.

Understanding the role of iGb3 may also provide clues about autoimmune disease. NKT cells play an important, although still poorly understood, role in regulating all sorts of immune responses. Defects in the system may allow the body to attack itself, leading to chronic inflammation or tissue damage. "It has been extremely difficult to explore the mechanisms that govern the recruitment, activation and development of NKT cells without knowledge of the natural antigens recognized by these cells," said Bendelac. "Because of their role in regulating a range of diseases, this has been a source of intense research and speculation for years."

The National Institutes of Health supported this research. Additional authors were lead author Dapeng Zhou, plus Jochen Mattner, Yuval Sagiv and Kelly Hudspeth of the University of Chicago; Carlos Cantu, Nicolas Schrantz and Luc Teyton of the Scripps Research Institute; Ning Yin, Ying Gao and Paul Savage of Brigham Young University; Yunping Wu, Tadashi Yamashita and Richard Proia of the NIH; Susan Teneberg of Goteborg University, Sweden; Dacheng Wang of the Chinese Academy of Sciences; and Steven Levery of the University of New Hampshire.

John Easton | EurekAlert!
Further information:
http://www.uchospitals.edu

More articles from Life Sciences:

nachricht Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz

nachricht Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Fighting drug resistant tuberculosis – InfectoGnostics meets MYCO-NET² partners in Peru

28.04.2017 | Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

 
Latest News

Wireless power can drive tiny electronic devices in the GI tract

28.04.2017 | Medical Engineering

Ice cave in Transylvania yields window into region's past

28.04.2017 | Earth Sciences

Nose2Brain – Better Therapy for Multiple Sclerosis

28.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>