Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Silencing a protein could kill T-Cells, reverse leukemia

24.10.2008
Blocking the signals from a protein that activates cells in the immune system could help kill cells that cause a rare form of blood cancer, according to physicists and oncologists who combined computer modeling and molecular biology in their discovery.

Researchers say the breakthrough could provide more efficient ways of targeting diseases such as leukemia, and help in the potential development of vaccines for viruses that cause AIDS.

The human immune system has a two-part strategy when dealing with infections. It generates antibodies that bind with bacteria and viruses to neutralize them. For a short time, the immune system also produces large numbers of a type of white blood cell, cytotoxic T-cell that kills other infected cells.

Once the pathogens are eliminated, these killer T-cells quickly die on their own, save for a few that remain in case the same infection returns. But in rare cases, these cells fail to follow their scripted lifecycle.

"When these cells don't normally die, they expand gradually over time and start attacking the body itself," said Thomas Loughran, M.D., lead author and director of Penn State Hershey Cancer Institute. "They can attack the joints to cause autoimmune diseases such as rheumatoid arthritis, and attack the bone marrow to cause leukemia."

Loughran, professor of medicine, and his Penn State colleagues are trying to tease out the conditions that cause the abnormal expansion of T-cells and trigger a disease known as large granular lymphocyte leukemia. So they constructed an intricate computer model illustrating the signaling network involved in the activation of the T-cells, as well as their programmed death.

The network model strings together complex data of molecular pathways inside a cell involving hundreds of genes and proteins and tries to predict an outcome based on how the genes and proteins interact.

"The interactions among proteins make them turn ON or OFF or intermittently ON or OFF to get billions of possibilities with hundreds of proteins," said Reka Albert, co-author and Penn State associate professor of physics and biology. "By simulating the protein interactions and tracing the ON/OFF states of all those proteins at the same time, we can see whether the cells live or die."

Albert explains that the model could help researchers zero in on the exact location of the signaling abnormalities that are keeping T-cells from dying. Once that is known, specific genes or proteins could be targeted with drugs to get rid of the abnormality.

Sifting through the billions of possibilities projected by the model, the researchers have found two proteins – IL-15 and PDGF – that appear to be crucial in keeping the T-cells alive. While IL-15 is key to the survival and activation of T-cells, PDGF stimulates the growth of those cells.

"You need the presence of both these proteins to create conditions in which the cytotoxic T-cells can proliferate," said Loughran, whose team's findings were recently published this week in the Proceedings of the National Academy of Sciences. "That is a major point of the discovery."

The researchers have also discovered another signaling protein -- NFêB -- controlled by the two proteins, which protects cancer cells from dying if it is over expressed.

"NFêB controls a host of other proteins related to inflammation in the body and our model suggests that if we keep it in the OFF state, it is able to induce cell death in the T-cells," explained Albert, who, together with graduate student Ranran Zhang, created the model. "In other words, we can reverse the disease by setting this molecule OFF."

When researchers blocked NFêB with drugs in cells from leukemia patients, they found a significant increase in mortality among the abnormal T-cells, suggesting that NFêB helps in the survival of leukemia cells.

"Basically when this protein is inhibited and not expressed anymore, the cells die," said Loughran. "It validates our model."

It is still unclear as to what prevents the T-cells from dying off, though researchers suspect that a chronic virus might be continually activating the cells. However, there is no clear evidence for the theory, but network modeling may be a start.

According to Albert, such models could save time and money in pointing out promising candidates – genes and proteins – for drug delivery. "Our model provides a shortlist of therapeutic targets that can be manipulated with drugs to kill off leukemia cells," she added.

The Penn State researchers are also looking to harness errant behavior of the T-cells in combating other deadly diseases.

"In complicated infections like HIV, and in diseases such as cancer, you need to have an immune response that comprises both antibodies and cytotoxic T-cells," explained Loughran. "The problem is nobody has been able to generate a long-lived cytotoxic T-cell response in normal people."

Since T-cells in people suffering from large granular lymphocyte leukemia are active, long-lived, and function like killer T-cells, Loughran believes that if his team can unlock the secret behind these cells' longevity, then T-cells in normal healthy people could be equipped with the same ability to fend off other deadly infections.

"The key is to find the master control switches that keep these cells alive," said Loughran, whose work is funded by the National Institutes of Health and the National Science Foundation. "And maybe those could be blocked directly."

Amitabh Avasthi | EurekAlert!
Further information:
http://www.psu.edu

More articles from Life Sciences:

nachricht Researchers identify potentially druggable mutant p53 proteins that promote cancer growth
09.12.2016 | Cold Spring Harbor Laboratory

nachricht Plant-based substance boosts eyelash growth
09.12.2016 | Fraunhofer-Institut für Angewandte Polymerforschung IAP

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Electron highway inside crystal

Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.

Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Researchers identify potentially druggable mutant p53 proteins that promote cancer growth

09.12.2016 | Life Sciences

Scientists produce a new roadmap for guiding development & conservation in the Amazon

09.12.2016 | Ecology, The Environment and Conservation

Satellites, airport visibility readings shed light on troops' exposure to air pollution

09.12.2016 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>