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!
Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory
How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
24.03.2017 | Materials Sciences
24.03.2017 | Physics and Astronomy
24.03.2017 | Physics and Astronomy