Study identifies mechanisms responsible for improved immune system activity, offering new approaches for more effective cancer treatments and vaccines.
Invariant natural killer T (iNKT) cells are powerful weapons our body’s immune systems count on to fight infection and combat diseases like cancer, multiple sclerosis, and lupus. Finding ways to spark these potent cells into action could lead to more effective cancer treatments and vaccines.
While several chemical compounds have shown promise stimulating iNKT cells in mice, their ability to activate human iNKT cells has been limited.
Now, an international team of top immunologists, molecular biologists, and chemists led by University of Connecticut chemistry professor Amy Howell reports in Cell Chemical Biology the creation of a new compound that appears to have the properties researchers have been looking for.
The compound – a modified version of an earlier synthesized ligand – is highly effective in activating human iNKT cells. It is also selective – encouraging iNKT cells to release a specific set of proteins known as Th1 cytokines – that stimulate anti-tumor immunity.
One of the limitations of earlier compounds was their tendency to cause iNKT cells to release a rush of different cytokines. Some of the cytokines turned the body’s immune response on, while others turned it off. The conflicting cytokine activity hampered the compounds’ effectiveness.
The new compound – called AH10-7 – is uniquely structured so that does not happen.
“One of the goals in this field has been to identify compounds that elicit a more biased or selective response from iNKT cells, and we were able to incorporate features in AH10-7 that did that,” says Howell, who has been studying the role of glycolipids in modulating the human immune system for more than 20 years.
The robust study, years in the making, also applied advanced structural and 3-D computer modeling analysis to identify the underlying basis for the new compound’s success. These highly detailed insights into what is happening at the molecular level open up new paths for research and could lead to the development of even more effective compounds.
“We synthesized a new compound, demonstrated its effectiveness with biological data, and learned more about its interactions with proteins through X-ray crystallography and computational analysis,” says UConn associate professor of chemistry José Gascón, a specialist in quantum and molecular mechanics. “We are providing protocols so that other scientists can rationally design related molecules that elicit desired responses from iNKT cells.”
The molecular analysis helped validate and explain experimental results.
“By exposing a crystalized form of the molecular complex to a high-intensity X-ray beam at the Australian Synchrotron, we were able to obtain a detailed 3-D image of the molecular interplay between the invariant natural killer T cell receptor and AH10-7,” says corresponding author Jérôme Le Nours, a structural biologist with the Biomedicine Discovery Institute at Monash University in Australia. “This enabled us to identify the structural factors responsible for AH10-7’s potency in activating iNKT cells. This valuable insight could lead to the development of even more effective anti-metastatic ligands.”
Efforts to harness the therapeutic potential of human iNKT cells began 20 years ago with the discovery that natural and synthetic forms of glycolipid ligands known as alpha-galactosylceramides, or ?-GalCers for short, were potent activators of iNKT cells. Scientists immediately recognized their possible value in fighting cancer and other diseases. These ?-GalCer ligands serve as tiny dock masters in our immune system, helping antigen-presenting cells attract and bind with iNKT cells so they can be activated to kill cancerous cells or fight off pathogens and other foreign invaders.
The first promising version of a synthesized ?-GalCer was a compound known as KRN7000. While KRN7000 powerfully stimulated iNKT cells in both mice and humans, it triggered the release of a flood of many types of cytokines, limiting its potential for clinical applications. Since then, researchers have been searching for new variations of KRN7000 that maintain their effectiveness in activating human iNKT cells while also favoring release of the powerful tumor fighting Th1 cytokines.
In the current study, Howell and colleagues made two significant modifications to an ?-GalCer ligand in an attempt to make it more effective. They found that adding a hydrocinnamoyl ester on to the sugar stabilized the ligand and kept it close to the surface of the antigen-presenting cell, thereby enhancing its ability to dock with and stimulate human iNKT cells. In addition, trimming off part of the molecule’s sphingoid base appears to initiate the critical Th1 cytokine bias. Both changes, working in tandem, strengthened the effectiveness of the entire molecular complex in terms of activating human iNKT cells, Howell says.
To further validate AH10-7’s effectiveness, the researchers tested the new compound in wild mice as well as partially “humanized” mice, whose genomes were modified to mimic the human iNKT cell response. Notably, AH10-7 was shown to be at least as effective as KRN7000 in suppressing the growth of melanoma cells in the partially humanized mice.
The Latest on: Immune system
via Google News
The Latest on: Immune system
Gut's 'taste buds' help school the immune system in the thymus
on July 18, 2018 at 10:58 am
Researchers were recently surprised to discover fully formed gut and skin cells in the thymus, a lemon-sized organ that sits in front of the heart and is responsible for training the T cells of the im... […]
Childhood Adversity – Risk for Addiction Via Immune Response
on July 18, 2018 at 9:41 am
‘Childhood adversity may increases susceptibility to addiction in adulthood by altering peripheral and central immune systems.’ The findings help explain why as many as 50 percent of people who experi... […]
Bioceutical Manufacturer Launches Products To Enhance Immune System, Increase Energy
on July 18, 2018 at 7:17 am
MIAMI, July 18, 2018 /PRNewswire/ -- Miami-based ScimeraMD, a leading bioceutical manufacturer, has announced the launch of two new physician-formulated, natural products that can enhance the immune s... […]
Powering up the Elderly's Immune System
on July 17, 2018 at 6:30 pm
As we age our immune system weakens, leading to diseases such as influenza and pneumonia taking a toll on the elderly across the world. For people over 65 years of age infections are a leading cause o... […]
Digital Immune System Launched to Prevent Wildfires and Power Outages
on July 17, 2018 at 2:43 pm
Dispatchr Inc. and Hitachi Consulting Corporation, a subsidiary of Hitachi, Ltd. have announced the limited availability of the industry's first Digital Immune System (DIS) designed for electric utili... […]
Childhood hardship primes immune system for addiction
on July 17, 2018 at 7:38 am
Childhood adversity permanently alters the peripheral and central immune systems, increasing the sensitivity of the body’s immune response to cocaine, reports a study by researchers at the IRCCS Santa ... […]
The immune system: T cells are built for speed
on July 17, 2018 at 2:45 am
Without T cells, we could not survive. They are a key component of the immune system and have highly sensitive receptors on their surface that can detect pathogens. The exact way that these receptors ... […]
Drug boosts immune system in elderly people by 40% and it also has antiaging effect in fruit flies
on July 16, 2018 at 1:56 am
Aging may be regulated by a discrete set of intracellular proteins including the mechanistic target of rapamycin (mTOR) kinase. mTOR functions within two multiprotein complexes called TORC1 and TORC2. ... […]
Two Cancer Drugs Found to Boost Aging Immune Systems
on July 13, 2018 at 9:20 am
Drugs that can lengthen life have long been a hallmark of speculative science fiction—many hope for an invention that could extend average lifespans well into the triple digits in the distant future. ... […]
via Bing News