Corporate Banner
Satellite Banner
Technology
Networks
Scientific Communities
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Study Casts Light on Deadly Immune Response

Published: Tuesday, March 19, 2013
Last Updated: Tuesday, March 19, 2013
Bookmark and Share
Volunteers’ extreme immune response helps create model for immune signals.

Examining a case study of near-death experiences for six healthy men who volunteered to test an experimental drug in London has yielded important insights into potentially deadly over-reactions of the human immune system.

Using a database containing detailed measurements of the men's haywire immune responses to the drug, researchers at Princeton University created an unprecedentedly clear model for how immune signals called cytokines interact with each other.

"We have developed tools that could ultimately reveal how and when clinicians might intervene to prevent these dangerous inflammatory reactions," said Andrea Graham, assistant professor of ecology and evolutionary biology at Princeton, who is an author of the study published in the journal PLoS-One.

The human immune system produces dozens of cytokines, with names like "interleukin-1" and "interferon-gamma," which act as messengers between cells, coordinating immune responses such as inflammation. The complex interactions among cells that cytokines mediate have been difficult to study, especially in the uncontrolled immune response — called a "cytokine storm" — experienced by the study volunteers. The Princeton research offers the first comprehensive way to calculate how cytokine signals interact to generate this potentially pathological storm.

The model could lead to a way to better predict immune system reactions to drugs as well as to pathogens such as viruses and bacteria.

From moon missions to medicine

An engineer and a biologist at Princeton, brought together by an undergraduate student, joined forces to study the experiment-gone-wrong. The research project began in 2009 when Graham was teaching her regular interdisciplinary immunology class for undergraduates in which she told her students about the ill-fated clinical trial, which took place at a research facility in London in 2006. The wealth of data from the mishap caught the attention of Hao Hong Yiu, a senior at the time majoring in chemical engineering. Looking to use the data as the basis for an independent project, Yiu sought out engineering faculty member Robert Stengel, professor of mechanical and aerospace engineering, to help guide his mathematical analysis.

"I thought the idea of combining the immunology with engineering was very exciting," said Yiu, who is now working on clinical and regulatory affairs at a medical device company.

As an aerospace engineer, Stengel designed the manual controls for the Apollo moon missions, but became interested in applying his mathematical skills to biological problems 10 years ago.

"The equations are just like those for planes and rockets, they just mean different things," said Stengel. "What we do for calculating how much fuel it takes to put a satellite in orbit, we can use to understand the minimum amount of drug to use to kill a pathogen."

An uncommon data set

Testing a new drug on healthy subjects is often done to establish a safe dose. In the London clinical trial, the volunteers received a drug called a monoclonal antibody, a particular variety of which was being developed as a possible way to boost the immune systems of leukemia patients whose own immune cells were killed by chemotherapy. But within minutes of receiving the drug, all the volunteers had signs of an inflammatory response. Within 12 hours, all were in intensive care. Each man’s immune system was undergoing a cytokine storm, posing a serious threat to his own tissues, including vital organs.

A cytokine storm can also be triggered by septic shock, blood transfusions or bone marrow transplants. Tens of thousands of people die from cytokine storms every year.

"The normal response of cytokines and how each is coupled in the overall reaction is not well understood," Stengel said.

The six men survived, but barely. A silver lining of the accident was the extensive data collected on each volunteer's immune reaction.

The data set presented an atypical case of well-documented immune responses in otherwise healthy people. Usually, such strong immune reactions only occur in patients with other critical illnesses, including those who have a compromised immune system.

The extensiveness of the data was also unusual — measurements of nine different cytokines were collected every six hours over five days, allowing the Princeton researchers to examine timing and interaction of the molecules over the short time period when the response occurred.

In previous studies of cytokine behavior, measurements were typically taken once per day for several days. "But everything is over by then," said Stengel. "The infection or inflammation process comes and goes in a matter of hours and is essentially over in two or three days. You really have to have data from the beginning."

The complexity of the analysis is also unique. Most previous studies examined only the interaction of a single type of cytokine with one other type, as opposed to the many interactions that are possible, said Yiu.

The researchers continued to refine their work after Yiu graduated in 2010 and the work was published in PLoS-One last October.

The research begins to address which cytokine inhibitors could have been given to the volunteers to prevent or at least lessen the immune reaction.

The work also helps solve a specific medical mystery surrounding the clinical trial: Would a lower dose of the experimental leukemia drug have avoided the reactions? The results indicate the answer is no — the model showed that even a lower dose would not have prevented the peak cytokine levels that caused the immune systems to go into overdrive.

Interdisciplinary approach

The researchers said the collaboration highlights how an interdisciplinary approach by an ecologist and an engineer, bridged by a talented undergraduate, can result in a novel insight into a biological process — an insight that an immunologist working alone may have missed.

"What I really enjoyed about the engineering collaboration is quantitatively integrating all of the molecular data to understand the consequences at the whole-organism level," Graham said. Beyond cytokines, the model also provides a general way to analyze different types of data collected over time, she added.

"It was really interesting to see Professor Stengel's and Professor Graham's expertise come together to analyze this biological event," Yiu said.

The ultimate goal is to understand how to best treat any immune over-reaction — for example one caused by a pathogen that gets in the blood stream. The researchers would like to see similar methods used to analyze clinical trials using safer drugs to help understand how the immune system responds to different stimuli.

"It seems to me that this is only the beginning," said Graham. "With these quantitative tools applied to larger and better cytokine and other data sets, imagine the immunological insights that would emerge."


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,500+ scientific posters on ePosters
  • More Than 5,000+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Quick, Early Test For Ebola Could Prevent Epidemics
Researchers from Princeton University are collaborating with U.S. government labs to develop a more rapid, accurate and inexpensive test for the Ebola virus with the aim of identifying infections before carriers become symptomatic and contagious.
Wednesday, July 06, 2016
Scoliosis Linked to Disruptions in Spinal Fluid Flow
A new study in zebrafish suggests that irregular fluid flow through the spinal column brought on by gene mutations is linked to a type of scoliosis that can affect humans during adolescence.
Tuesday, June 14, 2016
Structure of Essential Digestive Enzyme Uncovered
Using a powerful combination of techniques from biophysics to mathematics, researchers have revealed new insights into the mechanism of a liver enzyme that is critical for human health.
Thursday, May 26, 2016
Photoredox Catalyst Unlocks New Pathways for Nickel Chemistry
Using a light-activated catalyst, researchers have unlocked a new pathway in nickel chemistry to construct carbon-oxygen (C-O) bonds that would be highly valuable to pharmaceutical and agrochemical industries.
Friday, August 14, 2015
Solving Streptide from Structure to Biosynthesis
Researchers reveal new information about how bacteria communicate via the protein, streptide.
Monday, May 18, 2015
Measles Virus Said to Suppress Immune System for up to Three Years
New research suggests measles can suppress children’s immune systems for up to three years following infection, leaving them susceptible to a host of other deadly diseases.
Monday, May 11, 2015
A Gene That Shaped The Evolution Of Darwin's Finches
Researchers from Princeton University and Uppsala University in Sweden have identified a gene in the Galápagos finches studied by English naturalist Charles Darwin that influences beak shape and that played a role in the birds' evolution from a common ancestor more than 1 million years ago.
Thursday, February 12, 2015
A Single Cell Smashes and Rebuilds Its Own Genome
Life can be so intricate and novel that even a single cell can pack a few surprises, according to a study led by Princeton University researchers.
Tuesday, September 09, 2014
Wild Sheep Show Benefits of Putting Up With Parasites
Researchers used 25 years of data on a population of wild sheep living on an island in northwest Scotland to assess the evolutionary importance of infection tolerance.
Monday, August 18, 2014
Collaboration Leads to Possible Shortcut to New Drugs
The reaction, reported in Science, demonstrates how a carboxylic acid can be transformed into a very reactive site through use of a novel photoredox catalyst.
Thursday, June 26, 2014
Even if Emissions Stop, Carbon Dioxide Could Warm Earth for Centuries
Study suggests that it might take a lot less carbon than previously thought to reach the global temperature scientists deem unsafe.
Monday, November 25, 2013
Small Bits of Genetic Material Fight Cancer's Spread
A class of molecules called microRNAs may offer cancer patients two ways to combat their disease.
Monday, October 21, 2013
Physicists, Biologists Unite to Expose How Cancer Spreads
New study has found that cancer cells that can break out of a tumor are more aggressive and nimble than nonmalignant cells.
Thursday, May 02, 2013
Schmidt Fund Awards to Advance Innovations in Drug Therapy and Search for Planets
Two Princeton University research projects have been selected to receive grants from Princeton's Eric and Wendy Schmidt Transformative Technology Fund.
Friday, April 26, 2013
Parasite Metabolism can Foretell Disease Ranges under Climate Change
Knowing the temperatures that viruses, bacteria, worms and all other parasites need to grow and survive could help determine the future range of infectious diseases under climate change.
Thursday, February 28, 2013
Scientific News
Point of Care Diagnostics - A Cautious Revolution
Advances in molecular biology, coupled with the miniaturization and improved sensitivity of assays and devices in general, have enabled a new wave of point-of-care (POC) or “bedside” diagnostics.
Mass Spec Technology Drives Innovation Across the Biopharma Workflow
With greater resolving power, analytical speed, and accuracy, new mass spectrometry technology and techniques are infiltrating the biopharmaceuticals workflow.
One Step Closer to Precision Medicine for Chronic Lung Disease Sufferers
A study led by University of North Carolina at Chapel Hill, and National Jewish Health, has provided evidence of links between SNPs and known COPD blood protein biomarkers.
Blood Pressure Drug May Boost Effectiveness of Lung Cancer Treatment
Researchers at Imperial College London have suggested that the blood pressure drug may make a type of lung cancer treatment more effective.
Insight into Eye Diseases
Scientists recreate zebrafish cell regeneration from retinal stem cells in mice.
New Discovery May Benefit Farmers Worldwide
Scientists have shown how a crop-microbe 'team' protect against fungal infection.
Antibodies Paving the Way to HIV Vaccine
Researchers uncover factors responsible for the formation of broadly neutralizing HIV antibodies in humans.
Designing Drugs with a Whole New Toolbox
Researchers develop methods to design small, targeted proteins with shapes not found in nature.
Protein Studies Discover Molecular Secrets
Two protein studies have mapped proteins that reveal the secrets to recycling carbon and healing cells.
Tapping Evolution to Improve Biotech Products
Researchers show how 'ancestral sequence reconstruction' can be used to guide engineering of a blood clotting protein.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
5,000+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!