Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Small subset of cells has big role in controlling immunity, study finds

18.08.2003


A small subset of cells that tells the immune system whether to attack may be a future target for therapies to help patients fight tumors and keep transplanted organs, a Medical College of Georgia researcher says.


Dr. Andrew L. Mellor, director of MCG’s Immunotherapy Center.



Dendritic cells roam the body, picking up invaders, such as a virus or cancer, then show their finds to the T-cells and tell them how to respond, says Dr. Andrew L. Mellor, molecular geneticist and immunologist and director of the MCG Immunotherapy Center.

Work published in the Aug. 15 issue of The Journal of Immunology by Dr. Mellor and his colleagues gives further clues over what direction dendritic cells will give.


They have shown that giving mice an experimental immunosuppressive agent causes a select number of these cells to express an enzyme, indoleamine 2,3 dioxygenase, or IDO, and that those cells tell T-cells not to respond.

"They are a very fascinating new subset of dendritic cells previously not recognized," says Dr. Mellor, Georgia Research Alliance Eminent Scholar in Molecular Immunogenetics. "We do not think all dendritic cells have the capacity to express IDO. The magic of this subset is their ability to do that," he said of the enzyme first identified for its role in helping a fetus escape rejection by the mother’s immune system.

"One of the things we argue in this paper is that we can use IDO to help us find out if dendritic cells are going to stimulate the immune system or turn it off. If they express IDO, they will not stimulate T cells to respond. If they don’t express IDO, they are likely to stimulate immune responses once they mature," Dr. Mellor says.

Five years ago nearly to the day, Dr. Mellor and his colleagues, Drs. David Munn and Simon Conway, were reporting in the journal Science that the developing fetus uses IDO to locally disable the mother’s immune system. It works by degrading tryptophan, an amino acid critical to the survival of T-cells, which get their action cues from dendritic cells.

The MCG scientists have focused many of their efforts since on how to use the IDO mechanism to manipulate the immune system to the patient’s advantage. In the case of transplant patients, they want the immune system to ignore the new organ; in the case of autoimmune diseases such as type 1 diabetes, they want it to stop a self-destructive attack on pancreas cells that produce insulin. Conversely, they want to prompt the immune system to destroy persistent tumors. In fact, their subsequent studies have shown some tumors express IDO, apparently much as the fetus, which may help them escape the immune response. Persistent infections such as HIV, the virus that causes AIDS, may also rely on the IDO mechanism to avoid destruction by the patients’ immune system.

A second Science paper by Drs. Munn and Mellor in September 2002 reported that human dendritic cells could express IDO and showed how the expression suppressed the proliferation of T-cells. "The idea of it simply being expressed in the dendritic cells completely alters our understanding of how dendritic cells talk to T-cells," Dr. Mellor says. "What is it that makes a dendritic cell decide to express IDO or not, that is the key question."

Now in animal studies they have made a select number of dendritic cells do just that by giving the drug CTLA4-Ig, a reagent designed to block the action of T-cells. The reagent is still in clinical trials to evaluate its potential for patients with transplants and autoimmune diseases such as multiple sclerosis. In November, scientists from the University of Perugia in Italy were the first to report that treatment with CTLA4-Ig induced the IDO mechanism in dendritic cells, a move that ultimately keeps T-cells from responding.

Although dendritic cells were believed to be a fairly homogenous group, the MCG scientists have shown that only a small number of the cells respond to the reagent. They also used the IDO knockout mice developed at MCG to prove that IDO has to be present for the reagent to have maximal effect, Dr. Mellor says.

These findings take the researchers closer to their goal of targeted manipulation of the immune system. "In principal we can use the new immunosuppressive drug to do that. We can treat mice with the reagent, and introduce antigens that their immune systems would normally respond vigorously to. The prediction is that the mouse treated with this reagent will no longer respond vigorously to these antigens. Our preliminary data indicates that we are on the right track."

In fact, the Perugia scientists have shown that the mouse model for type 1 diabetes has a specific defect in the IDO mechanism. "That means that if you have a defect in that mechanism, those mice and, therefore by extrapolation, human beings too, are much more likely to get type 1 diabetes." That knowledge needs to be used to help eliminate or at least reduce the risk of children identified at risk, Dr. Mellor said, referencing a large newborn screening program for type 1 diabetes under way by Dr. Jin-Xiong She, director of the MCG Center for Biotechnology and Genomic Medicine and Georgia Research Alliance Scholar in Genomic Medicine. "We have to use our immunology knowledge to protect patients at risk from getting diabetes," Dr. Mellor said.

When the immune system is not responsive enough, such as in the case of a tumor, they can block the IDO mechanism in the cells so they would regain the ability to attack. His colleague, Dr. Munn, is moving toward clinical trials on blocking this mechanism pharmacologically, much as they did in the early days to show the role of IDO in helping a fetus avoid rejection.

"It comes back to the unifying theme of what it is at the molecular and cellular level that regulates whether the immune system is going to respond or not to any given circumstance," Dr. Mellor says. "That is what we are working on and the results reported in this paper represent a significant breakthrough in understanding how to control immune responses."


###
The MCG researchers have funding from the National Institutes of Health and Carlos and Marguerite Mason Trust.

Toni Baker | EurekAlert!
Further information:
http://www.mcg.edu/

More articles from Health and Medicine:

nachricht Lung images of twins with asthma add to understanding of the disease
06.12.2019 | University of Western Ontario

nachricht Between Arousal and Inhibition
06.12.2019 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Developing a digital twin

University of Texas and MIT researchers create virtual UAVs that can predict vehicle health, enable autonomous decision-making

In the not too distant future, we can expect to see our skies filled with unmanned aerial vehicles (UAVs) delivering packages, maybe even people, from location...

Im Focus: The coldest reaction

With ultracold chemistry, researchers get a first look at exactly what happens during a chemical reaction

The coldest chemical reaction in the known universe took place in what appears to be a chaotic mess of lasers. The appearance deceives: Deep within that...

Im Focus: How do scars form? Fascia function as a repository of mobile scar tissue

Abnormal scarring is a serious threat resulting in non-healing chronic wounds or fibrosis. Scars form when fibroblasts, a type of cell of connective tissue, reach wounded skin and deposit plugs of extracellular matrix. Until today, the question about the exact anatomical origin of these fibroblasts has not been answered. In order to find potential ways of influencing the scarring process, the team of Dr. Yuval Rinkevich, Group Leader for Regenerative Biology at the Institute of Lung Biology and Disease at Helmholtz Zentrum München, aimed to finally find an answer. As it was already known that all scars derive from a fibroblast lineage expressing the Engrailed-1 gene - a lineage not only present in skin, but also in fascia - the researchers intentionally tried to understand whether or not fascia might be the origin of fibroblasts.

Fibroblasts kit - ready to heal wounds

Im Focus: McMaster researcher warns plastic pollution in Great Lakes growing concern to ecosystem

Research from a leading international expert on the health of the Great Lakes suggests that the growing intensity and scale of pollution from plastics poses serious risks to human health and will continue to have profound consequences on the ecosystem.

In an article published this month in the Journal of Waste Resources and Recycling, Gail Krantzberg, a professor in the Booth School of Engineering Practice...

Im Focus: Machine learning microscope adapts lighting to improve diagnosis

Prototype microscope teaches itself the best illumination settings for diagnosing malaria

Engineers at Duke University have developed a microscope that adapts its lighting angles, colors and patterns while teaching itself the optimal...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

The Future of Work

03.12.2019 | Event News

First International Conference on Agrophotovoltaics in August 2020

15.11.2019 | Event News

Laser Symposium on Electromobility in Aachen: trends for the mobility revolution

15.11.2019 | Event News

 
Latest News

Solving the mystery of carbon on ocean floor

06.12.2019 | Earth Sciences

Chip-based optical sensor detects cancer biomarker in urine

06.12.2019 | Life Sciences

A platform for stable quantum computing, a playground for exotic physics

06.12.2019 | Information Technology

VideoLinks
Science & Research
Overview of more VideoLinks >>>