Nav: Home

Can we get the immune system to tolerate organ transplants?

July 09, 2018

Currently, people receiving organ transplants must take drugs to suppress the inflammatory immune response that leads to rejection. Even so, almost all recipients eventually lose their transplant. A new approach, which maintains a population of immune cells that naturally temper immune responses, could greatly enhance people's long-term tolerance for transplants, report researchers at Boston Children's Hospital.

In a study published July 3 in the American Journal of Transplantation, increasing the activity of a regulatory protein called DEPTOR in immune cells enabled heart transplants to survive in mice much longer than usual.

In initial experiments, the mice received no immunosuppressive drugs, and heart transplants survived for an average of 7 days. But in mice with genetically enhanced DEPTOR activity in their T cells, average transplant survival was 35 days.

"We got prolonged graft survival in the mice, similar to what you would see with standard immunosuppressants," says David Briscoe, MB, ChB, director of the Transplant Research Program at Boston Children's and the study's senior investigator.

The most exciting results came when DEPTOR enhancement was combined with immunosuppressive drugs. These mice appeared to develop transplant tolerance: their transplants survived almost indefinitely (100 days or longer).

Curbing the inflammatory response

The immune system has two arms: An inflammatory arm, led by effector T-cells, and a regulatory arm, led by regulatory T cells or Tregs, which resolve or suppress inflammation. The immune system maintains different mixes of effector and regulatory T-cells, depending on the situation. After transplantation, the balance generally shifts toward effector cells, and existing Tregs can switch to the effector type.

Standard immunosuppressive drugs suppress transplant rejection by curbing effector T-cell responses. But the study suggests the possibility of adding a second approach: enhancing and stabilizing the regulatory T-cell response via DEPTOR. In multiple experiments, boosting DEPTOR activity within Tregs made them more long-lived and functional.

"Normally, when a recipient's immune system 'sees' a transplant, Tregs are overwhelmed by the effector T cell response and cannot shut down inflammation. They may even become effector cells," says Johannes Wedel, MD, PhD, a postdoctoral fellow in the Briscoe lab and first author on the paper. "But when we turn on DEPTOR, they don't do that - they remain stable and active, and potently inhibit rejection-causing effector cells."

The effects of enhancing DEPTOR seem to be specific to Tregs; turning DEPTOR "on" in effector T cells didn't inhibit organ rejection. But in Tregs, enhancing DEPTOR was enough to tip the immune system toward long-term transplant survival.

Deconstructing DEPTOR

To better understand how DEPTOR functions in T cells, Briscoe and colleagues collaborated with David Sabatini, of the Whitehead Institute for Biomedical Research, and Mathieu Laplante, now at Université Laval (Quebec City), who originally identified DEPTOR in other cell types. Wedel worked with Peter Sage, PhD, of Harvard Medical School, to sequence Tregs' messenger RNA to see what genes DEPTOR was turning on and off. Many of the genes that came up as "hits" are involved in cell metabolism.

"Metabolism of T cells is very important to their function," says Wedel. "By boosting the activity of DEPTOR, we can shape metabolism in a direction that makes regulatory T cells much more stable and more active."

Drug treatment for transplant and autoimmune disease?

Briscoe thinks the study findings also have potential implications for treating autoimmune disease. "Classically, Tregs are not fully functional in autoimmune diseases," he says. "So enhancing Treg stability or activity could help."

While the study used a special "knock-in" mouse that allowed Briscoe, Wedel and colleagues to turn on DEPTOR expression, Briscoe thinks it may be possible to boost DEPTOR with drugs. Existing compounds known as Cullin-RING E3 ligase inhibitors are known to increase DEPTOR activity by preventing its destruction.

"We are interested in identifying specific DEPTOR enhancing agents and moving this area of research forward in pre-clinical models," says Briscoe.

Briscoe envisions two possible forms of treatment. The drugs, with some formulation work, could be designed to be given to patients directly, along with immunosuppressants, to maintain a stable, functional pool of Tregs that suppress rejection. Alternatively, Tregs isolated from a patient's blood could be manipulated genetically or treated with a DEPTOR-enhancing drug to make them more stable, then reinfused back into the patient.

In the meantime, Briscoe, Wedel and colleagues are trying to understand better how DEPTOR works. They are creating new models to track Tregs with different levels of DEPTOR expression and further investigate how they behave in different situations and disease models.
-end-
The study (DOI 10.1111/ajt.14995) was supported by the National Institutes of Health (R21AI114223 and R01AI136503), an Advancing Research in Transplantation Science Investigator Initiated Grant from Pfizer Inc., the Casey Lee Ball Foundation, the German Research Foundation and Heidelberg University. Coauthors were Sarah Bruneau and Kaifeng Liu of the Transplant Research Program at Boston Children's; Sek Won Kong of the Computational Health Informatics Program at Boston Children's; Peter Sage of Harvard Medical School; David Sabatini of the Whitehead Institute for Biomedical Research (Cambridge, MA); and Mathiue Laplante of Université Laval (Quebec City).

About Boston Children's Hospital

Boston Children's Hospital, the primary pediatric teaching affiliate of Harvard Medical School, is home to the world's largest research enterprise based at a pediatric medical center. Its discoveries have benefited both children and adults since 1869. Today, more than 3,000 scientists, including 8 members of the National Academy of Sciences, 17 members of the National Academy of Medicine and 12 Howard Hughes Medical Investigators comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's is now a 415-bed comprehensive center for pediatric and adolescent health care. For more, visit our Vector and Thriving blogs and follow us on social media @BostonChildrens, @BCH_Innovation, Facebook and YouTube.

Boston Children's Hospital

Related Immune System Articles:

The immune system may explain skepticism towards immigrants
There is a strong correlation between our fear of infection and our skepticism towards immigrants.
New insights on how pathogens escape the immune system
The bacterium Salmonella enterica causes gastroenteritis in humans and is one of the leading causes of food-borne infectious diseases.
Understanding how HIV evades the immune system
Monash University (Australia) and Cardiff University (UK) researchers have come a step further in understanding how the human immunodeficiency virus (HIV) evades the immune system.
Carbs during workouts help immune system recovery
Eating carbohydrates during intense exercise helps to minimise exercise-induced immune disturbances and can aid the body's recovery, QUT research has found.
A new model for activation of the immune system
By studying a large protein (the C1 protein) with X-rays and electron microscopy, researchers from Aarhus University in Denmark have established a new model for how an important part of the innate immune system is activated.
Guards of the human immune system unraveled
Dendritic cells represent an important component of the immune system: they recognize and engulf invaders, which subsequently triggers a pathogen-specific immune response.
How our immune system targets TB
Researchers have seen, for the very first time, how the human immune system recognizes tuberculosis (TB).
How a fungus inhibits the immune system of plants
A newly discovered protein from a fungus is able to suppress the innate immune system of plants.
A new view of the immune system
Pathogen epitopes are fragments of bacterial or viral proteins. Nearly a third of all existing human epitopes consist of two different fragments.
TB tricks the body's immune system to allow it to spread
Tuberculosis tricks the immune system into attacking the body's lung tissue so the bacteria are allowed to spread to other people, new research from the University of Southampton suggests.

Related Immune System Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#532 A Class Conversation
This week we take a look at the sociology of class. What factors create and impact class? How do we try and study it? How does class play out differently in different countries like the US and the UK? How does it impact the political system? We talk with Daniel Laurison, Assistant Professor of Sociology at Swarthmore College and coauthor of the book "The Class Ceiling: Why it Pays to be Privileged", about class and its impacts on people and our systems.