The key to healthy aging brains

As people age, they often experience problems with their memory and cognitive abilities. This happens in part because their brains become mildly inflamed. But there may be a solution: a small group of special T cells, called regulatory T cells, could help reduce this inflammation in aging brains. Administering a protein called interleukin-2 (IL2) can help these special T cells grow and prevent inflammation. Now, researchers at VIB, KU Leuven, Babraham Institute, and i3S have tested this approach in mice and found that it can prevent neurological decline. Their findings, published in EMBO Molecular Medicine suggest that targeting the immune system might keep people’s brains healthy as they age.

Emanuela Pasciuto, co-first author of the study: “Our goal was to see whether we could slow down the aging process of the brain by changing its immune system through the delivery of IL2. We know that inflammation plays a significant role in various aging processes, and IL2 could help us tilt the balance back in our favor.”

Inflammation in the aging brain

Aging is a degenerative process that affects the whole body, including the brain. As we age, our brains may experience cognitive decline, affecting our memory and ability to think clearly. Increasing evidence suggests that inflammation in the brain, called “inflammaging,” can worsen this decline. Inflammaging is caused by immune cells entering the brain as we age. This inflammation can activate microglia, the resident immune cells in the brain, and induce neuroinflammation, leading to cognitive decline and dementia.

However, researchers have found a way to reduce inflammation in the brain by targeting a small group of special immune cells in the brain called regulatory T cells. Previously, the team of Adrian Liston (VIB-KU Leuven, Babraham Institute) and Matthew Holt (VIB-KU Leuven, i3S Porto) showed that administering a protein called Interleukin-2 (IL2), which helps regulate the immune response, increased the number of regulatory T cells in the brain. This treatment has been successful in mouse models of traumatic brain injury and neuroinflammation.

Now, the researchers want to see if delivering IL2 directly to the brain can help reduce age-induced inflammation and cognitive decline.

Gene therapy improves brain aging

In their latest study, the team discovered that delivering IL2 to the brain improved brain function in aging mice. The research showed that the treatment restored cognitive performance in spatial memory tests, allowing older mice to form new memories almost as well as young mice. The mice given IL2 treatment were better at remembering visual cues than those that did not receive the treatment. Additionally, some of the changes in cellular aging in the brain were reversed, especially among several types of glial cells, which are critical to support overall brain function and health.

Pierre Lemaitre, co-first author of the study: “Our approach was to harness the body’s own system to regulate inflammation and to boost it precisely where it was needed.”

IL2 was delivered to the brain using a gene therapy vector, which is a tool that provides genetic material to specific cells. The additional dose of IL2 allowed the regulatory T cells to survive and create an anti-inflammatory environment. Matthew Holt and Lidia Yshii, co-senior authors of the study: “This reinforces our belief that viral vector-based systems are the way forward for the delivery of therapeutics to combat chronic neurodegenerative diseases and preventing cognitive decline in aging populations.”

Adrian Liston, senior author of the study: “The most important part of this study is the high potential for translation into patients. Inflammation is a process that is conserved in both mice and humans, and regulatory T cells can respond to IL2 in both species. However, there are still regulatory hurdles to clear, and it’s crucial to ensure safety before testing it in patients. Nonetheless, we see a clear path to conducting clinical trials.”

The laboratory is working through spin-off company Aila Biotech to drive entry of this therapeutic into clinical trials. Read the full study here. 

Lab move complete!

Department of Pathology annual meeting

Happy International Women's Day

From Magda Ali, Ntombizodwa Makuyana and Amy Dashwood, PhD students in our lab.

Overnight staining of flow cytometry samples │ Oliver Burton

Innovative treatment prevents development of diabetes

Key points:

• Researchers from the Babraham Institute have been able to prevent the development of diabetes in mice.
• Their study prevented the death of insulin-producing beta cells in the pancreas, blocking the development of diabetes
• The treatment used a modified virus to manipulate a key molecular pathway in pancreatic cells, which controls the decision of stressed cells on whether to live or die.
• The team hope that their findings will translate into clinical treatment for both types of diabetes.

Researchers from the Liston lab have recently published a preventative therapeutic for diabetes in mice. Their team have been able to prevent diabetes in mice by manipulating signalling pathways in pancreatic cells and preventing stress-induced cell death. The treatment targets a pathway common to both major types of diabetes and therefore could have huge therapeutic potential once translated into a clinical treatment. 

For over 35 years there have been failed attempts to prevent type 1 diabetes development. Previous approaches have sought to target the autoimmune nature of the disease, but Dr Adrian Liston, senior Group Leader in the Immunology research programme, wanted to investigate if there was more causing the deterioration in later stages than just the immune response.

The Liston lab sought to understand the role of cell death in the development of diabetes and therefore approached this problem by identifying the pathways that decide whether stressed insulin-producing cells of the pancreas live or die, and therefore determine the development of disease.

Their hope was to find a way to stop this stress-related death, preventing the decline into diabetes without the need to focus solely on the immune system. First, the researchers had to know which pathways would influence the decision of life or death for the beta cell. In previous research, they were able to identify Manf as a protective protein against stress induced cell death, and Glis3 which sets the level of Manf in the cells. While type 1 and 2 diabetes in patients usually have different causes and different genetics, the GLIS3-MANF pathway is a common feature for both conditions and therefore an attractive target for treatments.

In order to manipulate the Manf pathway, the researchers developed a gene delivery system based on a modified virus known as an AAV gene delivery system. The AAV targets beta cells, and allows these cells to make more of the pro-survival protein Manf, tipping the life-or-death decision in favour of continued survival. To test their treatment, the researchers treated mice susceptible to spontaneous development of autoimmune diabetes. Treating pre-diabetic mice resulted in a lower rate of diabetes development from 58% to 18%. This research in mice is a key first step in the development of treatments for human patients.

 “A key advantage of targeting this particular pathway is the high likelihood that it works in both type 1 and type 2 diabetes”, explains Dr Adrian Liston. “In type 2 diabetes, while the initial problem is insulin-insensitivity in the liver, most of the severe complications arise in patients where the beta cells of the pancreas have been chronically stressed by the need to make more and more insulin. By treating early type 2 diabetes with this approach, or a similar one, we have the potential to block progression to the major adverse events in late-stage type 2 diabetes.”

New Editor-in-Chief at Immunology and Cell Biology

Using animal models to study traumatic brain injury

Doing more with less: Improving flow cytometry staining

Our latest paper isn't going to cure cancer. But it may just making research into curing cancer 10-fold cheaper. A major cost for immunology, oncology and haematology labs is antibodies, especially with the fancy (and expensive!) new dyes coming on the market, which let us hit the 40-50 parameter range in flow cytometry. Fortunately, Dr Oliver Burton in our lab has developed a simple and easy approach to reduce those costs by 10-fold, while also improving the quality of the data: shifting to overnight staining. You can read the full paper here, describing the protocol, fixatives and optimisation approaches, but essentially, lower antibody concentrations give less background, and if left overnight to stain are able to give even better signal detection. It is also a game-changer for wet-lab staff: rather than having all day dissections and staining, and then cueing for flow cytometer hours in the evening, you can set everything up, put on the staining and get an early night. Next morning your cells are ready to go! 

Out now at Current Protocols!

Update on Thursday, November 17, 2022 at 4:54PM by Adrian Liston

We have had multiple requests for a detailed staining protocol, so here it is!

Congratulations to Dr Ana Acosta!

Well done to Dr Ana Acosta, who successfully defended her PhD today! Ana tackled a challenging and exciting project on the role of HNF1A in monogenic diabetes, generating a new mouse model and validating results in primary human islets. Her work dramatically alters the way we see HNF1A in glucose homeostasis and diabetes. A very productive PhD, performed at University of Lille, with Prof Caroline Bonner, and the University of Leuven, with my team. The 20th PhD student to graduate from my lab, and one of the last from our Leuven days! Great job Dr Acosta!