The immune system’s job is to fight infections. Nearly everyone leaves it at that, but a few years ago, when she was a Wallenberg Academy Fellow, Phillipson and her research team discovered functions in the immune cells that differed from the classical pattern.

“We saw that a large number of immune cells accumulated in damaged tissue. When we created oxygen deficiency by reducing blood flow in various ways, we could see that neutrophils quickly appeared on the scene to help with the formation of new blood vessels so the tissue survived.”

Neutrophils are the most common immune cells in the body. The Scholar project is focusing on macrophages, another common immune cell. Phillipson and her team have continued to investigate whether other immune cells gather in damaged tissue, and if so, what they do there. This time they are studying how the immune cells behave in damaged muscles starved of oxygen, as after a heart attack, for instance. They discovered that a large number of macrophages piled up around the newly formed blood vessels.

“They got in very close and hugged the new blood vessels, seemingly transforming into support cells. When we removed them, the blood vessels didn’t work nearly as well, and muscle function deteriorated. We’re now trying to understand what happens. What function do these macrophages have, and how do they affect blood vessels? How long do they remain? Do they change identity to become support cells, and if so, is the change permanent or just for the duration of the healing process? Can they assume other identities? What signals cause this to happen, and can we influence those signals to help damaged tissue to heal? And we already have really exciting data!”

It seems as though macrophages take over functions from other cell types.

“Our hypothesis is that they serve as a resource, deploy and take over functions that are impaired in the damaged tissue. It appears they expand the blood vessels, increasing blood flow and oxygen supply. These functions of immune system cells are completely new to us.”

The team is now in the process of sequencing individual cells to see whether they take over functions from other cells or whether they are converted into another cell type.

Using a GM bacterium to heal wounds

Phillipson thinks the project funded by the Fellow grant began quite naively.

“We saw that immune cells were involved in healing the damaged muscle, and we needed a quick test – a proof-of-concept model – to ascertain how we can stimulate them to heal the injury more quickly. We chose to start by inducing wounds in the skin.”

Their method of stimulating the cells they suspected of playing a key role in wound healing was to genetically modify the lactic acid-producing lactobacilli so they produced chemokines – signal molecules that communicate with immune cells.

“Our findings clearly showed that we could improve wound healing in both skin and intestines of mice.”

In 2016 the discovery led Phillipson and her PhD student Evelina Vågesjö to start a company called Ilya Pharma, whose mission is to turn develop drugs to accelerate healing of wounds in skin and mucosa.

“It’s the first genetically modified bacterium in the world that has now been tested for healing human wounds. And it happened in Uppsala! When the idea came to us, we thought it might seem crazy. But we’ve now shown the treatment to be safe, and that wounds heal more quickly.”

“Being able to lead a pure research project the whole way to clinical studies is fantastic. This journey has been made possible by the generous support of the Foundation. We’ve been given the time and resources, as well as the opportunity to patent some of our discoveries, which is necessary if they are ever to become new therapeutics.”

She explains that the treatment actually fools the body into believing that the wound is larger than it is, so the cells concentrate on healing it.

In a few years’ time, when it has undergone the final clinical tests, the method, which is a form of immunotherapy, can be used to heal chronic wounds. At present these are so difficult to treat that they often lead to amputation.

Covid research

Phillipson considers that the no-strings grant from Knut and Alice Wallenberg Foundation was vital.

“The funding enabled us to undertake this crazy project. It also shows how important fundamental scientific research is, and that it can also result in therapeutics fairly quickly.”

To date, immunotherapies have mainly been used to treat cancer, but Phillipson thinks they can be much more widely used.

“Wound healing is only one application. Immune cells are involved in most diseases. But our ability to treat diseases is limited by our knowledge of what the cells actually do. This is what my research aims to find out. We want to understand which molecules control the various immune cell functions – knowledge that can then be used to develop therapeutics.”

For much of 2020 parts of her lab were also dedicated to supporting Covid-19 research.

“We had a joint project with Charlotte Thålin at Danderyd hospital just north of Stockholm. When clinical cancer studies had to be discontinued, we changed over to studying Covid-19 patients to ascertain which of them will need ICU care. We have found that those who become really ill have more neutrophil DNA in their blood, which can cause blood clots.”

The lab is also busy examining how T-cell immunity is related to B-cell antibodies in people who have had Covid-19.

“This is something we hadn’t really done before, but it’s incredibly important at the moment of course, and we’re learning a great deal.”

Text Carina Dahlberg
Translation Maxwell Arding
Photo Mikael Wallerstedt, David Ahl