Our body’s immune system protects us, but if it goes awry it can underpin inflammatory diseases. Dr Karen English is developing stronger, ‘calming’ cells for therapies to get things back on track.
Your immune system is amazing: not only does it fight off invaders such as bacteria and viruses, it also rushes in to help when tissues and organs are ailing. This ‘inflammation’ response to disease and injury is important for keeping us healthy – but what happens when we really do want an invader in our body in the form of a replacement organ or a bone marrow transplant? Or what if the fire of inflammation burns too long and damages our tissues, fuelling conditions such as diabetes and chronic lung damage?
Dr Karen English is on a mission to calm inflammation when it goes out of control, and her approach harnesses the power of cells. “We are using a type of cell called a mesenchymal stem cell, which the body naturally makes in places such as the bone marrow,” explains Dr English, a Principal Investigator in Maynooth University Department of Biology and head of the Cellular Immunology Lab.
These mesenchymal stem cells, or MSCs, are naturally able to calm down inflammation in the body, and Dr English is looking to make them even stronger and use them as a form of therapy in inflammatory diseases.
“In inflammatory diseases, the immune system has an overzealous response and causes damage to tissues,” she explains. “That’s what we see happening in the lung in conditions such as COPD and pulmonary fibrosis, and in the pancreas in Type 1 diabetes.”
The guard dog-nature of the immune system can also cause trouble for potentially life-saving operations such as organ transplants and bone marrow transfusions. “In these cases, you get inflammation because the recipient is genetically different than the donor, so the organ or tissue coming in is foreign and the host can reject the organ or the incoming graft can reject the host,” says Dr English. “These patients often have to take immune-suppressing drugs for life to stop that rejection, but these drugs can have unwanted side-effects, so we are always looking for new and less toxic therapies to help.”
Enter the MSCs with their immune-calming and pro-healing powers. “These cells come from a lot of different tissues in the body, including fat, but we get them from bone marrow and we look at ways to treat them in the lab so they can be better administered as therapy,” says Dr English.
Her lab explores the possibilities for MSCs in a range of ‘models’ of diseases in the lab, and the research has shown the positive effects of MSCs in animal models of lung fibrosis (particularly when the cells are given early in the development of the condition) and chronic obstructive pulmonary disease or COPD.
Another focus is Type 1 diabetes, where the pancreas becomes damaged and cannot function properly. “We have an animal model in the lab where the pancreas is not working,” explains Dr English. “We transplant human pancreas cells into the animals to cure the diabetes, but those transplants get rejected because they are not a match. So we add in our MSCs as cell therapy, and we look at how these cells can prevent rejection, and how we can make the MSCs more effective.”
Dr English has also recently made strides to understand why an incoming graft, such as a bone marrow transfusion, might reject the host. This ‘graft versus host disease’ can have serious implications for the recipient patient, and while it can often be overcome with steroid drugs, in some patients the incoming graft continues to attack the body.
“MSC therapy can be used to treat these patients who don’t respond to steroids, but again the cell therapy doesn’t work well in all of those patients,” says Dr English. “So we are trying to figure out why MSC therapy works in some people and not in others, and we want to make the cell therapy more potent in general.”
Her lab’s research has shown that if you give the MSCs a naturally occurring molecule called interferon-gamma before the cells are used as cell therapy, they are more effective.
“Giving the cells interferon-gamma before they are administered sets in motion a train of events that starves another cell type in the body’s immune system called T cells, giving the MSCs more of an opportunity to work,” explains Dr English.
“We think that some patients don’t make enough interferon-gamma naturally and that is why perhaps the MSCs don’t work so well in them to address graft versus host disease. We think that is a large part of why the therapy works in some patients and not in others. When we give the MSCs interferon-gamma in the lab, the cells no longer rely on the host to make interferon-gamma, so they can get on with their work.”
Dr English is now looking at other ways to boost the performance of MSCs, including switching off various genes in the cells, and she is keen that the discoveries made in Maynooth will move towards the clinic to help patients.
Her lab works with companies Athersys in the USA and Regenesys in Belgium, which produce cell therapy products, and she has a long-standing collaboration with Irish pharmaceutical company Sigmoid Pharma, which specialises in delivering therapies to specific sites in the body.
“We are aligned to the people who are key to getting this therapy translated into the clinic and that is absolutely my goal,” says Dr English. “We want to make sure that our findings are relevant for tackling diseases and that they get to patients.”