Bone marrow transplantation (BMT) is a very effective treatment for leukaemia but the beneficial effects are often outweighed by the side effects. Graft-versus-host disease (GvHD) is probably the most threatening as it complicates 40% of people post-transplant. Professor Dazzi and his team have identified a rare population of stem cells in the bone marrow – mesenchymal stem cells (MSC) – which have the ability to potently suppress immune responses and have successfully used them to control severe GvHD. The mechanisms of their therapeutic effect is poorly understood, preventing attempts to improve effectiveness. Leuka has award a Project Grant to support Professor Dazzi and his team as they pursue MSC-based therapies in three different ways.
The inflammatory microenvironment that determines clinical responses to mesenchymal stem cell infusions for GvHD
One of the major difficulties to make a therapy effective is selecting the right patient. This project was aimed at understanding the characteristics which make a patient with GvHD more likely to respond to MSC. Professor Dazzi and his team have observed that patients who respond to MSC have a particular cell population in their blood. By confirming these findings a clinical trial, they will be in the position to select patients as soon as they exhibit this marker and maximize therapeutic results. By finding a new treatment for GvHD more patients, including the high-risk ones, will be eligible for a bone marrow transplant.
The role of MSC in modulating immunosuppression
Within Professor Dazzi's team Dr Trento's PhD project focused on the role MSC in modulating immunosuppression. This aspect is very important because we do not know how MSC work to stop GvHD. Dr Trento found that MSC promote a change in blood stem cells to macrophages - an inflammatory cell that plays a crucial role in coordinating inflammatory responses.
She observed that MSC induce strong immunosuppressive activity. Her findings indicate that MSC do not work alone to stop GvHD but recruit further allies to make their therapeutic activity more effective. The research also identified one of the key molecules mediating such an effect: nitric oxide. With this information available, Professor Dazzi and his team, will be in the position to strengthen this MSC-macrophage interaction and harness it to make MSC therapies more effective.
The Mesenchymal stromal niche protects CML from Imatinib: a high throughput screening to identify molecular mechanisms
Normally, in the human body MSC constitute building block to the house in which blood stem cells live. Without their home, blood stem cells would be exposed to toxic agents and die prematurely. Unfortunately, since MSC do not distinguish between normal and leukaemia stem cells, they also protect leukaemia from the activity of chemotherapy. It is believed that eradication of leukaemia is difficult because leukaemia stem cells are protected. Professor Dazzi's team have investigated the molecules by which MSC protect leukaemia and found one which is particularly important, named CXCR4. By targeting this molecule in a mouse model we made leukaemia cells more susceptible to chemotherapy. The team are now planning to test this in patients who have responded only partially to chemotherapy.