Funded research projects

Mesenchymal stem cells and graft-versus-host disease
Principal Investigator: Prof Francesco Dazzi

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 post-transplant courses. We 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. For this reason we have used them to successfully control severe GvHD. The mechanisms of their therapeutic effect is poorly understood, thus preventing attempts to improve efficacy. Leuka has invested into our programme to pursue MSC-based therapies in three different ways.

The inflammatory microenvironment determines clinical responses to multipotent mesenchymal stromal 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. We have observed that patients who respond to MSC have a particular cell population in their blood. If these findings will be confirmed in a clinical trial, we will be in the position to select patients as soon as they exhibit this marker and maximize therapeutic results. The implications of having a new treatment for GvHD are that more patients, including the high-risk ones, will be eligible for BMT.

The role of MSC in modulating immunosuppression
In this PhD project Dr Trento focused her activity on the role MSC in modulating immunosuppression. This aspect is very important because we do not know how MSC work to stop GvHD. She found that MSC promote the differentiation of blood stem cells into macrophages. Macrophages are a well-known inflammatory cell that plays a crucial role in coordinating inflammatory responses. She observed that MSC induce the differentiation of a macrophage subset with a strong immunosuppressive activity. Her findings indicate that MSC do not work alone to stop GvHD but also recruit further allies to make their therapeutic activity more effective. We also identified one of the key molecules mediating such an effect: nitric oxide. With this information available we will be in the position to strengthen this MSC-macrophage interaction and harness it to make MSC therapies more efficacious.

The Mesenchymal stromal niche protects CML from Imatinib: a high throughput screening to identify molecular mechanisms
Normally, in the human body MSC constitute bricks of the house in which blood stem cells live. Without their home, blood stem cells would be exposed to toxic agents or insults 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. We have investigated the molecules by which MSC protect leukaemia and found one which is particularly important, the name of which is CXCR4. By antagonising this molecule in a mouse model we made leukaemia cells more susceptible to chemotherapy. We are now planning to test this hypothesis in patients who have responded only partially to chemotherapy.