Group leader: 

Paul Travers

Position: 

Associate Researcher; MSc Course Co-ordinator

Contact: 

paul [dot] travers [at] ed [dot] ac [dot] uk

Aim
Our aim is to shape the immune system to improve the success rate of bone marrow transplants for patients.

Background
Haematopoietic stem cell transplantation, also called bone marrow transplant, was the first stem cell therapy to be introduced clinically.  The first bone marrow transplant was carried out in 1968; now more than 4000 transplants from donated stem cells are carried out each year.

Haematopoietic System

The  majority of bone marrow transplants are carried out to treat  cancers of the blood, though a number of inherited diseases and other conditions can also be treated this way.  In the case of cancers, the treatment the patient is given to kill the cancer cells also kills off the healthy cells that make the blood, the haematopetic stem cells. These must be replaced if the patient is to live.

On average, about half of the patients who receive a bone marrow transplant from an unrelated donor will not survive. Of those, roughly one half will die from a relapse of their cancer, one quarter from infections while their immune systems are weakened after the transplant, and one quarter from graft-versus-host disease, where immune cells from the donor attack tissues of the patient.  
All of these causes, to a greater or lesser extent, involve the immune system in the patient after the transplant. 

Bone Marrow

Approaches and progress
We have created a novel set of reagents, crosslinking MHC peptide complexes with ligands for either positive or negative signalling receptors on T cells, to deliver specific combinations of signals to direct antigen specific cells into defined memory or effector compartments. In vitro we have primed naïve T cells against viral antigens, tumour specific antigens and potential minor Histocompatibility antigens.

Because the immune system plays an important role in the survival of patients after bone marrow transplants, we have asked whether there are measurements we can make in the patient and the donor before the transplant that will tell us about the likely outcome.

One notable finding is that deaths from relapse of the patient’s cancer are more frequent in patients who, before the transplant, have high levels of the cells - called T regulatory cells - that normally help control the immune system.

As we understand more about these regulatory cells, how the immune system creates them and uses them to control immune responses, we can start to use this knowledge to control rejection of other transplanted tissues, such as those derived from stem cells.

With the recognition of a number of factors that can induce the production of regulatory T cell populations comes the potential to manipulate these cells to control the immune responses to transplanted tissues, responses that currently require prolonged immunosuppression to maintain the viability of the graft.  

Depletion of certain amino acids has been shown to induce regulatory T cells, notably the depletion of tryptophan by indoleamine -2,3-dioxygenase (IDO).  We have cloned and expressed IDO and propose to attach this to a synthetic scaffold that will provide the framework for tissue grafts.  In addition, since local inflammatory responses also damage engrafted tissues, we have expressed a number of galectins, gal-1, gal-8 and gal-9, that have immune regulatory properties, causing inhibition of granulocytes as well as lymphocytes.

Funding
University of Edinburgh