Study looks at transplant organ rejection

“The body's natural defences can be ‘re-educated’ to stop them attacking organ transplants,” The Daily Telegraph has reported. The newspaper said the development could remove the need for patients to take the combination of immune-suppressing drugs currently used to prevent organ rejection.

This news is based on mouse research that looked at laboratory techniques for isolating and reproducing certain human immune system cells that can block the body’s attacks on donor tissue. It found that injecting these cells into mice that had received a human skin graft, reduced the damage the immune system did to the transplanted skin tissue.

Currently, people who receive a donor transplant need to take immune system-suppressing drugs for the rest of their lives to stop their body from rejecting the transplant. These drugs suppress the entire immune system, making the person more susceptible to infections and increasing their risk of cancer. If more targeted ways of suppressing just the parts of the immune system that will attack a transplant could be developed, this could potentially reduce these side effects.

The current study is a promising step towards potentially achieving this goal. However, this early, experimental technique will need to be tested in humans before we can judge its effectiveness and safety.

Where did the story come from?

The study was carried out by researchers from King’s College London and was funded by the Medical Research Council Centre for Transplantation, the British Heart Foundation, the National Institutes of Health, the Wellcome Trust, and the Guy’s and St Thomas’ Charity.

The study was published in the peer-reviewed scientific journal Science Translational Medicine.

The Daily Telegraph has reported on this research but does not make it clear that this particular study was carried out in mice. It is not yet clear whether the technique will work in humans and therefore reduce the need for immune suppressant drugs and make transplanted organs last longer, as suggested in the article.

What kind of research was this?

This was an animal study looking at whether the researchers could develop a way to use special immune system cells to improve ‘tolerance’ of transplants and reduce transplant rejection in mice.

Currently, people who receive a donor transplant need to take immune system-suppressing drugs (immunosuppressants) for the rest of their lives to stop their immune system attacking the foreign tissue, which can lead their body to reject the transplant.

While these drugs fulfil a vital role, they also suppress the entire immune system, which makes the person more susceptible to infections and increases their risk of cancer. Researchers would like to develop a way of suppressing just the parts of the immune system that will attack a transplant without interfering with the rest of the immune system. This current, early stage research tried to develop a technique that might be able to achieve this.

The research focused on immune system cells called Regulatory T cells, or Tregs, which can suppress the activation of the immune system. Different Tregs have different 'targets' within the immune system, and using an unselected pool of Tregs could result in suppressing the entire immune system in a similar way to immunosuppressant drugs. A better approach would be to isolate only those Tregs which are specifically targeted against the immune system’s ‘anti-donor cells’ that specifically attack donor tissue.

Previous experimental research has suggested that using only these targeted Tregs would be more promising than using unselected Treg cells as a means to block organ rejection. However, methods to isolate these specially-targeted Treg cells, and to also generate large numbers of them in the laboratory for research, have not yet been perfected.

This type of research is an essential first step in developing promising treatments that could go on to be tested in humans. Unfortunately, due to differences between species, some treatments that show promise in animals do not show the same effects in humans.

The current study tried to make their research as representative as possible of human biology, by using special ‘humanised’ mouse models, which are mice that carry human genes, cells, tissues or organs. However, the method will still need to be tested in humans before its effectiveness and safety in transplant patients can be judged.

What did the research involve?

The researchers first carried out a range of experiments to see if they could develop methods to first isolate human Treg cells targeted against anti-donor cells, and then to get them to multiply in the laboratory. They then carried out studies on a humanised mouse model that had been transplanted with human immune cells. These mice were also given a small (1cm2) human skin graft.

Some of the mice were then injected with Treg cells that specifically target anti-donor cells, some were injected with unselected Treg cells, and others did not receive an injection. After four to six weeks, the researchers examined the skin grafts for damage caused by the humanised immune system attacking the donor tissue.

What were the basic results?

The researchers found they could successfully generate a population of human Treg cells that mostly contained Tregs targeted against anti-donor cells. They could get these cells to divide in the laboratory, which allowed them to generate large numbers of them. This is important because enough cells can now be generated for their mouse experiments and for any future human testing. They also showed that these cells could indeed suppress the immune system cells that were targeting the transplanted tissue in the laboratory.

In their experiments in the humanised mouse model with a human skin graft, the researchers found that after four to six weeks the human immune cells were attacking and damaging the graft tissue. They found that injection of these mice with the anti-donor cell targeted Treg cells was more effective at reducing the damage to the graft compared to using unselected Treg cells. This meant that the skin grafts in the mice injected with the targeted Treg cells looked like normal, undamaged skin under the microscope.

How did the researchers interpret the results?

The researchers conclude that their method of selecting and generating large numbers of targeted human Treg cells should be viable for scaled-up use in clinical settings. They say that their results suggest that these targeted Treg cells may improve current treatments where immune system cells are used.

Conclusion

Currently, people who receive a donor transplant will need to take immunosuppressant drugs for the rest of their lives to stop their immune system attacking the foreign tissue, leading to their body rejecting the transplant. Even with the use of immunosuppressants, organ rejection can still be a common complication of transplant treatment. For example, an estimated 15-25% of people who receive a new kidney will experience acute organ rejection within a year of their transplant.

These drugs also suppress the entire immune system, which makes the person more susceptible to infections and increases their risk of cancer. If more targeted ways of suppressing just the parts of the immune system that are attacking the transplant could be developed, this could potentially reduce these side effects.

The current study is an early step towards potentially achieving this goal. It utilised immune system cells called Regulatory T cells, or Tregs, which can suppress the activation of the immune system. It successfully developed a method for isolating human Treg cells that will block those cells of the immune system that attack transplanted tissues. It was also able to generate large numbers of these targeted Treg cells in the lab.

This type of research is an essential first step in developing promising treatments that can go on to be tested in humans. Unfortunately, due to differences between species, some treatments that show promise in animals do not show the same effects in humans.

The researchers have tried to make their study as representative of human biology as possible, using special humanised mouse models that utilise mice carrying human immune system cells and human skin grafts. This means that in future the results will be more representative of what might eventually be seen in humans. However, we will need to wait for these human studies before we can judge the effectiveness and safety of this method in transplant patients.