Could new research help to reduce the need for immunosuppression after a kidney transplant? | Webinars

Regulatory T cells are a type of immune cell that naturally calm down unwanted immune reactions. On Thursday 26th February, Professor Fadi Issa joined us to describe how researchers are trying to harness these cells to reduce the need for life long immunosuppressant drugs after a transplant. He shared what the lab and early clinical results show so far and discussed what this research could mean for patients in the future.

The research

When someone has a kidney transplant, the immune system naturally sees the transplanted kidney as something foreign and tries to attack it. This is called rejection. To prevent this, transplant recipients need to take medicines that weaken parts of the immune system. These are called immunosuppressive or anti-rejection medicines.

Anti-rejection medicines are essential, but they can also cause problems over time. These include infections, certain cancers, heart disease, diabetes, and even damage to the transplanted kidney itself. Because of these risks, researchers are exploring ways to protect the transplanted organ while reducing the amount of immunosuppressive medication patients need.

Read the full summary of this research 

 

The webinar

Watch the webinar here 

 

Your submitted questions

Below are your submitted questions from the webinar, with answers provided by the speaker Fadi Issa.

How will T-reg therapy differ from conventional immunosuppression in terms of side effects like chronic infections and cancer, given that it still downregulates the immune system?

T-regs work in a targeted, specific way rather than suppressing the immune system broadly. They carry receptors that recognise which responses need to be suppressed, primarily autoimmune responses where T cells might attack the body's own tissues. Unlike conventional drugs such as tacrolimus, which are non-specific and suppress all immune activity globally, T-regs are unlikely to interfere with responses to infections because that is simply not their normal role.

On the question of cancer, there is some evidence that T-regs can suppress anti-tumour immune responses. However, the boost being given to T-reg numbers in the trials is relatively modest (around 5%) and over 10 years in the phase one trial, no increase in infections was observed. In fact, patients who received T-reg therapy had far fewer infections than the control group. This is likely because, by allowing the overall immunosuppressive drug burden to be reduced, the patient is effectively less immunocompromised overall, even if T-regs are slightly elevated.

Could T-reg therapy be given to patients who are already transplanted (rather than just at the time of transplantation), and could it help people receiving second or subsequent transplants?

This is absolutely part of the future vision. A small trial of seven patients gave T-regs at six months after transplantation rather than at day five, and those patients all did well; they came off their immunosuppression and had no rejection episodes. T-reg therapy could also potentially be useful during a rejection episode or when chronic rejection develops. Achieving this for already-transplanted patients would require the allogeneic approach (using banked T-regs from healthy donors), since it is not practical to take blood from a patient experiencing rejection, expand T-regs, and give them back a month later. People living with an existing transplant represent a larger patient population than those being newly transplanted each year and helping them is firmly within the plans.

Would T-reg therapy be applicable to patients receiving second or subsequent kidney transplants?

Yes, and this patient group is actually at even greater risk of rejection because prior transplants sensitise the immune system, making rejection of future transplants more likely. This makes them a priority population to target. There is already a trial running in London looking at whether T-regs can be given to sensitised patients, with results expected within a couple of years. Moving towards banked, allogeneic T-reg therapy would help make this more practical.

How does the therapy perform in older patients, given that immune responses change with age? Are there concerns about applying it more broadly to an older population?

The trials have not discriminated by age and no differences in response to T-reg therapy have been seen across age groups. There may be some practical challenges in older patients, as their immune systems tend to have more memory and exhausted cells, which could make it harder to isolate and expand T-regs in the lab, though failures cannot be pinpointed to a specific age range. Reducing immunosuppression is important for all age groups because the side effects of immunosuppression are actually more pronounced in older patients who are already predisposed to conditions such as skin cancer. T-reg therapy should be available to everyone, and moving to an allogeneic, off-the-shelf approach would help address challenges in older patients.

Could T-reg therapy eventually be stopped altogether? Might the T-regs take up residence in the thymus and continue to be produced when needed?

T-regs have a property called "infectious tolerance", meaning they can convert other non-regulatory cells into T-regs, amplifying their effect beyond their own lifespan. The phase one trial suggests a single dose may be sufficient, possibly because the cells migrate to the right locations (the transplant and lymph nodes), induce other cells to become T-regs, or simply survive long-term in those sites. The thymus in these patients has likely involuted and is no longer functional, so that is not where new T-regs would be generated.

On stopping immunosuppression altogether, clinicians are not yet ready to take that step, as the risk of losing a transplant remains too high without clearer evidence of safety. Patients in the trial have come off MMF, and tacrolimus doses have come down substantially to low trough levels, but complete withdrawal has not yet been attempted.

What is the rough timescale for T-reg therapy to become available to patients if the trials prove successful?

This depends heavily on the outcome of the ongoing phase two trial, for which full data is expected the following year. If the results are sufficiently clear, it may be possible to bypass a phase three trial. The next step would be review by NICE (the National Institute for Clinical Excellence), who would assess the evidence and consider health economics. Early health economic modelling has already indicated a net positive economic benefit from T-reg therapy, as reductions in transplant loss, immunosuppression use, and complications offset the cost of production. Being optimistic, if the phase two trial is positive, T-reg therapy could potentially be available in around four to five years, though these things often take longer than anticipated.

Were there any differences in outcomes when T-regs were given six months after transplantation compared to five days after?

No major differences were observed, though the two groups were not entirely comparable. The six-month group had received Campath induction therapy, whereas the five-day group had no induction immunosuppression. Both groups came off MMF and had no adverse outcomes. It is not yet clear when the optimal time to give T-reg therapy is, but giving it early and without induction immunosuppression is preferred, as this removes an additional layer of immunosuppression from the outset.

Is there concern that current immunosuppressive regimens could interact with and harm the T-regs?

This is a valid concern, as all immunosuppressive drugs, including tacrolimus, are toxic to T cells and are not ideal for T-reg survival. Despite this, the T-regs in the trials appear to survive, remain active, and migrate to the correct locations. To address the problem more directly, T-regs that are resistant to tacrolimus are being developed by deleting the specific protein through which tacrolimus acts inside cells. These tacrolimus-resistant T-regs are still in development but are expected to be even more effective than the current standard T-regs.

Could T-reg therapy be applied to other types of organ transplant beyond kidneys?

Absolutely. Other organ transplants such as lung and bowel transplants have much higher rejection rates than kidney transplants, meaning any benefit from T-reg therapy would be easier to detect in those populations, and these higher-risk transplant types could be particularly promising targets. The kidney transplant was addressed first as it is the most common.