New treatment can bring people experiencing islet graft rejection after islet transplantation back from the brink

Disease and treatment 9. jan 2024 7 min Medical doctor and PhD Cyril Landstra, Endocrinologist Michiel Nijhoff +1 Written by Eliza Brown

Type 1 diabetes management is challenging, but recent advances in pancreatic islet transplantation offer hope. This technique, less invasive than whole-pancreas surgery, implants insulin-producing cells into the liver, which results in less (severe) hypoglycaemia, improved glucose regulation and reduction of diabetes-related complications, greatly improving people’s quality of life and disease burden. One threat to these promising results is acute graft rejection, in which the immune system rejects the islets, resulting in loss of islet graft function. A new treatment combining steroids and insulin seems to be effective in preventing this loss of islet graft function. This method is currently the first available option to save islets from rejection.

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People with type 1 diabetes rely on injecting insulin to regulate their blood sugar. For people with severely complicated diabetes, “this is like a full-time job,” says Michiel Nijhoff, an endocrinologist at the Leiden University Medical Center in the Netherlands. “They are busy with diabetes four to six hours a day.”

“We often compare it to tightrope walking, every minute, every second of every day,” adds Cyril Landstra, a physician and PhD candidate studying type 1 diabetes and islet transplantation at the University of Leiden.

“They have to make hundreds of medical decisions each day, which all can have major consequences – in the worst cases death or hospital admission,” Cyril Landstra explains.

But new research on transplanting healthy pancreatic islets – the insulin factories of the human body – could lessen or completely eliminate the need for insulin for some people with diabetes. To ensure that the graft survives, patients receive lifelong medication that suppresses the immune system to prevent rejection of the islets.

A team of medical researchers at the Leiden University Medical Center has published the first guide to saving a failing islet transplant if the immune system rejects the islets. The new protocol challenges a longstanding idea that steroids – the frontline treatment to support transplants by reducing inflammation and suppressing the immune system – might harm islets.

With this new playbook in action, “we see right now that we can really save islet function,” Cyril Landstra says. And that could mean dramatically improving the quality of life of these islet transplant patients.

Transplantation with low procedural risk

Nestled deep behind the other internal organs in the upper abdomen, the pancreas is at the epicentre of type 1 diabetes. It secretes hormones that signal the body to increase or decrease the amount of blood sugar in circulation.

Whole-pancreas transplantation requires major surgery with the risk of severe complications – the most severely ill patients, including older people, are ineligible. For whole-organ transplants, “you have to be young, you have to be fit,” Cyril Landstra says.

And the outcome is “much more dichotomous” with whole-pancreas transplants – “either you are insulin independent or you have nothing,” Michiel Nijhoff adds.

But an islet transplant is a procedure with much lower procedure-related risk. The pancreatic islets, clusters of hormone-producing cells, are the body’s insulin factory, and it turns out that they can function independently from the rest of the pancreas after transplantation.

Protects foreign cells by reducing inflammation

Using a catheter that is inserted into the portal vein, the pancreatic islets from a deceased donor are infused into the recipient’s liver. “From there, they spread out through the liver until they get stuck in tiny veins called venules. And there they begin their new life producing insulin,” Cyril Landstra explains.

The first islet transplants were performed in the 1980s, but 40 years later, the procedure is still considered experimental in many countries, including the United States. According to Cyril Landstra, as simple as the procedure is, islet transplants pose two unique challenges.

First, checking in on the transplanted islets is difficult. Since the islets disperse throughout the recipient’s liver, doctors cannot take a biopsy as if they were assessing rejection in a heart or lung transplant.

And maddeningly, if transplant specialists suspected that the recipient’s immune system was rejecting the islets, they had nothing to offer patients.

Steroids are one of the frontline treatments to prevent the rejection of organ transplants, protecting the foreign cells by reducing inflammation and suppressing the recipient’s immune system. Soon after steroids were first isolated in the 1930s, researchers found that they have a diabetogenic effect, suppressing the effect of insulin and increasing blood sugar.

This is less than ideal for people with severe insulin problems. Without any options to save the islets, “we are just standing there waiting for the transplant to fail,” Michiel Nijhoff says.

A salvage mission

Leiden University Medical Center began its islet transplantation programme in 2007. Michiel Nijhoff remembers the frustration of his colleague Eelco de Koning, Professor of Diabetology at Leiden University, when islet transplants seemed to be failing. “What I got from de Koning was despair,” Michiel Nijhoff recalls. “He said, ‘there is nothing we can do to diagnose, there is nothing we can do to treat.’”

But after several years, Eelco de Koning and Michiel Nijhoff began to question two things: the nature of a rejection episode and whether steroids really are a non-starter for people receiving islet transplants.

Allograft rejection episodes have an important unknown, Michiel Nijhoff explains. In a rejection episode, when the blood sugar spikes with potentially dangerous consequences, have the transplanted islets actually died or have they just stopped functioning because of stress?

“Because if it is dysfunction, then if I take away the stressor, then perhaps we can salvage many cells – then basically function picks back up again,” Eelco de Koning says. “We think that this is what happens – the cells are not completely gone yet.”

If Eelco de Koning’s hunch was correct, rejection episodes were no death sentence for the transplant – doctors just needed to relieve the pressure on the surviving cells until they could get back on their proverbial feet.

The biggest strain on transplanted islets is the recipient’s immune system, so the team re-evaluated the very brief history of steroid use in pancreas and islet transplants. The researchers found that the reason for steroids’ diabetogenic effect was unclear – although scientists in the early 2000s believed that steroids were toxic to islets, that had never been rigorously proven.

An article in 2008 suggested that “islets themselves are not really bothered by steroids,” Michiel Nijhoff explains. It could be that the response of cells around the body to insulin is actually what is dampened.

And in 2012, researchers from France reported that a high dose of steroids had brought back a woman’s islet transplant from the brink of rejection. Eight months after the treatment, she was insulin independent. Could this be reproduced in a larger series of patients?

The difference was striking

In 2015, the team at Leiden University Medical Center set out to pilot a new treatment protocol for people whose islet transplants seemed to be failing.

Rather than relieving symptoms once they had crashed, as was the standard of care before treatment was available, the doctors asked patients to come in at the first sign of unexplained blood glucose spikes. Early intervention would maximise the number of islets that could be saved – as long as doctors could relieve pressure on the survivors.

If, as Michiel Nijhoff suspected, steroids influence the body’s response to insulin rather than negatively affect the islets themselves, could flooding the patient’s systems with insulin compensate for the diabetogenic effect?

In the new protocol, a high dose of the steroid methylprednisolone is administered at the same time as a high dose of insulin. “You cannot just give methylprednisolone and wait,” Michiel Nijhoff emphasises. “You have to add the high-dose insulin to keep the glucose levels within the normal range or otherwise it will create problems.”

Over the next several years, the researchers compared the health of people who received the new treatment protocol with those they treated before the protocol was developed.

The difference in outcomes was striking, the authors say – three patients who received the new treatment fared much better than the four who did not.

Ease the transition

Six months after their rejection episodes, all three patients who received the protocolised treatment had good islet function, and three of the untreated patients’ transplanted islets completely failed and a fourth retained marginal function. And the researchers found minimal side-effects from the steroid treatment.

The realisation that steroids could be used on people undergoing islet transplants with proper compensation through insulin was something of a sea change, the researchers say. Since the success of the treatment protocol for rejection episodes, that finding has changed the standard course of treatment following islet transplants at Leiden University Medical Center.

“Most of the rejection episodes happened in a short window after the transplantation,” explains Cyril Landstra. “That of course creates an opportunity to do more in relation to immunosuppression in that window.”

Now, islet transplant recipients at Leiden University Medical Center receive immunosuppressive medication for a longer period of time after transplantation – before there are any signs of rejection – to ease the transition during what appears to be a critical period for the islets.

The results of the post-rejection protocol were peer-reviewed and published in 2023. The change in immunosuppressive regimen that followed included aiming for higher target blood values of tacrolimus for a longer duration after the transplantation. 

Between 2008 and 2019, 22% of islet transplant recipients at Leiden University Medical Center experienced a suspected rejection episode. Since the new post-transplant protocol has been in place, that rate has plummeted to 4%, the researchers say.

“That is really a big difference,” Cyril Landstra says.

Why aren’t islet transplants more common?

Although islet transplants are increasingly common in some countries, including the Netherlands, the procedure has not been widely adopted. An international census of islet transplants identified just 99 institutions and networks worldwide that had performed an islet transplant between 2000 and 2020. Nearly half of these had performed fewer than 10 transplants, and just 26 centres performed transplants in 2020. (Compare that with the 250 kidney transplant centres active in the United States alone in 2015.)

One major stumbling block to widespread adoption is how human islets are legally classified. In 2002, the United States Food and Drug Administration (FDA) ruled that human islets should be considered a biologic drug – a category that also includes vaccines and monoclonal antibodies – and requires a special licence to use. To date, no such licence has been issued, leaving human islet transplantation experimental and ineligible to be covered by third-party health insurance. Transplant teams across the United States continue to petition the FDA for a rule change, but it remains an uphill battle.

Another issue is that many countries have separate waitlists for whole-pancreas and islet transplants that essentially compete for the same high-quality donated pancreases.

Islet transplants are no silver bullet for type 1 diabetes, the authors of the study emphasise. The steroids or other anti-rejection drugs that prevent the immune system from attacking the transplanted islets leave patients vulnerable to infection and disease. But unlike people undergoing chemotherapy whose immune system is only suppressed during treatment, transplant recipients have to take immunosuppressants for the rest of their lives. This means that islet transplants would not be a worthwhile trade-off for people whose type 1 diabetes is well managed.

Nevertheless, the response to the new findings on steroids has been “overwhelmingly enthusiastic,” Cyril Landstra says. “I think that other islet transplant specialists were initially surprised because steroids were a controversial topic, but I think that people in the field are happy to see that there is now an option to save islet transplants after rejection.”

Diagnosis and treatment of allograft rejection in islet transplantation” has been published in the American Journal of Transplantation. The research was funded by the Dutch Diabetes Research Foundation, DON Foundation, Bontius Foundation, RegMed XB, Diabetes Cell Therapy Initiative, Tjanka Foundation and the Novo Nordisk Foundation via a grant for the Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW).

Cyril Landstra is a medical doctor who joined the islet group in November 2019, directly after obtaining her medical degree with Honours and distincti...

Michiel Nijhoff is a medical doctor working as a medical specialist and researcher in the field of diabetology and transplantation. He obtained his me...

Eelco de Koning is professor of diabetology at the Leiden University Medical Center. He heads the LUMC diabetes center and coordinates the human islet...

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