In Depth

The journey of islet cell transplantatio, part 1: origins, drawbacks and optimism

The concept of islet cell transplantation is, on paper, a straightforward way of treating type 1 diabetes.

People with type 1 diabetes cannot produce insuli, so transplanting insulin-producing cells into their bodies ostensibly solves this problem. But the drawbacks, side effects and obstacles of islet cell transplantation have stumped researchers for decades. The procedure isn’t always successful and immunosuppressant drugs are nearly always required, which carry their own risks.

Now, though, progress is advancing significantly. Solutions are being discovered, and optimism is rising.

So, just how beneficial could islet cell transplantation be in treating diabetes? This is the question we’ll be investigating across two articles: the first of which will elucidate the journey of islet cell transplantatio, while part two will concentrate on the strides achieved through encapsulatio, an innovative new branch of transplantation.

Complex treatment

Earlier this month there was a major notch on the progress belt. An encapsulation device mimicking the way water beads on a spider’s web enabled transplanted islet cells to be more easily removed once used by the body. This, Cornell University researchers said, will help to prevent lasting damage caused by the cells, such as the potential to form tumours.

Developments such as this mark acute progress compared to the early days of islet cell transplantatio, but before we delve into the origins, a little background information is required.

Islet cell transplantation is a complex, extreme treatment for people with type 1 diabetes. It has been reserved for patients unable to manage the condition with insuli, either due to clinical or emotional factors, who have experienced complications as a result, such as regular severe hypoglycemia. Whilst a pancreas transplant has been offered in some instances, islet transplantation is safer because if the body rejects the cells it is not as dangerous as if the body was to reject an organ.

For those severely struggling with diabetes every day, islet cell transplantation has been hugely beneficial. In many ways, it has helped give these people their lives back.

Islet cell transplantation is a complex, extreme treatment for people with type 1 diabetes.

However, there are several drawbacks. Off the bat, the cells could be rejected. Thousands of islets are required to normalise blood glucose levels, and there is a limited donor pool. Because of the inevitably destructive immune response in people with type 1 diabetes, immunosuppressant drugs are eventually required to protect the cells. These drugs are designed to hold back the immune system, and this increases the risk of infection.

Despite these obstacles, the situation is actually very encouraging. This is because a plentitude of novel techniques have been developed over the last 20 years to greatly improve the success of transplantation.

If at first you don’t succeed…

While most of the big moves have been made recently, the origins behind transplantation actually trace back hundreds of years.

Our journey begins in 1869 in the laboratory of a German medical student whose research into the pancreas led to a groundbreaking discovery. Paul Langerhans identified that the pancreas contains a type of cell that secretes tiny cell islands; these islands eventually went on to be known as the “Islets of Langerhans”. When we read about islets, in this instance they refer to islands of cells isolated from pancreatic donors. And islets contain a plenitude of cell types, including insulin-producing beta cells.

The Islets of Langerhans are named after German scientist Paul Langerhans

In the early 1890s, an attempt was made to implant a sheep pancreas into a 15-year-old boy with diabetes, but the experiment was unsuccessful. Then in 1924, English surgeon Dr Charles Pybus became the first to attempt to graft human pancreatic tissue to cure a patient’s diabetes, but as with the sheep transplant, the grafts were swiftly destroyed because of immune rejection[1]. These failures occurred before scientists understood how to prevent rejection of donor organs.

For much of the 1900s, research stalled. But the seminal research of Dr Paul Lacy in the 1960s ushered a much-needed change in direction. Dr Lacy’s method of isolating insulin-producing cells, a collagenase-based treatment, was shown to reverse diabetes in rodents[2], and his process became revered for its impact on future experiments.

These results eventually led to the first human islet transplantation trials in the mid 1980s. These were ultimately unsuccessful, but a breakthrough was near. Ten years later the University of Pittsburgh conducted the first successful islet cell transplant, with one patient reported to have been free from insulin for six months[3].

“The longest survivor, who requires neither parenteral alimentation nor insuli, is the first unequivocal example of successful clinical islet-cell transplantatio,” wrote Starzl et al.

The Edmonton Protocol

The Edmonton protocol was introduced at the turn of the Millennium, a game-changing development by the University of Alberta, Canada, which conceptualised administering immunosuppressant drugs immediately after transplantatio, and then periodically afterwards, as a means of extending the lives of the cells.

In 2000, Dr James Shapiro and colleagues utilised the Edmonton Protocol on seven patients who had a history of severe hypoglycemia. All patients received islets from two donor pancreases, while one patient required a third, and quickly attained insulin independence and normal blood sugar levels. Episodes of severe hypoglycemia were nullified[4].

The immunosuppressant drugs administered were steroid-free, which lessened the risk of complications, such as hypertension[5], and the Edmonton Protocol became adapted by islet transplant centres worldwide.

Coming off insulin

As previously mentioned, though, it is partly because patients still subsequently require these drugs that islet cell transplantation has remained reserved for those with the greatest need for it.

There is no guarantee that patients can live without insuli, and most people will revert to needing insulin within years, or even months. Moreover, because immunosuppressant drugs can lead to side effects, such as higher risk of infectio, knock-on problems can occur where treatment may need to be ceased to allow the body to fight an infection. During this time, the immune system can start attacking the transplanted cells.

However, a salient benefit is that following transplantation people often require lower doses of insulin than before.

One of the great early successes of islet cell transplantation was Richard Lane. Lane retired through ill health and 2004 and was encouraged to sign up to a waiting list for transplantation. In 2004 he became the first person in the UK to come off insulin, which he did for a year before a viral infection forced him into taking insulin again via his insulin pump. In November 2008, Lane was announced as the new President of Diabetes UK, and went on to set up the Islet Cell Consortium, which joined nine islet centres in the UK to together to provide the treatment. Eventually, transplantation was accepted by the NHS.

So the objective of science is two-fold: to guarantee that islets will succeed upon transplantatio, and to prevent the destructive immune response in people with type 1 without the need for drugs. It’s a complex feat, but research teams worldwide are tackling this challenge and having success.

In part two we’ll explicate the exciting new branch of transplantation known as encapsulatio, an innovative technology designed to help islet cells survive with reduced need for the immunosuppressant drugs.

We’ll also discuss the groundbreaking US research from the City of Hope that aims to predict which people will most benefit from transplantatio, and why the omission of immunosuppressant drugs could occur sooner than we think.

[1] https://books.google.co.uk/books?id=FQXZBAAAQBAJ&pg=PA395&lpg=PA395&dq=pybus+islet&source=bl&ots=-R9iaXyNIB&sig=Crr8eUYqwCNS4sPmO9m2cT5uBik&hl=en&sa=X&ved=0ahUKEwi2r9mv-8_YAhWMyaQKHcSCBkMQ6AEIXTAI#v=onepage&q=pybus%20islet&f=false

[2] https://www.nature.com/articles/244447a0

[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2972674/

[4] http://www.nejm.org/doi/full/10.1056/NEJM200007273430401

[5] http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071251

 

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