Establishing a medical therapy requires a great deal of patience. An interdisciplinary group of researchers at the University Hospital Tübingen knows this from experience. It took more than three years before researchers succeeded in transplanting insulin-producing cells. However, the huge effort has paid off two-fold: the diabetes sufferer feels well after the intervention and secondly, Tübingen became the first German centre to receive the authorisation to produce such cells under the German Medicines Law.
People suffering from diabetes mellitus type 1 occasionally lose the ability to produce insulin as early as childhood. This is due to autoimmunological processes that lead to the destruction of the insulin-producing cells in the islets of Langerhans in the pancreas. In order to control the blood glucose level, diabetes sufferers need to regularly inject insulin. However, neither the control of the blood glucose level at short intervals, nor sophisticated treatment regimes are able to fully prevent the occurrence of long-term damage, particularly in the blood vessels. Some diabetics also suffer from recurrent episodes of life-threatening hypoglycaemia. In the majority of cases, pancreas transplants are then the only possibility. However, in some patients, the risk posed by such operations is unjustifiably high. The transplantation of islet cells now offers new hope to such patients. This method, which was established as an alternative treatment option after the introduction of what is known as the Edmonton protocol in 2000, no longer involves the transplantation of the entire organ. “Instead, the islet cells are taken from the organ of a donor and infused through a catheter into the vascular system of the recipient’s liver. Once implanted, these islets start to make and release insulin,” explains Dr. Marc Waidmann from the Centre for Clinical Transfusion Medicine at the University Hospital of Tübingen (UKT).
It is a matter of debate as to whether organs other than the liver can be transplanted with islet cells. “The liver has the great advantage that it is easily accessible for such a minimally invasive intervention and it is also supplied with large enough amounts of blood so that the islet cells are able to quickly react to blood glucose level fluctuations,” reports Roland Klaffschenkel, who had a leading role in the establishment of islet cell transplantation at the UKT. The biologist started work on a pig model – back then he was working with Dr. Nicolas Lembert in the Department of General Visceral and Transplantation Surgery. In 2005, he started to work with scientists at the Centre for Clinical Transfusion Medicine (ZKT) led by Prof. Dr. Hinnak Northoff in order to transfer the newly developed method to people.
The preparation of islet cells is a very tricky process. The cells are produced at the ZKT in a special laboratory of the highest clean-room status according to the standards of Good Manufacturing Practice (EU-GMP). The process begins with the specific enzymatic digestion of pancreas tissue, followed by the purification of the cells using a density gradient where the islets of Langerhans are obtained. “The procedure takes about eight to twelve hours; the subsequent quality control takes almost as long,” said the pharmacist Waidmann, who is in charge of producing the cells at the ZKT.
A great deal of experience is necessary to isolate and purify the cells. That explains why there are only three people at the UKT who are currently able to carry out the procedure: Waidmann, Klaffschenkel and one of their colleagues. “We are on call 24 hours a day,” said Waidmann explaining that the pancreas cannot be stored due to the digestion enzymes it produces. “No more than twelve hours must elapse between the removal of the organ and the beginning of the procedure to isolate and purify the cells,” knows Waidmann.
A few months ago, doctors at the UKT together with surgeons and radiologists, carried out the first islet cell transplantation - after more than three years of development. The patient was in good health after the successful intervention and now produces his own insulin. However, despite the success achieved, Waidmann and Klaffschenkel are well aware that the method is not yet perfected and needs to be further optimised.
Firstly, the isolation and purification of pancreatic islet cells is not always successful. "Even the most experienced centres in the USA only achieve a success rate of 30 to 40 percent," reports Waidmann. Secondly, the number of islet cells obtained is often not sufficient to enable diabetes sufferers to be independent from insulin injections. Often two to three pancreases are needed, and this poses a big problem in view of the small number of donor organs available. Thirdly, islet cell transplants do not lead to a permanent cure for diabetics. The function of the transplanted cells gradually decreases over time because the immune system of the recipient tends to reject the foreign tissue. Taking immunosuppressive drugs can slow down this process, but cannot prevent it.
“The transplantation of islet cells will therefore initially remain a niche procedure,” said Klaffschenkel. However, despite all these limitations – for all those suffering from instable type 1 diabetes and frequent hypoglycaemias - islet cell transplants represent a considerable improvement in quality of life. The insulin production achieved with islet transplants is actually sufficient to stabilise the labile metabolic situation over a long period of time.The Centre for Clinical Transfusion Medicine is the first German centre to receive an authorisation to produce pancreatic islet cells according to the German Medicines Law. This was partly as a result of the fact that the Tübingen scientists have from the start isolated and purified the human islets of Langerhans under GMP (Good Manufacturing Practice) conditions. “Therefore, we refrained from using a well-proven enzyme, which contained cattle components, for the digestion of the pancreas. This particular enzyme had to be withdrawn from the market due to the risk of BSE, which could not be excluded. The result was that many centres had to re-establish the procedure for producing islet cells and the number of islet transplantations decreased dramatically. While more than 250 transplantations were carried out in 2004 in the USA, there were only 20 worldwide in 2008. The fact that Tübingen has now become part of this small illustrious circle, rewards the persistence of all the scientists and physicians who have been involved in this long-term development process.
Further information:University Hospital TübingenCentre for Clinical Transfusion Medicine Dr. Marc Waidmann Roland A. KlaffschenkelOtfried-Müller-Straße 4/172076 TübingenTel: +49 7071/ 29 81606Fax: +49 7071/29 5240E-mail: marc.waidmann(at)med.uni-tuebingen.deE-mail: Roland.Klaffschenkel(at)ed.uni-tuebingen.de