A research team led by Professor Eckhard Wolf and Professor Jochen Seißler of Ludwig-Maximilians-Universität, Munich and affiliated with the German Center for Diabetes Research (DZD) has succeeded in generating xenografted islet cell clusters from transgenic pigs in humanized mice. Initial experiments in the pigs have confirmed that these cells regulate blood glucose levels and are not rejected by the human immune system. This raises hope for a cure of type 1 diabetes by means of xenotransplantation, i.e. by transplanting animal tissue into the human body.
The onset of type 1 diabetes typically occurs at a young age. The disease is often caused by an autoimmune reaction which ultimately leads to the destruction of the insulin-producing cells of the pancreas. The missing hormone must be administered to the patient on an as-needed basis, and despite strict compliance with all dietary and therapeutic targets, a potentially life-threatening hypoglycemia may occur.
That is why for many patients with type 1 diabetes a pancreas transplant or transplant of the insulin-producing beta cells may represent the best treatment option. However, although there are about a quarter of a million patients with type 1 diabetes in Germany, fewer than 200 transplantations have been carried out over the course of the last several years, mainly because donor organs are so rare. “Pigs represent a possible alternative source because glucose homeostasis in this species is very similar to that of humans,” Seißler said.
Pig insulin differs from human insulin in only one single amino acid and has been used in diabetes therapy for decades. But after transplantation, pig cells are soon recognized by the human organism as foreign tissue and are thus destroyed. One way of avoiding this difficulty is to encapsulate the foreign tissue in a biologically inert material that is permeable to insulin but not to cells of the immune system. However, the drawback of this approach is the chronically restricted supply of oxygen and essential nutrients to the transplanted cells, thereby reducing its lifespan.
Wolf and his research team chose a different route and generated genetically modified pigs that express the protein LEA29Y specifically in beta cells. LEA29Y effectively inhibits the activation of a class of immune cells that are required to initiate a rejection reaction. The researchers then transplanted these cells into a diabetic mouse strain that has a humanized immune system. Seißler’s group showed that these mice were able to restore glucose metabolism and were protected from human-anti-pig rejection. As Wolf was quick to point out, “It is not yet clear whether this will also work in humans. However, we will now attempt to validate the effects of this very promising approach using beta-cells expressing immune modulators in other transplantation models.”
“Xenografted Islet Cell Clusters From INSLEA29Y Transgenic Pigs Rescue Diabetes and Prevent Immune Rejection in Humanized Mice”
Nikolai Klymiuk, Lelia van Buerck, Andrea Bahr, Monika Offers, Barbara Kessler, Annegret Wuensch, Mayuko Kurome, Michael Thormann, Katharina Lochner, Hiroshi Nagashima, Nadja Herbach, Rudiger Wanke, Jochen Seissler, and Eckhard Wolf
Diabetes online, April 20, 2012