Technion/BGU find may lead to diabetes treatment

With autoimmune type I diabetes requiring potentially injurious insulin injections several times a day and type II diabetes showing a growing role for insulin-producing pancreatic islets in disease progression, researchers around the world are searching for better ways to cope.

New animal research at the Technion-Israel Institute of Technology in Haifa and Ben-Gurion University of the Negev in Beersheba offer the hope that one day, transplants of tissue from the pancreas could lead to better glucose control for diabetics.

Prof. Shulamit Levenberg of the Technion, who has spent many years trying to create replacement human organs by building them up on a “scaffold,” has created tissue from the insulin-producing islets of Langerhans in the pancreas surrounded by a three-dimensional network of blood vessels.

The tissue she and her team created has significant advantages over traditional transplant material that has been harvested from healthy pancreatic tissue.

The insulin-producing cells survive longer in the engineered tissue, and produce more insulin and other essential hormones, Levenberg and colleagues wrote in the latest issue of the US medical journal PLOS One. When they transplanted the tissue into diabetic mice, the cells began functioning well enough to lower blood sugar levels in the mice.

Transplantation of islets – the pancreatic tissue that contains hormone-producing cells – is one therapy considered for people with type 1 diabetes, who produce little or no insulin because their islets are destroyed by their own immune systems.

But as with many tissue and organ transplants, donors are scarce, and there is a strong possibility that the transplantation will fail.

The well-developed blood vessel network built into the engineered tissue is key to its success, the researchers concluded. The blood vessels encourage cell-tocell communication, by secreting growth hormones and other molecules that significantly improve the odds that transplanted tissue will survive and function normally.

The findings confirm that the blood vessel network “provides key survival signals to pancreatic, hormone-producing cells even in the absence of blood flow,” Levenberg and colleagues wrote. One reason transplants fail, Levenberg said, “is that the islets are usually transplanted without any accompanying blood vessels.”

Until the islets begin to connect with a person’s own vascular system, they are vulnerable to oxygen and nutrient starvation.

The 3-D system developed by the Technion researchers tackled this challenge by bringing together several cell types to form a new transplantable tissue.

Using a porous plastic material as the scaffold for the new tissue, the scientists seeded the scaffold with mouse islets, tiny blood vessel cells taken from human umbilical veins, and human foreskin cells that encouraged the blood vessels to develop a tube-like structure.

Islets grown in these rich, multicellular environments lived three times as long on average as islets grown by themselves, Levenberg and colleagues found.

The technology “is still far from tests in humans,” Levenberg said, but she noted that she and her colleagues are beginning to test the 3-D tissue scaffolds using human instead of mouse islets.

“The advantages provided by this type of environment are really profound,” said Xunrong Luo, an islet transplantation specialist at the Northwestern University Feinberg School of Medicine in Chicago. She noted that the number of islets used to lower blood sugar levels in the mice was nearly half the number used in a typical islet transplant.

According to the Northwestern researcher, the 3-D model demonstrated in the study “will have important and rapid clinical implications” if the results can be replicated with human cells. “This model system also provides a good platform to study the details and mechanisms that underlie successful transplantation.”

Meanwhile, other islet research relevant to both type I and type II diabetes is being conducted by Dr. Eli Lewis, a member of the Clinical Biochemistry and Pharmacology department at BGU and the head of Israel’s only clinical islet lab.

In a recent report, Lewis, working with doctoral students Eyal Ozeri, Mark Mizrahi and Galit Shahaf, addressed the immune system that arrives at the grafted islets. The team examined cells relevant for the early response of the immune system. These so-called dendritic cells normally collect molecules from the site of the graft and deliver them to the draining lymph nodes for presentation to the graft-recipient’s lymphocytic cells.

The group found that the naturally occurring protein alpha1-antitrypsin (AAT) employs these cells for the purpose of elevating the levels of regulatory protective T cells and thereby affords critical protection to islet grafts. According to the experiments, AAT causes dendritic cells to advance from immature to semi-mature, instead of completing their final T cell-activating mature phenotype.

At this point a crucial question was raised: Do these semimature dendritic cells have the ability to migrate to the draining lymph nodes? After all, if they fail to migrate, they won’t be able to alter the course of the immune system in favor of the islet grafts.

The group unexpectedly noticed that in detailed migration experiments in the presence of AAT treatment – both in cultures and in whole animals – not only do the dendritic cells display migratory capabilities, but they actually migrate faster.

One of the implications of these findings relates to current immunosuppressive treatment protocols that do not afford the fine control of the immune system toward a favorable outcome, such as observed in the current study.

The approaches developed by these two Israeli research groups hold an intriguing practical scientific overlap. When an organ graft, such as kidney, is connected to the recipient’s blood supply, a rapid entry of the immune system occurs such that gravely injures the graft. Islets, paradoxically, benefit in this respect from some spatial separation from blood-borne immune cells in that they are non-vascularized upon engraftment. With their vascularization enhanced by the Technion group, an answer to the aggressive immune system can be found in the work performed at BGU.