Successful Islet Cell Transplant Without Immunosuppressive Therapy In Mice With Type 1 Diabetes

Reporting in the Proceedings of the National Academy of Sciences, the team greatly boosted the number of immune T-cells able to shield transplanted pancreatic islet cells from attack by the immune system. Insulin-producing islet cells are deficient in type 1 diabetes.

"If we can replicate this in humans, we might someday do away with the lifelong use of powerful immunosuppressive drugs that patients must take after islet cell transplant -- drugs that we believe also do harm to islet cells over time," explains the study's senior author Dr. Manikkam Suthanthiran, chief of the Division of Nephrology and Hypertension at Weill Cornell Medical College and chief of the Department of Transplantation Medicine at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

Type 1 diabetes is an inherited disorder in which the body's immune cells attack islet cells in the pancreas, reducing or eliminating the body's ability to produce the blood-sugar hormone. It is distinct from the much more common type 2 form of diabetes, where obesity and other factors cause a gradual decline in cells' sensitivity to insulin.

Scientists have sought to reverse type 1 diabetes by transplanting new islet cells. The procedure has met with some success -- in fact, Dr. Suthanthiran's team at NewYork-Presbyterian/Weill Cornell performed the first successful islet transplantation in the tri-state area in patients with type 1 diabetes in 2004.

However, problems remain. "To stave off the destruction of transplanted cells, patients must be placed on lifelong immunosuppressive therapy," Dr. Suthanthiran explains. "Besides having powerful side effects, we're learning that these drugs can be toxic to islet cells, too."

Now, an innovative biochemical manipulation of immune cells may get around that problem.

Working in collaboration with researchers at The Rockefeller University, the research team focused on immune system regulatory T-cells (T regs). These cells help the immune system decide which entities are "enemies" and which are "friendly" and should be left alone.

"Specifically, there are a subset of T-cells with cell-surface proteins CD4 and CD25, which are called natural regulatory T-cells," Dr. Suthanthiran explains. "These cells express a key factor called Foxp3, and the CD4+CD25+Foxp3+ regulatory T-cells suppress the runaway immune response to islet cells. Without Foxp3, the suppression of the islet destructive response cannot take place."

Unfortunately, Foxp3-positive T-cells make up a paltry 2 to 5 percent of the total T-cell population, so they have little impact in shielding transplanted islet cells from harm.

However, working with the standard mouse model for type 1 diabetes, the researchers were able to convert the much more common form of CD4+ CD25- T-cells into CD4+CD25+ T-cells that did express protective Foxp3.

"We did so by a two-pronged approach," Dr. Suthanthiran says. On the one hand, the research team exposed the much more common form of CD4+ CD25- T-cells to transforming growth factor-beta (TGF-b), which helps switch the T-cell over to a Foxp3 expressing cell.

But TGF-b on its own is too blunt an instrument.

"If we turn all of these T-cells into random immune suppressors, that could lead to more cancers and other problems," the researcher explains. "So, we used another immune system signaler, the dendritic cell, to target Foxp3 activity much more specifically and shield only the islet cells from immune system attack."

Study co-researcher Dr. Ralph Steinman of The Rockefeller University actually discovered the dendritic cell and its role in immune system signaling, and was instrumental in this research, Dr. Suthanthiran says. Dr. Steinman's group has shown that dendritic cells are highly efficient in turning on natural regulatory cells into islet protective cells.

"When CD4+ CD25- T-cells came into contact with both TGF-b and the specific antigen-presenting dendritic cells, they switched over to the immunosuppressive Foxp3 variety," he says. "The dendritic cells made sure that this protective immunosuppression was targeted to islet cells, specifically."

The result: successful islet transplantation in diabetic mice without any pharmacologic immunosuppression; the transplanted islet cells stayed healthy and produced insulin over the full nine weeks of the study.

And there was a bonus: "We also determined that this approach shields the pancreas' own islet cells from harm," the researcher says. "That's important, because newly diagnosed type 1 diabetes patients often have some percentage of working islet cells remaining. This strategy might protect those cells, as well as the transplanted cells."

According to Dr. Suthanthiran, there's no reason to believe this approach wouldn't also protect other types of transplanted cells or organs, including lung, kidney and hearts transplants.

"It's also important to note that we were treating established diabetes in this mouse model," Dr. Suthanthiran says. "Most of the success so far has been in preventing disease before it sets in, but this is akin to going into a house and putting out the fire after it has already started."

Of course, it remains to be seen if success in mice will translate to success in human type 1 diabetes. But Dr. Suthanthiran says he is optimistic.

"We want to create a transplant situation where we don't have to deliver any outside immunosuppressive drugs," he says. "That would truly be the best kind of cure."

This work was funded by the American Society of Transplantation, the Juvenile Diabetes Research Foundation and the U.S. National Institutes of Health.

Co-researchers include lead author Dr. Xunrong Luo, formerly at Weill Cornell Medical College, now at Northwestern University, Chicago; Dr. Hua Yang and Dr. Ruchuang Ding of Weill Cornell Medical College; Samantha L. Bailey and Kathryn Pothoven of Northwestern University; and Dr. Kristin V. Tarbell (co-lead author) and Dr. Ralph M. Steinman of The Rockefeller University, New York City.