Recent funding may help researchers get closer to finding a solution for Type I diabetes, also called juvenile diabetes, through various procedures involved in transplanting islet cells, the body’s natural insulin producers.
The Juvenile Diabetes Research Foundation (JDRF) recently awarded a three-year, $4.1 million grant to Emory University in Atlanta, essentially creating Georgia’s first clinical islet transplantation center. The money will be used to further research of islet cell transplantation, which has traditionally faced a number of limitations, most notably rejection by the immune system.
“This is the first major grant like this in the Southeast,” said Christian Larsen, the director of Emory’s clinical islet transplantation program. “We have other grants of that magnitude that support our basic and translational work at the primate center. But this is exciting because it involves basic research, translational research and clinical research.”
The JDRF consists of 27 centers, but only seven are involved with clinical islet transplants, including Emory. The others include the University of San Francisco, Harvard University, the University of Pennsylvania and the University of Alberta, Canada. The JDRF said two other centers have not yet been named publicly.
The research is aimed at replacing islets, whose insulin-producing characteristics are lost in Type I diabetes. Two methods will be tested at Emory first, developing an immunosuppressive agent without creating side effects associated with current therapies, and second, researching whether animal islets can avoid a human immune response if they are sheathed in a microscopic porous membrane.
In human islet transplantation, which has been explored to varying degrees of success since the 1970s, islets are harvested from pancreases culled from cadaveric organ donors.
“It’s got old roots, but it’s actually very new as a clinical therapy,” Larsen said.
The cells are then inserted through a needle puncture into a vein that runs to the liver, where the islets are infused. Like any organ transplant, though, the procedure is subject to a negative immune response.
“The body will respond to foreign things, like infections, which is good, or transplants, which is undesirable,” Larsen said. “If you give immunosuppressive drugs to an organ recipient drugs like cyclosporin, steroids and other drugs you can prevent rejection.”
In islet transplants, drugs such as Tacrolimus, Sirolimus and Daclizumab are used as immunosuppressants.
“They can prevent rejection, but they have side effects,” Larsen said. “So that’s going to limit islet transplantation. Our interest is in developing less toxic immunosuppression, and ultimately tolerance.”
Emory’s JDRF Center will be involved in four initial studies.
Two Emory studies will explore steroid-free approaches with the new class of co-stimulation blocker compounds. Larsen will lead a clinical trial of human islet transplantation using a drug that already has shown promise in protecting kidney transplants from attack by the immune system. In the second related project, researchers will perform preclinical studies and examine tolerance induction to islet grafts using the co-stimulation blockade approach in nonhuman primates.
The drugs being developed involve T cells, the part of the immune system responsible for rejection.
“When they reject, they have to become activated,” Larsen said. “They see something is foreign that gives them one signal but then they need a second signal to become fully activated. That’s called co-stimulation.”
Targeting the T cells, the research is aimed at producing a co-stimulation blockade, essentially halting the second signal before the T cell can receive it and reject the transplant.
“The T cells that want to reject see the transplant, but the co-stimulation blockade makes them die,” Larsen said. “It’s a part of tolerance induction, so it’s very specific for targeting the T-cell response, whereas the other drugs that are currently used unfortunately target pathways that are used by other cells. I don’t mean to say that this drug is not going to have any side effects, but it potentially moves away from some of them.”
Emory’s research also will involve two other projects, both of which focus on using microencapsulated pig islets, addressing the issue of limited availability of human pancreatic tissue. Investigators will examine the ability of pig islets encapsulated in a protective membrane to correct diabetes in laboratory mice. Researchers will design the protective membrane to prevent immune attack of the pig islets while maintaining their function. The technique may also be applied to the transplantation of human islets.