Pancreatic Islet Transplantation May Be Extended by Microgel Delivery Method

In type 1 diabetes, the beta cells of the pancreas no longer make insulin, so a person who has type 1 diabetes must take insulin daily to live. Transplanted islet cells, however, can take over the work of the destroyed cells. Islets are cells found in clusters throughout the pancreas and are made up of several types of cells. One of these is beta cells, which make insulin.

Islet transplantation is the process of separating the islet cells from a donor pancreas and then transplanting these cells into a person with type 1 diabetes. However, most transplant recipients lose insulin independence an average of three years after transplantation.

Using an animal model, the researchers at the Georgia Institute of Technology and the University of Missouri developed a new biomaterial microgel that could deliver safer, smaller, and more cost-effective dosages of an immune-suppressing protein that could extend the effectiveness of pancreatic islet transplantations.

Their findings, “Immunotherapy via PD-L1–presenting biomaterials leads to long-term islet graft survival,” were recently published in the journal Science Advances and led by Maria Coronel, PhD, a postdoctoral fellow in the lab of Andrés J. García, the Parker H. Petit chair and executive director of the Petit Institute for Bioengineering and Bioscience.

“Here, we implement a synthetic biomaterial platform for the local delivery of a chimeric streptavidin/programmed cell death-1 (SA-PD-L1) protein to direct “reprogramming” of local immune responses to transplanted pancreatic islets,” the researchers wrote.

Inspired by the 2018 Nobel Prize for medicine for discovering how cancer cells send molecular signals to suppress immune response, the researchers developed a method to turn off an immune response to transplant a graft.

“The work we are doing is taking a page from that discovery and using immunotherapy in the opposite sense used by cancer treatments to control and ‘turn off’ an immune response to transplant a graft,” Coronel explained. “When you get a transplant, like an islet transplant or organ transplant, even if it’s matched, you will have an immune response to that graft, and your immune system will recognize it as non-self and will try to reject and attack the site of the graft.”

The new method reduced the dosage needed, which will significantly reduce or eliminate side effects currently caused by today’s systemic drug treatments. After transplant surgery, traditional postoperative treatments use immune-suppressing systemic drugs that affect the entire body and in some cases can be toxic.

The microgels held and delivered a protein (SA-PD-L1) to a specific transplant area that successfully signaled the immune system to hold back an immune response, protecting a transplanted islet graft from being rejected. This locally delivered molecular signal, using SA-PD-L1, was designed to quietly suppress any immune response and was effective for up to 100 days with no additional systemic immune-suppressing drug intervention.

Peg microgels, stained green, are the engineered biomaterial microgels used for transplants that carry the SA-PD-L1 protein. Source: Maria Coronel, Georgia Tech.

“We wanted to use PD-L1 for the prevention of allogeneic islet graft rejection by simulating the way tumor cells use this molecule to evade the immune system, but without resorting to gene therapy,” noted Haval Shirwan, professor of child health and molecular microbiology and immunology at the University of Missouri School of Medicine.

“Microgels presenting SA-PD-L1 represent an important technological development that has potential not only for the treatment of type 1 diabetes, but also other autoimmune diseases and various transplant types,” added Shirwan.

“Furthermore, local induction of allograft acceptance is achieved in a murine model of diabetes only when receiving the SA-PD-L1–presenting biomaterial in combination with a brief rapamycin treatment. Immune characterization revealed an increase in T regulatory and anergic cells after SA-PD-L1-microgel delivery, which was distinct from naïve and biomaterial alone microenvironments. Engineering the local microenvironment via biomaterial delivery of checkpoint proteins has the potential to advance cell-based therapies, avoiding the need for systemic chronic immunosuppression,” noted the researchers.

The researchers will further investigate combining this therapy with antibodies that block positive costimulatory pathways. The researchers believe their study may provide a platform technology that is applicable to other transplantation settings and may enlarge the pool of candidates who can safely receive transplants.

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