Researchers at the University of Missouri School of Medicine have developed a method to transplant insulin-producing islets for type 1 diabetes (T1D) treatment that illuminate the need for immunosuppressive drugs. The approach, details of which are published in JCI Insight, uses ex vivo engineering of donor islets with immune-regulating molecules that reduce both innate and adaptive immune rejection after transplantation. By adding thrombomodulin (TM) and CD47 to the surface of islets, the team created a localized immune-modulating barrier that allowed transplanted cells to survive and function while still responding to glucose and producing insulin.
“Immunosuppressant medications affect and weaken the whole body, so we instead focused on how we could improve our delivery of the transplanted islets,” said study senior author Haval Shirwan, PhD, a professor of molecular microbiology and immunology at University of Missouri. “We provided islets with a protective shield consisting of two molecules that help the transplants evade rejection from the immune system, a solution that lengthens the survival of islet cells with minimal side effects.”
To create the islets, the researchers used a surface-engineering approach known as a ProtEx platform. Islets were biotinylated and then coated with streptavidin-fused immune ligands (SA-TM and SA-CD47), allowing transient display of immune-regulating proteins without genetic modification. The purpose of this design was to reduce early inflammatory injury and block immune cell activation signals that normally lead to graft destruction following transplantation.
To discover whether these engineered cells reduced immune response, the cells were testing in allogenic mouse models. The data showed that in eight of the 11 mice tested the grafts survived from 120 to 330 days without resulting immunosuppression. By comparison unmodified islets were rejected quickly in the mouse models with survival time averaging 12 days.
The team also showed that islets engineered with only one of the molecules had limited benefit, while islets with both TM and CD47 produced the strongest effect. In recipients receiving modified islets, normal blood glucose levels were achieved in more than 72% of the mice, and the grafts maintained glucose-responsive insulin secretion.
The inclusion of two different molecules on the islets served different purposes. TM was used to reduce early inflammatory and coagulation-driven damage that occurs immediately after transplantation, while CD47 signaled to immune cells to inhibit phagocytosis and dampen adaptive immune activation.
“The double-engineered islets generated a localized tolerogenic immune environment characterized by low frequencies of inflammatory innate immune cells and increased frequencies of M2 macrophages, myeloid-derived suppressor cells, and CD4+FoxP3+ T regulatory cells,” the researchers wrote.
This new approach builds on the team’s prior work which showed that single-molecule engineering of islets with either CD47 or TM could partially improve graft survival. Earlier studies demonstrated that CD47 signaling reduced immune cell–mediated killing and that TM reduced early inflammatory injury linked to coagulation and cytokine release.
Importantly, the researchers noted that the engineering process does not impair islet function, viability, or metabolic activity, which can frequently happen as a result of cell engineering. Because the proteins are displayed transiently on the islet surface rather than permanently encoded, the methods does not produce long-term genetic alteration but still reshapes early immune responses during transplantation.
The researchers said that additional work now needs to evaluate the safety and effectiveness of these cells in humans and to determine whether the approach can reduce or eliminate the need for multiple donor islet sources, which are needed in current approaches due to early immune loss. The study also suggests that the modular nature of the platform could allow additional immune-regulating molecules to be added to further improve outcomes or tailor responses in different patients.
