Research from the Shea Lab uses implantable synthetic immunological niches to monitor immune activity, with the goal of identifying islet transplant rejection before conventional clinical measures can.
For some people with type 1 diabetes, even careful insulin therapy cannot prevent dangerous fluctuations in blood glucose. Islet transplantation can help by replacing the insulin-producing cells destroyed by the disease, but clinicians currently have limited tools to determine whether a patient’s immune system is rejecting the transplanted cells.
Researchers in the lab of Lonnie Shea, the Steven A. Goldstein Collegiate Professor of Biomedical Engineering at the University of Michigan, in collaboration with Esma Yolcu, Professor of Molecular Microbiology & Immunology at the University of Missouri, are investigating whether implantable biomaterial-based immunological niches can detect early immune changes associated with islet transplant rejection and characterize the underlying immune mechanisms.
Shea noted that “ transplantation of organs such as liver or kidney has established biomarkers that indicate organ engraftment and function. However, for transplantation of adult islets or the emerging stem cell derived islets, early stage markers indicating engraftment have not been identified and are needed to guide post-transplant patient management.”
Jyotirmoy Roy, a Ph.D. candidate in Shea’s lab, is studying how these immunological niches could reveal early signs of immune dysregulation following islet transplantation. His research, published in Advanced Science, formed the foundation for a newly funded Breakthrough T1D project aimed at advancing the technology toward clinical use.
“One of the major challenges with islet transplantation is that the transplanted islet grafts are extremely difficult to biopsy,” Roy said. “Clinicians rely largely on blood glucose and C-peptide levels to assess graft function, but these measurements provide limited insight into the immune processes driving rejection. By the time blood glucose rises, substantial loss of insulin-producing cells has already occurred.”
Pancreatic islets contain beta cells, which produce insulin. In type 1 diabetes, the immune system destroys those cells, leaving patients dependent on externally administered insulin. Islet transplantation introduces donor islets that can restore the body’s ability to produce insulin.
The procedure can be particularly valuable for people with brittle type 1 diabetes, who experience severe and unpredictable episodes of low blood glucose despite insulin treatment. If the transplanted islets are accepted, recipients may reduce or eliminate their need for externally administered insulin for a long period of time.
Monitoring these transplants is difficult because donor islets are commonly infused into the liver and cannot be sampled as readily as a transplanted solid organ. The Shea Lab’s microporous biomaterial-based immunological niche is implanted beneath the skin, where it vascularizes and recruits immune cells. Minimally invasive biopsies of the niche allow researchers to track cellular changes associated with the immune response to the transplant.
“A blood draw provides a snapshot of circulating immune cells,” Roy said. “An immunological niche remains in the body between sampling points, capturing dynamic immune changes over time. Analyzing the niche can reveal tissue-associated immune changes that may not be reflected in circulating blood cells.”
The researchers evaluated the immunological niche in several mouse models of islet transplantation, including models with and without immunosuppression and models incorporating autoimmunity.
That distinction is important because islet transplant recipients can experience two overlapping immune responses: alloimmunity, in which the recipient’s immune system targets donor cells as foreign, and recurrent autoimmunity, in which the immune response that caused type 1 diabetes targets the graft’s insulin-producing beta cells.
By integrating spectral flow cytometry, transcriptomics, and data-driven analysis, the team showed that immunological niches captured cellular and molecular changes associated with the immune response in transplanted islets. They also identified a gene signature that distinguished mice that subsequently rejected their grafts from those that maintained graft function, before blood glucose levels rose.
The experiments also offered insight into how treatment may influence rejection. Under immunosuppression, rejection appeared to be driven more strongly by innate immune activity. Without immunosuppression, adaptive immunity played a larger role.
“We were not only able to identify whether rejection was likely to occur, but also to begin to distinguish the immune responses involved in rejection with or without immunosuppression, as well as in alloimmune and autoimmune rejection” Roy said.
Understanding those mechanisms could eventually help clinicians move away from broadly suppressing the immune system and toward therapies tailored to an individual patient’s immune response.
“If we can understand which immune components are driving rejection in a patient, we may be able to tailor treatment to target the cells directly contributing to that rejection rather than broadly suppressing the entire immune system,” Roy said.
The newly funded project will build on these findings by testing whether early inflammatory responses detected in the immunological niche can predict successful islet engraftment. The researchers will also investigate how a recipient’s inflammatory state influences graft outcomes, with the goal of enabling earlier intervention, improving graft survival, and enhancing quality of life for people living with type 1 diabetes.
“Our recently published findings showed that the synthetic immunological niche can detect immune changes associated with transplant outcomes, highlighting the power of collaboration between the University of Michigan and the University of Missouri,” said Esma S. Yolcu. “By combining expertise in engineering, transplantation, and immunology, we developed a promising approach for monitoring transplant health. With support from our new multiple-PI award, we will build on these findings to determine whether early inflammatory responses can predict successful islet engraftment, with the goal of enabling earlier intervention, improving transplant success, and enhancing the lives of people living with Type 1 diabetes.”
The team is pursuing broader translation of the biomaterial platform as well, including Good Manufacturing Practice and engagement with the U.S. Food and Drug Administration.
Ultimately, the researchers hope the immunological niche can shorten the time needed to recognize a failing transplant and give clinicians an opportunity to intervene while more of the graft remains functional.
“Our goal is to determine much earlier whether a patient is unlikely to respond to an islet transplant,” Roy said. “Understanding differences in each recipient’s inflammatory and immune responses could help us guide earlier intervention and advance this approach toward clinical use over the next several years.”