Regenerative medicine holds the extraordinary promise that future patients who need new cells, tissues or organs will no longer have to rely on donors. Organ shortages and cell type discrepancies will become problems of the past and will be replaced by safe, on-demand options for anyone needing a transplant.
This revolutionary field still faces many challenges, including the non-trivial task of convincing stem cells to differentiate into the cell types desired for treatment. And even if the right cells or tissues are created and can function successfully in the body, immune rejection presents a formidable barrier to their use. To overcome this obstacle, regenerative medicine treatments used today require systemic immunosuppression, leaving patients vulnerable to environmental hazards such as viruses, bacteria, and cancer cells.
In a novel approach to addressing these obstacles, researchers from the Medical University of South Carolina and the University of Florida recently collaborated on a novel, highly specific strategy to treat type 1 diabetes (T1D) using a transplant of labeled beta cells along with localized immunotherapy. protection provided by specialized immune cells also tagged with a complementary but inert target molecule.
According to Leonardo Ferreira, Ph.D., a researcher at MUSC Hollings Cancer Center and one of the study’s principal investigators, combining stem cell engineering with regulatory T cell (Treg) engineering allowed the first step toward an unavailable technology and easily available. solution available to treat type 1 diabetes.
In his recent study published in the journal Cellular reportsThe researchers described a unique collaboration that leveraged the beta cell engineering expertise of the laboratory of Holger Russ, associate professor of pharmacology and therapeutics at the University of Florida, combined with delicate surgical expertise and chimeric antigen receptor T cell expertise. (CAR). Available at Hollings.
For patients with type 1 diabetes, the problem begins with an immune system self-attack against pancreatic beta cells, the cells that produce the hormone insulin to regulate blood sugar levels. Without a reliable way to self-regulate blood glucose levels, patients are forced to live with a high-maintenance regimen of glucose control and insulin control to maintain health and avoid dangerous complications such as neuropathy, amputation and blindness.
For now, some patients with poorly controlled type 1 diabetes may consider islet cell transplantation using beta cells from a donor. Beta cells are isolated from a donor’s pancreas, purified, and delivered to the patient’s liver, where they can establish themselves and begin secreting insulin. However, this option requires patients to undergo immunosuppression for the rest of their lives to prevent the body from rejecting foreign beta cells. It also requires the availability of donor cells, which may require long waits or may not happen at all.
To focus on an alternative solution, the researchers used an engineering strategy with labeled beta cells generated from stem cells. And to induce localized immune protection, the researchers chose to use Tregs, a type of immune cell that monitors and controls the immune response.
“Most cells in the immune system are focused on killing invasive elements,” Ferreira said. “But Tregs are the generals of the immune system. They make sure nothing goes too far and train the immune system how to respond in the future.”
The researchers used a mouse model to test their strategy. By transplanting beta cells that were engineered from stem cells and included a non-reactive tag (an inactivated version of the epidermal growth factor receptor) into the kidney capsules of immunodeficient mice, they showed that the cells took up and began making functional insulin. . In the next phase of the test, the mice were exposed to an aggressive type of immune cell to test the viability of the transplanted beta cells against a simulated immune response. As expected, all the beta cells were destroyed by the immune response, the same thing that happens in people with Type 1 diabetes.
To avoid the lethal response in the next phase, the researchers added specialized Tregs along with the immune challenge. These cells were labeled with CAR technology using a receptor that specifically recognized the inert EGFR tag present on transplanted beta cells. With this additional step, the researchers saw the immune protection they expected, as they observed that the transplanted beta cells remained safe, healthy and functional in their new home.
Ferreira was delighted with the results and energized to take the next steps. “With this approach,” he said, “we made both the lock and the key to create immune tolerance.”
Now that Ferreira and his colleagues have demonstrated the feasibility of their approach for treating type 1 diabetes, they plan to continue their research efforts, including creating a complete library of locks and keys (differentiated stem cells and labeled protective Tregs) to multiple purposes, such as targeting certain cancers, lupus and other autoimmune diseases.
Some questions remain, such as the specific ligand that should be used for human transplantation and the longevity of Treg-mediated immune protection. The ligand or tag must be inert and not have a negative impact on cell function or create any reaction that could cause side effects. And it is still unknown whether a Treg treatment will be effective or whether it will need to be repeated at intervals that have not yet been established. Because Tregs can educate immune cells to maintain immune tolerance, a treatment may be appropriate, but more research is needed to understand the long-term effects.
Answering these questions and confirming the validity of the approach in humans could soon transform type 1 diabetes from a high-maintenance chronic disease with many complications to one that can be much more easily treated.