Revolutionary bioengineering research may transform type 1 diabetes care, pave way for tackling cancer and autoimmune disease

This revolutionary field still faces many challenges, including the nontrivial task of convincing stem cells to differentiate into desired cell types for treatment. And even if the correct 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 in use today require systemic immunosuppression, leaving patients vulnerable to environmental hazards like viruses, bacteria and cancer cells.

In a novel approach to tackle these obstacles, researchers at 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 tagged beta cell transplant in tandem with localized immune protection provided by specialized immune cells also tagged with a complementary but inert targeting molecule.

According to Leonardo Ferreira, Ph.D., a researcher at MUSC Hollings Cancer Center and one of the principal investigators on the study, marrying stem cell engineering and regulatory T cell (Treg) engineering allowed the first step toward a readily available, off-the-shelf solution to treating T1D.

In their recent study published in the journal Cell Reports, the researchers described a unique collaboration that leveraged the beta cell engineering expertise of the lab of Holger Russ, an associate professor of pharmacology and therapeutics at the University of Florida, combined with the delicate surgical expertise and chimeric antigen receptor (CAR) T cell expertise available at Hollings.

For T1D patients, the trouble begins with an immune system self-attack on 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 monitoring and insulin management to maintain health and avoid dangerous complications like neuropathy, amputation and blindness.

For now, some patients with poorly controlled T1D may consider islet cell transplantation using beta cells from a donor. Beta cells are isolated from a donor pancreas, purified and delivered to the patient's liver, where they can take up residence and begin secreting insulin. However, this option requires patients to undergo immunosuppression for the rest of their lives to keep the body from rejecting the foreign beta cells. It also requires the availability of donor cells, which might require long waits or may not happen at all.

To focus on an alternative solution, the researchers used an engineering strategy with tagged 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 of the cells of the immune system are focused on killing invasive elements," Ferreira said. "But Tregs are the generals of the immune system. They make sure that nothing goes overboard, and they train the immune system on 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 nonreactive tag -- an inactivated version of epidermal growth factor receptor -- into the kidney capsules of immunodeficient mice, they showed that the cells were incorporated and began to manufacture functional insulin. In the next phase of testing, the mice were exposed to an aggressive type of immune cell to check on the viability of the transplanted beta cells in the face of a simulated immune response. As expected, all of the beta cells were killed by the immune response, the same thing that happens in people with T1D.

To avoid the killing response in the next phase, the researchers added specialized Tregs along with the immune challenge. These cells were tagged with CAR technology using a receptor that specifically recognized the inert EGFR tag present on the transplanted beta cells. With this added step, the researchers observed the immune protection they hoped for, as they observed the transplanted beta cells remaining safe, sound 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 for creating immune tolerance."

Now that Ferreira and colleagues have shown the feasibility of their approach to T1D treatment, they plan to continue their research efforts, including building a whole library of locks and keys -- differentiated stem cells and tagged protective Tregs -- for multiple purposes, such as targeting certain cancers, lupus and other autoimmune diseases.

A few 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 have no negative impact on the function of the cells or create any reaction that could cause side effects. And it is still unknown if one Treg treatment will be effective or might need to be repeated at intervals that have yet to be established. Because Tregs can educate immune cells to maintain immune tolerance, it is possible that one treatment will be adequate, but further research is needed to understand the long-term effects.

Answering these questions and confirming the validity of the approach in humans may soon transform T1D from a chronic, high-maintenance disease with many complications to one that can be managed much more easily.