A combination strategy for stem cell graft rejection
A novel strategy has been developed to combat immune rejection of beta cell transplants for type 1 diabetes patients.
In a collaborative study, researchers from the Medical University of South Carolina (SC, USA) and the University of Florida (FL, USA) have developed a precise strategy to treat type 1 diabetes (T1D) by combining beta cells and CAR-Tregs cells, engineered to express complementary tags. By integrating expertise in beta cells and CAR-T cell therapy, this innovative approach could not only enhance diabetes treatment but also offer valuable insights for treating other autoimmune diseases and cancer.
Type 1 diabetes occurs when the immune system mistakenly attacks and destroys beta cells in the pancreas, which are responsible for producing insulin. Donor beta cell transplantation has been a treatment option for diabetes, but it is limited by donor cell availability and immune rejection, which requires long-term immunosuppression. Regenerative medicine offers a promising alternative by generating beta cells from stem cells, however, immune rejection remains a challenge, as the immune system can still attack the transplanted cells.
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To address this, the researchers developed an innovative strategy to protect transplanted beta cells from the immune system. The team engineered stem cell-derived beta cells to express an inactive version of epidermal growth factor receptor (EGFRt). Alongside this, the team also engineered CAR-Treg cells to recognize EGFRt. This modification was a key aspect of their strategy, as CAR-Treg cells play a crucial role in maintaining immune tolerance. Recent studies have shown their ability to modulate immune responses in organ transplantation, effectively shielding the transplanted beta cells from being attacked by the immune system.
Commenting on the strategy, Leonardo Ferreira, an investigator of the study at MUSC Hollings Cancer Center, stated:
“Most of the cells of the immune system are focused on killing invasive elements, 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.”
To evaluate their strategy, the researchers carried out a series of experiments. First, the team transplanted the engineered stem cell-derived beta cells into the kidney capsules of immunodeficient mice. The engineered beta cells successfully integrated into the kidney tissue and began producing functional insulin.
Next, the mice were exposed to an aggressive type of immune cell to assess the viability of the transplanted beta cells under a simulated immune response. Unsurprisingly, the beta cells were destroyed by the immune system – the same process that occurs in individuals with T1D.
To overcome this challenge, the researchers introduced the CAR-Treg cells that were engineered to recognize EGFRt expressed by the engineered beta cells. The CAR-Treg cells were able to suppress the immune response, which allowed the engineered beta cells to engraft, achieving immune intolerance.
Looking ahead, the researchers plan to develop a portfolio of differentiated stem cells and tagged protective Tregs to address cancers and other autoimmune diseases, such as lupus, following the encouraging findings from this study. In the words of Ferreira, “With this approach, we made both the lock and the key for creating immune tolerance.”
Although the research is still in its early stages and requires further investigation, the researchers are optimistic about the potential of this strategy to transform high-maintenance diseases, like T1D, into more manageable conditions.
