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Further studies by Strober and others, including study co-author and professor of medicine Judith Shizuru, MD, PhD, showed it’s possible to hobble, rather than eliminate, the recipient’s immune system before introducing the donor’s stem cells. The result is a hybrid immune system, made up of both donor and recipient stem cells, and a reduced likelihood of graft-versus-host disease. The hybrid, or chimeric, immune system is also less likely to reject the transplanted organ, particularly if it is immunologically well matched. In 2020, Strober and his colleagues showed that most people who received kidney transplants from fully matched siblings were able to stay off immunosuppressive drugs for at least two years.
Until now, the conditioning regimen to accomplish this chimeric immunity was too harsh for use in non-life-threatening situations, and the organs had to be at least partially immunologically matched to avoid the drugs.
Three step prep
In the current study, Kim and his colleagues experimented with a three-pronged approach to prepare diabetic recipients for the stem cell transplant. They combined low-dose radiation, one dose of an antibody called c-Kit that selectively targets and kills blood stem cells (which give rise to immune cells), and another antibody that targets mature immune cells called T cells. They found that was enough to allow the donor cells to establish themselves in the animals’ bone marrow and create a fully functioning, chimeric immune system without the severe side effects seen with other methods. These diabetic animals were then able to accept a transplant of islet cells from the stem cell donor, even if that animal was completely immunologically mismatched.
“We had a notion that we could get the bone marrow ready to accept the donor stem cells with less toxic, alternative approaches,” Kim said. “We found we could reduce the radiation dose by 80% and replace broad-acting chemotherapy drugs with targeted antibodies. The animals rapidly gained back the weight they had lost due to the disease and were able to maintain normal blood glucose levels until the study ended after more than 100 days.”
If we are successful, we could see a future where we can treat people with diabetes at an early age to prevent or mitigate a lifetime of health problems.
The mice were no more susceptible to infection than control mice, showing their immune systems were functioning normally, and they could breed and give birth to healthy pups.
“This is exciting for many reasons,” Kim said. “This approach could be applied to autoimmune diabetes, including type 1 diabetes, and suggests that completely mismatched islet cells could be used for transplant. Beyond diabetes, it has important implications for solid organ transplants.”
One caveat in the study is that the donor stem cells and islet cells must come from the same animal, and human islet cells are difficult to procure. Kim and colleagues in the Stanford Pancreatic Islet Replacement and Immune Tolerance Initiative are investigating whether functional islet cells could be created in the laboratory from pluripotent stem cells, or if a small population of human islet cells can be grown and expanded in the laboratory to make many more transplantable islet cells.
“If we are successful, we could see a future where we can treat people with diabetes at an early age to prevent or mitigate a lifetime of health problems,” Kim said.
The study was funded by the JDRF, the National Institutes of Health (grants R01 DK107507, R01 DK108817, U01 DK123743 and P30 DK116074), the Stanford Maternal and Child Health Research Institute, the Stanford Medical Scientist Training Program, the HL Snyder Foundation, the Stanford Diabetes Research Center Islet Core, the Reid family, and the Skeff family.
Chang is an employee and stockholder of Jasper Therapeutics, Inc., and study coauthor Judy Shizuru is a co-founder, stockholder and director of the company.