A “gentle” islet cell transplant cures diabetes in mice with fewer side effects, say researchers at the Stanford University School of Medicine.news center

Further research by Strover et al., including study co-authors and professors of medicine Judith Shizuru, MD, PhD, have shown that it is possible to disrupt, rather than eliminate, the recipient’s immune system prior to the introduction of donor stem cells. As a result, a hybrid immune system composed of both donor and recipient stem cells is formed, reducing the likelihood of graft-versus-host disease. Hybrid or chimeric immune systems are also less likely to reject transplanted organs, especially if they are immunologically compatible. In 2020, Strober and his colleagues showed that most people who received kidney transplants from perfectly matched siblings were able to stay immunosuppressant-free for at least two of his years.

To date, conditioning regimens to achieve this chimeric immunity have been too harsh for use in non-life-threatening situations. Avoiding drugs required organs to be at least partially immunologically matched.

Preparation in 3 steps

In the current study, Kim and his colleagues experimented with a three-pronged approach to preparing diabetic recipients for stem cell transplantation. They used low doses of radiation, his one dose of an antibody called c-Kit that selectively targets and kills blood stem cells (which give rise to immune cells), and mature immune cells called T cells. combined with another antibody that They found that the donor cells were sufficient to colonize the animal’s bone marrow and create a fully functioning chimeric immune system without the severe side effects seen otherwise. were able to accept islet cell transplants from stem cell donors even though the animals were completely immunologically mismatched.

“We had the idea that we could prepare the bone marrow to accept donor stem cells with an alternative, less toxic approach,” says Kim. “We found that we could reduce radiation dose by 80% and replace broad-acting chemotherapeutic agents with targeted antibodies. I was able to maintain normal blood sugar levels.

If we are successful, we may see a future where people with diabetes can be treated early to prevent or alleviate lifelong health problems.

The mice were less susceptible to infection than control mice, had a normally functioning immune system, and were able to breed and produce healthy pups.

“This is exciting for many reasons,” says Kim. “This approach may be applicable to autoimmune diabetes, including type 1 diabetes, suggesting that fully mismatched pancreatic islet cells can be used for transplantation. It makes sense.”

One caveat in this study is that the donor stem cells and islet cells must be derived from the same animal, and human islet cells are difficult to procure.Kim and his colleagues Stanford Pancreatic Islet Replacement and Tolerance Initiative We are investigating whether functional islet cells can be generated in the laboratory from pluripotent stem cells, or whether small populations of human islet cells can be propagated and propagated in the laboratory to generate larger numbers of transplantable islet cells. We are investigating.

“If successful, we could see a future where people with diabetes can be treated early to prevent or alleviate lifelong health problems,” said Kim.

This research was supported by the JDRF, the National Institutes of Health (grant grants R01 DK107507, R01 DK108817, U01 DK123743, and P30 DK116074), the Stanford Institute for Maternal and Child Health, 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 shareholder of Jasper Therapeutics, Inc., and study co-author Judy Shizuru is a co-founder, shareholder and director of the company.