A combination blood stem cell and pancreatic islet cell transplant from an immunologically mismatched donor completely prevented or cured Type 1 diabetes in mice in a study by Stanford Medicine researchers. Type 1 diabetes arises when the immune system mistakenly destroys insulin-producing islet cells in the pancreas.
None of the animals developed graft-versus-host disease — in which the immune system arising from the donated blood stem cells attacks healthy tissue in the recipient — and the destruction of islet cells by the native host immune system was halted. After the transplants, the animals did not require the use of the immune suppressive drugs or insulin for the duration of the six-month experiment.
A follow-up study published April 21 in mice with induced diabetes found that a further tweak to the pretransplant regimen allowed a drastic reduction in the dose of radiation necessary to dampen the recipient animal’s immune response to the foreign cells: from 225 centigray (cGy) to 10 cGy. For reference, a full bone marrow transplant (in which a patient’s entire immune system is destroyed prior to transplant) typically requires a dose of around 1,200 cGy; a dose of 225 cGy is well tolerated but can cause infertility and increase the risk of cancer.
“The possibility of translating these findings into humans is very exciting,” said Seung K. Kim , MD, PhD, the KM Mulberry Professor and a professor of developmental biology, gerontology, endocrinology and metabolism. “The key steps in our study — which result in animals with a hybrid immune system containing cells from both the donor and the recipient — are already being used in the clinic for other conditions. We believe this approach will be transformative for people with Type 1 diabetes or other autoimmune diseases, as well as for those who need solid organ transplants.”
Kim, who directs the Stanford Diabetes Research Center and the Northern California Breakthrough T1D Center of Excellence , is the senior author of the study , which published online Nov. 18 in the Journal of Clinical Investigation . Graduate and medical student Preksha Bhagchandani is the lead author of the research.
“Bringing radiation doses down to a level that carries minimal clinical risk dramatically reduces barriers to achieving immune tolerance and curing diabetes,” said postdoctoral scholar Stephan Ramos, PhD. “This gentler preconditioning regimen also opens the door to using similar strategies in a much broader range of patients and diseases than was previously feasible.”
Ramos is the lead author of the second study , which was published April 21 in the Journal of Clinical Investigation Insight . Kim is the study’s senior author.
Setting the table
The findings in the recent reports dovetail with those from a 2022 study by Kim and collaborators, in which researchers first induced diabetes in mice by destroying insulin-producing cells in the pancreas with toxins. They then cured them with a gentle pre-transplant treatment of immune-targeting antibodies and 200 cGy or 300 cGy radiation, followed by transplantation of blood stem and islet cells from an unrelated donor.
The November study tackled a more complex problem: curing or preventing diabetes caused by autoimmunity, in which the immune system spontaneously destroys its own islet cells. In people this is called Type 1 diabetes. Unlike in the induced-diabetes study — in which the researchers’ goal was to prevent the recipient’s immune system from rejecting donated islet cells — the transplanted islet cells in the autoimmune mice have two targets on their backs: Not only are they foreign, but they are vulnerable to autoimmune attack by a misguided immune system bent on destroying islet cells regardless of their origin.
“Just like in human Type 1 diabetes, the diabetes that occurs in these mice results from an immune system that spontaneously attacks the insulin-producing beta cells in pancreatic islets,” Kim said. “We need to not only replace the islets that have been lost but also reset the recipient’s immune system to prevent ongoing islet cell destruction. Creating a hybrid immune system accomplishes both goals.”
Unfortunately, the inherent features that lead to autoimmune diabetes in these mice also make them more challenging to prepare for a successful blood stem cell transplant.
The solution the researchers found was relatively simple: adding a drug used to treat autoimmune diseases to the pre-transplant regimen the researchers had discovered in 2022. Doing so, then transplanting blood stem cells, resulted in an immune system made up of cells from both the donor and the recipient and prevented development of Type 1 diabetes in 19 out of 19 animals. Additionally, nine out of nine mice that had developed long-standing Type 1 diabetes were cured of their disease by the combined blood stem cell and islet transplantation.
Because the antibodies, drugs and low-dose radiation the researchers administered to the mice are already used in the clinic for blood stem cell transplantation, the researchers believe that translating the approach to people with Type 1 diabetes is a logical next step.
The April study incorporated two additional drug agents that target and deplete stem cells in the recipient animal’s bone marrow, clearing the way for the transplanted stem cells to engraft and thrive in their new home and allowing the researchers to significantly reduce the radiation dose required for successful transplantation to 10 cGy. Five out of five mice with induced diabetes were cured of the disease, remained fertile and showed no signs of graft-versus-host disease. They did not require insulin or immunosuppression after transplant. Because this study focused on mice with induced diabetes, rather than the autoimmune form of the disease, the researchers plan to test the new regimen in mice with Type 1 diabetes in the near future.
Where the concept began
The study builds on the work of the late Samuel Strober , MD, PhD, a professor of immunology and rheumatology, and his colleagues, including study co-author and professor of medicine Judith Shizuru , MD, PhD. They and other Stanford researchers had shown that a bone marrow transplant from a partially immunologically matched human donor allowed formation of a hybrid immune system in the recipient, and subsequent long-term acceptance of a kidney transplant from the same donor. In some cases, Strober and colleagues showed that transplanted donor kidney function lasted for decades, without the need for drugs to suppress rejection.
A blood stem cell transplant can be used to treat cancers of the blood and immune system, such as leukemia and lymphoma. But in those settings, high doses of chemotherapy drugs and radiation needed to treat the cancer and replace the recipient blood and immune system often result in severe side effects. Shizuru and colleagues have devised a safer, gentler avenue to prepare recipients with non-cancerous conditions such as Type 1 diabetes for donor blood stem cell transplantation — knocking their bone marrow back just enough to provide a foothold for the donated blood stem cells to settle in and develop.
“Based on many years of basic research by us and others, we know that blood stem cell transplants could also be beneficial for a wide range of autoimmune diseases,” Shizuru said. “The challenge has been to devise a more benign pre-treatment process, diminishing risk to the point that patients suffering from an autoimmune deficiency that may not be immediately life-threatening would feel comfortable undergoing the treatment.”
“Now we know that the donated blood stem cells re-educate the recipient animal’s immune system to not only accept the donated islets, but also not attack its healthy tissues, including islets,” Kim said. “In turn, the donated blood stem cells and the immune system they produce learn to not attack the recipient’s tissues, and graft-versus-host disease can be avoided.”
What comes next?
Challenges remain using this approach to treat Type 1 diabetes. Pancreatic islets can be obtained only after death of the donor, and the blood stem cells must come from the same person as the islets. It is also unclear whether the number of islet cells typically isolated from one donor would be enough to reverse established Type 1 diabetes.
But the researchers are working on solutions, which could include generating large numbers of islet cells in the laboratory from pluripotent human stem cells, or finding ways to increase the function and survival of transplanted donor islet cells.
In addition to diabetes, Kim, Shizuru and their colleagues expect that the gentler pre-conditioning approaches they are developing could make stem cell transplants a viable treatment for autoimmune disease such as rheumatoid arthritis and lupus, and non-cancerous blood conditions like sickle cell anemia (for which current blood stem cell transplant methods remain harsh), or for transplants of mismatched solid organs.
“The ability to reset the immune system safely to permit durable organ replacement could rapidly lead to great medical advances,” Kim said.
JCI Insight
Experimental study
Animals
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21-Apr-2026