Stanford Scientists Cure Type 1 Diabetes in Mice Without Insulin or Immune Suppression

An “immune system reset” eliminated autoimmune, or Type 1, diabetes in mice in a study conducted at Stanford Medicine. Researchers say the strategy could also have potential for treating other autoimmune diseases and improving outcomes in organ transplantation.

In a new study from Stanford Medicine, researchers reversed Type 1 diabetes in mice using a combined transplant of blood stem cells and insulin-producing pancreatic islet cells from a donor whose immune profile did not match the recipient. Type 1 diabetes develops when the immune system mistakenly attacks and destroys the islet cells in the pancreas that produce insulin, leaving the body unable to properly regulate blood sugar.

The dual transplant approach both restored insulin production and retrained the immune system. None of the treated animals developed graft-versus-host disease, a dangerous complication in which immune cells from donated blood stem cells attack healthy tissue in the recipient.

At the same time, the mice’s original immune systems stopped targeting and destroying the newly transplanted islet cells. For the full six months of the experiment, the animals did not need insulin injections or immune suppressive medications.

“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 directs the Stanford Diabetes Research Center and the Northern California Breakthrough T1D Center of Excellence and is the senior author of the study, which was published online Nov. 18 in the Journal of Clinical Investigation. The lead author is graduate and medical student Preksha Bhagchandani.

Setting the table

The new results build directly on a 2022 study led by Kim and colleagues. In that earlier work, the team first created diabetes in mice by using toxins to eliminate the insulin-producing cells in the pancreas. They then reversed the disease by preparing the animals with a mild pre-transplant regimen that included immune-targeting antibodies and low-dose radiation, followed by the transplantation of blood stem cells and pancreatic islet cells from an unrelated donor.

The current 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: Bhagchandani and Stephan Ramos, PhD, a postdoctoral fellow and study co-author, added 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.

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 approach they developed could make stem cell transplants a viable treatment for autoimmune diseases 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.

Reference: “Curing autoimmune diabetes in mice with islet and hematopoietic cell transplantation after CD117 antibody-based conditioning” by Preksha Bhagchandani, Stephan A. Ramos, Bianca Rodriguez, Xueying Gu, Shiva Pathak, Yuqi Zhou, Yujin Moon, Nadia Nourin, Charles A. Chang, Jessica Poyser, Brenda J. Velasco, Weichen Zhao, Hye-Sook Kwon, Richard Rodriguez, Diego M. Burgos, Mario A. Miranda, Everett Meyer, Judith A. Shizuru and Seung K. Kim, 18 November 2025, The Journal of Clinical Investigation.
DOI: 10.1172/JCI190034

The study was funded by the National Institutes of Health (grants T32 GM736543, R01 DK107507, R01 DK108817, U01 DK123743, P30 DK116074, and LAUNCH 1TL1DK139565-0), the Breakthrough T1D Northern California Center of Excellence, Stanford Bio-X, the Reid Family, the H.L. Snyder Foundation and Elser Trust, the VPUE Research Fellowship at Stanford, and the Stanford Diabetes Research Center.

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