New transplant approach resets immune system to stop type 1 diabetes

New transplant approach resets immune system to stop type 1 diabetes

In a study by Stanford Medicine researchers, a combination of blood stem cells and pancreatic islet cell transplantation from an immunologically mismatched donor prevented or completely cured type 1 diabetes in mice. Type 1 diabetes occurs when the immune system accidentally destroys the 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 host's natural immune system was stopped. After the transplants, the animals did not require immunosuppressive drugs or insulin for the duration of the six-month experiment.

The possibility of transferring these findings to humans is very exciting. The key steps in our study—leading to animals with a hybrid immune system that includes cells from both the donor and the recipient—are already being used in the clinic for other diseases. We believe this approach will be transformative for people with type 1 diabetes or other autoimmune diseases, as well as those in need of an organ transplant.”

Seung K. Kim, MD, PhD, KM Mulberry Professor and Professor of Developmental Biology, Gerontology, Endocrinology and Metabolism

Kim, who directs the Stanford Diabetes Research Center and the Northern California Breakthrough T1D Center of Excellence, is the senior author of the study, published online Nov. 18 in theJournal of Clinical Investigation. Graduate and medical student Preksha Bhagchandani is the lead author of the study.

Lay the table

The findings in the current report are consistent with those of a 2022 study by Kim and colleagues, in which researchers induced diabetes in mice for the first time by destroying insulin-producing cells in the pancreas with toxins. They then cured her with a gentle pre-transplant treatment of immune system-targeting antibodies and low-dose radiation, followed by the transplant of blood stem and islet cells from an unrelated donor.

The current study looked at a more complex problem: curing or preventing diabetes caused by autoimmunity, in which the immune system spontaneously destroys its own islet cells. In humans this is called type 1 diabetes. Unlike the induced diabetes study—where the researchers' goal was to stop 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 also vulnerable to autoimmune attack from a misdirected immune system bent on destroying islet cells regardless of their origin.

“Just like human type 1 diabetes, the diabetes that occurs in these mice is due to an immune system that spontaneously attacks the insulin-producing beta cells in the pancreatic islets,” Kim said. "Not only do we need to replace the lost islets, but we also need to reboot the recipient's immune system to prevent further destruction of the islet cells. Creating a hybrid immune system achieves both goals."

Unfortunately, the inherent characteristics that lead to autoimmune diabetes in these mice also complicate preparation for a successful blood stem cell transplant.

The solution the researchers found was relatively simple: Bhagchandani and Stephan Ramos, PhD, a postdoctoral researcher and co-author of the study, added a drug to treat autoimmune diseases to the pre-transplant regimen discovered by the researchers in 2022. This, and subsequent blood stem cell transplantation, created an immune system consisting of cells from both the donor and the recipient and prevented the development of type 1 diabetes in 19 of 19 animals. In addition, nine of nine mice that had long developed type 1 diabetes were cured of their disease by the combined blood stem cell and islet transplant.

Because the antibodies, drugs and low-dose radiation the researchers gave the mice are already used in the clinic for blood stem cell transplantation, the researchers believe extending 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. She and other Stanford researchers had shown that a bone marrow transplant from a partially immunologically matched human donor enabled the formation of a hybrid immune system in the recipient and the subsequent long-term acceptance of a kidney transplant from the same donor. In some cases, Strober and colleagues showed that the function of the transplanted donor kidney 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 such situations, high doses of chemotherapy drugs and radiation needed to treat the cancer and replace the recipient's blood and immune system often result in serious side effects. Shizuru and colleagues have developed a safer, gentler way to prepare recipients with non-cancerous conditions such as type 1 diabetes for donor blood stem cell transplantation - by shrinking their bone marrow just enough for the donated blood stem cells to take hold and develop.

“Based on many years of basic research by us and others, we know that blood stem cell transplants could also be beneficial in a variety of autoimmune diseases,” Shizuru said. “The challenge was to develop a gentler pretreatment process that would reduce the risk enough that patients suffering from an autoimmune deficiency that may not be immediately life-threatening would feel comfortable with treatment.”

"Now we know that the donated blood stem cells retrain the recipient animal's immune system to not only accept the donated islets, but also not attack its healthy tissue, including the islets," Kim said. “In return, the donated blood stem cells and the immune system they produce learn not to attack the recipient’s tissue, and graft-versus-host disease can be avoided.”

What's next?

Using this approach to treat type 1 diabetes continues to present challenges. Pancreatic islets can only be harvested after the donor's death, 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 a donor would be sufficient to reverse established type 1 diabetes.

However, researchers are working on solutions. This could include creating large quantities 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 believe that the gentler preconditioning approach they developed could make stem cell transplants a viable treatment for autoimmune diseases such as rheumatoid arthritis and lupus, as well as for noncancerous blood disorders such as sickle cell anemia (for which current blood stem cell transplant methods remain harsh) or for mismatched solid organ transplants.

“The ability to safely reset the immune system to enable permanent organ replacement could quickly lead to major medical advances,” Kim said.

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 HL Snyder Foundation and Elser Trust, the VPUE Research Fellowship at Stanford, and the Stanford Diabetes Research Center.

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