Stanford Medicine scientists report that giving mice both blood-forming stem cells and pancreatic islet cells from an immunologically mismatched donor either completely prevented or fully reversed Type 1 diabetes. In this disease, the body's own immune defenses mistakenly attack and destroy the insulin-producing islet cells in the pancreas.
None of the animals developed graft-versus-host disease, a condition 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 animals' original immune system came to a stop. After receiving the transplants, the mice no longer needed immune suppressive drugs or insulin at any point during the six-month study.
"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.
Building on earlier stem cell and islet work
The new results extend a 2022 study by Kim and his collaborators. In that earlier work, the researchers first triggered diabetes in mice by using toxins to destroy the insulin-producing cells in the pancreas. They then used a gentle pre-transplant preparation involving immune-targeting antibodies and low-dose radiation, followed by a transplant of blood stem cells and islet cells from an unrelated donor, to restore blood sugar control.
In the latest study, the team set out to solve a more difficult challenge: preventing or curing diabetes driven by autoimmunity, where the immune system spontaneously targets and kills the body's own islet cells. In people, this form of the disease is known as Type 1 diabetes. Unlike the induced-diabetes model, where the main goal was to stop the recipient's immune system from rejecting donor islet cells, the new model involved transplanted islets that faced two problems at once. They were recognized as foreign tissue and were also targeted by an immune system already primed to attack islet cells from any source.
"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 same biological traits that cause autoimmune diabetes in these mice also make them harder to prepare safely for a blood stem cell transplant.
Simple drug tweak enables full diabetes protection
The team found a relatively straightforward way around this problem. Bhagchandani and Stephan Ramos, PhD, a postdoctoral fellow and co-author of the study, added a medication commonly used to treat autoimmune diseases to the pre-transplant regimen that had been identified in 2022. With this adjusted protocol, followed by blood stem cell transplantation, the mice developed a hybrid immune system made up of cells from both donor and recipient and did not go on to develop Type 1 diabetes in 19 out of 19 cases. In a separate group of animals with long-standing Type 1 diabetes, nine out of nine were cured after receiving the combined blood stem cell and islet cell transplant.
Because the antibodies, drugs and low-dose radiation used in the mice are already part of standard clinical practice for blood stem cell transplantation, the researchers see moving this strategy toward trials in people with Type 1 diabetes as a realistic next step.
From kidney tolerance to hybrid immunity for diabetes
This new work builds on research led by 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. Strober, Shizuru and other Stanford investigators had shown that a bone marrow transplant from a partially immunologically matched human donor could create a hybrid immune system in the recipient and allow long-term acceptance of a kidney transplant from the same donor. In some patients, they found that kidney function from the transplanted organ remained stable for decades without the need for ongoing drugs to prevent rejection.
Blood stem cell transplants are already used to treat cancers of the blood and immune system, including leukemia and lymphoma. However, in cancer care these procedures typically require high doses of chemotherapy and radiation to eliminate the original blood and immune system, which often causes serious side effects. Shizuru and colleagues have designed a safer, less intense way to prepare people with non-cancerous conditions such as Type 1 diabetes for donor blood stem cell transplantation, reducing bone marrow activity just enough to let donor blood stem cells settle in and grow.
"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."
Future hurdles for Type 1 diabetes treatment
Although the mouse results are encouraging, significant obstacles remain before this strategy could be widely used to treat Type 1 diabetes. Pancreatic islets can currently be obtained only from deceased donors, and the blood stem cells need to come from the same individual as the islets. It is also uncertain whether the number of islet cells typically recovered from a single donor would always be sufficient to reverse established Type 1 diabetes.
The scientists are exploring ways to overcome these limitations. Possible solutions include producing large amounts of islet cells in the laboratory from pluripotent human stem cells or developing methods that help transplanted donor islets survive longer and function more efficiently after transplantation.
Beyond diabetes, Kim, Shizuru and their collaborators believe that the gentle pre-conditioning strategy they have developed could open the door to stem cell transplants for other autoimmune diseases such as rheumatoid arthritis and lupus and for non-cancerous blood disorders like sickle cell anemia (for which current blood stem cell transplant methods remain harsh), as well as for transplants involving 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.
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.
