Scientists achieve major breakthrough in treating Type 1 diabetes

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.

Report informs with reference to an article published in the Journal of Clinical Investigation (JCI) that 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.

"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 November 18 in the JCI. Graduate and medical student Preksha Bhagchandani is the lead author of the research.

The findings in the current report 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 low-dose radiation, followed by transplantation of blood stem and 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.