Scientists cured type 1 diabetes in mice by creating a blended immune system

Scientists have cured type 1 diabetes in mice, without long-term immune suppression.

In type 1 diabetes, the immune system attacks insulin-producing cells, and replacing them with transplanted cells from donors has historically required people to take strong immunosuppressants for life, which severely limited the reach of such transplants.

But in a new study, researchers created a "chimeric," or blended immune system that contains elements of both the recipient's and the donor's immune systems. This enabled mice to tolerate a transplant of insulin-producing cells without long-term immune suppression.

Much more research is needed before this kind of treatment could be available to patients in a clinic, and keeping the blended immune system balanced is tricky. But if extensive follow-up testing in humans shows the transplantation process is safe and durable, it could offer an avenue for reversing the potentially deadly disease.

"This is potentially a way to cure diabetes," Dr. John DiPersio, an oncologist at Washington University in St. Louis who researches cellular therapy but was not involved in the study, told Live Science. "It does represent, in theory, a big step forward."

Inducing intolerance

In type 1 diabetes, the immune system mistakenly attacks insulin-producing cells, or islets, in the pancreas. Without insulin, blood sugar rises and people eventually die, so people with the disease must take insulin for life. Even with the best treatment available, people with type 1 diabetes still face high rates of complications such as heart disease, kidney disease and eye damage.

For decades, scientists have been trying to cure the disease by replacing destroyed islets with new ones, such as those harvested from cadavers. But to keep the body from attacking the transplanted cells, patients must take strong immune-suppressing drugs for life. As a result, islet transplants are typically performed only in clinical trials and in patients who need another organ replacement, such as a kidney or liver transplant.

Using bone-marrow stem cells and islet cells from the same donor could solve the immune rejection problem. The stem cells, which are transplanted into special niches in the bone, would regenerate the white blood cells of the immune system. The new, regenerated immune system wouldn't have the islet-attacking cells and would recognize the transplanted islets as "self," rather than foreign.

But that process required eliminating the host's own bone-marrow stem cells. "It's like musical chairs," study lead author Dr. Judith Shizuru, a professor of medicine at Stanford University, told Live Science. "If you don't get the recipient stem cells out of the niche, you can't get the donor cells in."

In the past, the process required chemotherapy and radiation to completely wipe out the host's immune system, which leaves people vulnerable to infection for weeks.

Shizuru's team wondered if there was a less-toxic regimen that could reeducate the host's immune system, rather than erasing it. "If you have a mixture of donor and recipient, the donor's immune system ‪—‬ the blood system ‪—‬ can influence the behavior of the [immune cells] of the recipient," Shizuru said.

They came up with a multistep process that uses multiple antibodies, low-dose radiation and a rheumatoid arthritis drug called baricitinib, and tested that protocol in more than a dozen mice. This immune system "conditioning" process made space in the recipient's bone marrow for some donor stem cells, without wiping out all of the recipient's stem cells. It also muted different parts of the immune system just long enough for the donor's stem cells and islets to take root.

This allowed the team to transplant bone-marrow stem cells and islets ‪from the same donor into the recipient mouse. As the donor stem cells matured, the cells educated the rest of the recipient's immune system to tolerate the foreign tissue. The mature, blended immune system also culled recipient cells that had been trained to specifically attack islets, thereby eliminating the cells that fuel autoimmunity. "The graft sticks and stays," Shizuru said. "It's there long term."

From start to finish, the process took around 12 days, the immune system was never completely wiped out, and the radiation dose was lower than is typically used in bone-marrow transplants. "We've made this [a] much more gentle regimen," Shizuru said.

The mice were still making insulin 20 weeks later, and blood tests and postmortem analysis showed their immune systems were functioning well and not rejecting the transplants, the study authors noted in the paper, which was published in the January issue of The Journal of Clinical Investigation.

Still, many hurdles remain before this could become a viable treatment in humans, said DiPersio, who was the author of an accompanying commentary piece in the same journal. First, some of the antibodies that worked in mice don't have approved analogues in humans, so this would need to be remedied. Second, the method requires getting both bone marrow and islets from the same donor, and the latter are already scarce.

But a thornier problem is that creating a mixed host-recipient immune system is a delicate balancing act, DiPersio said.

The researchers maintained this balance in mice, but they usually live just a year or two.

For this process to represent a cure, humans would need the different immune system elements to stay balanced for decades. "It's hard to do that over a long period of time," DiPersio said. If the balance shifted, the islets could gradually die or you could get a dangerous tissue rejection reaction, he said.