In patients with Type 1 diabetes, T cells in the immune system mistakenly attack islet cells in the pancreas that make insulin. Scientists at Boston Children’s Hospital have come up with a way to thwart this wayward autoimmune reaction, and it involves a protein that plays a prominent role in new immunotherapy treatments for cancer: PD-L1.
PD-L1 is called an immune “checkpoint” because it prevents T cells from recognizing and attacking cancer. Drugs that inhibit PD-L1, like Genentech’s Tecentriq, have proven effective for fighting some cancers. But the Boston Children’s researchers believe that in diabetes, PD-L1 may actually need to be boosted. That’s because the protein appears to be instrumental in crippling the “autoreactive” T cells that destroy insulin-producing cells.
The researchers tested their theory by pre-treating blood stem cells so they would produce excess PD-L1 and then infusing them into mouse models of diabetes. The treated stem cells sped towards the pancreas, curing almost all of the mice of diabetes in the short term, according to a press release. About 30% of the animals remained diabetes-free for the duration of their lives. The research was published in the journal Science Translational Medicine.
The idea of using blood stem cells to reverse diabetes isn’t new. In fact, bone marrow transplants have been tried in diabetes patients, but they haven’t been uniformly effective. The Boston Children’s team wanted to find out why, so they set out to profile all the proteins made by blood stem cells from diabetic people and mice.
They discovered that genetic factors controlling the production of PD-L1 are altered in diabetes, hampering production of the protein. They reversed diabetes in the mice by introducing a healthy PD-L1 gene into the stem cells. But they also discovered they could stimulate PD-L1 production with the chemicals interferon beta, interferon gamma and polyinosinic-polycytidylic acid.
"We think resolution of PD-L1 deficiency may provide a novel therapeutic tool for the disease," said lead author Moufida Ben Nasr in the statement.
Counteracting the relentless attack on insulin-producing islet cells that causes diabetes is the idea behind many experimental approaches to treating the disease. Last month, scientists in North Carolina described artificial beta cells they created that can detect the need for insulin and automatically secrete it. They believe the technology could be delivered in a painless skin patch. And earlier this year, Medtronic began marketing the first automatic insulin pump with a built-in glucose sensor.
But completely reversing diabetes has proven considerably more challenging. In August, researchers in the U.K. reported encouraging results from a small trial of a proinsulin peptide that inhibits insulin-destroying T cells. And scientists at Massachusetts General Hospital have been testing their theory that an old tuberculosis vaccine, bacillus Calmette-Guérin (BCG), boosts the activity of genes that have the power to prevent the immune system from attacking islet cells.
The Boston Children’s team is now working with San Diego-based Fate Therapeutics to optimize the chemical cocktail used to stimulate PD-L1. They are planning further studies to determine the safety of the treatment, as well as the ideal dosing schedule and the duration of the positive effects from boosting PD-L1. They have also met with the FDA to discuss plans for a clinical trial in people with Type 1 diabetes.