PNNL team pinpoints changes that ease immune attack.
PNNL scientist Wei-Jun Qian and colleagues have contributed to a study that offers clues for delaying or even preventing the autoimmune attack that’s at the core of type-1 diabetes.
The study team, led by Rohit Kulkarni at the Joslin Diabetes Center at Harvard, spurred young mice to produce modified cells known as beta cells before they become the target of the body’s immune system. The process altered the identity of the beta cells, changing them in fundamental ways that made them less of a target. The scientists published their results in Nature Metabolism.
The body’s autoimmune attack on beta cells, located in the pancreas, is at the root of type-1 diabetes. The beta cells produce insulin, and when the cells die, insulin production drops or ceases.
The Harvard team created mice that produced more beta cells than typical when young, when an organism’s immune system is still learning to distinguish self from non-self and friend from enemy. While the mice were bred to be especially prone to developing type 1 diabetes, the team showed that with the extra modified beta cells, the mice were much less likely to develop the disease than their control counterparts.
To learn why, the team turned to PNNL researchers, sending to the laboratory a handful of coveted beta cells culled from the islets in the pancreas of the mice.
The PNNL team used highly sensitive mass spectrometry to measure levels of a few thousand proteins from beta cells. Qian and colleagues, including Paul Piehowski and Richard Smith, found that the cells are less likely to carry auto-antigens that provoke an attack by the immune system’s effector T cells. They also found that the beta cells from the modified mice had much lower levels of a complex of proteins known as MHC, which invite attack from the immune system.
The Harvard team also noted broader changes in the immune environment of the modified mice. For instance, they had more regulatory T cells, which helps keep other T cells, including the ones that stage the attack seen in diabetes, in check.
In an accompanying “news and view” column in the journal, scientists not involved in the study wrote, “All these data support the novel concept that the induction of proliferation in beta cells may serve as a tool not only to regenerate insulin-producing islets but also to restore immunological self-tolerance.”
Qian had been doing diabetes-related research for several years when an experience with friends drove home the importance of the work. His friends’ young daughter suddenly became ill, and the family ended up in the emergency room, thinking their daughter was suffering from the flu or a similar illness. Instead, doctors found that the girl had a blood sugar level near 500 as a result of Type 1 diabetes.
“It’s a lifelong disease, and these patients are on insulin for life. To find a cure would be amazing,” said Qian.
Qian’s team has a longstanding collaboration with Harvard researchers through the Human Islet Research Network and other mechanisms supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The measurements were made at the Environmental Molecular Sciences Laboratory, a DOE Office of Science user facility located at PNNL.