LJI Professor, Matthias von Herrath, M.D., is exploring the hypothesis that there’s something in the pancreas driving its own destruction in type 1 diabetes. Scientists have found that beta cells draw harmful T cells to the pancreas prior to the onset of clinical signs of diabetes. His lab is testing the theory that there’s something wrong with the beta cells themselves.
One mission of his lab is to unravel the roles of different immune cells, cytokines and other signaling molecules as type 1 diabetes progresses. The team analyzes human pancreas tissues obtained from the Network for Pancreatic Organ Donors with Diabetes (nPOD), and also human isolated islets. The lab also studies how predisposing genes and environmental factors, such as viral infections, may interact and trigger the disease. Several viruses, mainly from the Enterovirus genus have been considered as potential causal agents for type 1 diabetes.
By approaching type 1 diabetes from several angles, von Herrath and his colleagues hope to unlock the root of many autoimmune diseases.
A nervous system connection
The pancreas is studded with islets, the cell clusters that house insulin-producing beta cells. In people with type 1 diabetes, the body’s own immune cells head for the islets and start attacking the beta cells. No one knows exactly what triggers this attack.
One clue may lie in the pattern of beta cell death. Many beta cells are killed off in big patches while other beta cells are mysteriously untouched. Something seems to be drawing immune cells to attack specific groups of beta cells while ignoring others.
In a 2020 Science Advances study, researchers in the von Herrath Lab reported that the nervous system may be driving this patchy cell die-off. Their new findings in a mouse model suggest that blocking nerve signals to the pancreas could stop patients from ever developing type 1 diabetes. Learn more
Examining T cell behavior
It’s long been thought that having “autoreactive” T cells in the pancreas was a sure sign of type 1 diabetes. In 2020, a study from the von Herrath Lab showed that even healthy people have these cells lurking in the pancreas—in surprisingly high numbers. It appears that high numbers of these T cells in the pancreas are the default—whether you have type 1 diabetes or not. In people with type 1 diabetes, tissue samples showed autoreactive T cells very close to—and even infiltrating—the islets.
These results add evidence for the theory that type 1 diabetes is not caused by malfunctioning T cells attacking beta cells. Instead, the body is already making these T cells and something in the pancreas is triggering the attack. Von Herrath thinks this could mean that an effective type 1 diabetes therapy would need to be local to the pancreas.
Going forward, the researchers plan to take a closer look at how the preproinsulin-specific T cells behave. The team also hopes to investigate other proteins in islets that might attract T cell attacks.
Testing a therapeutic candidate
In 2021, translational research resulted in a promising combination therapeutic candidate for adults with recent-onset type 1 diabetes. The combination therapy was tested in a randomised, double-blind, placebo-controlled, phase 2 trial run and funded by pharmaceutical company Novo Nordisk. The results pointed to a potential way to treat the autoimmune disease without leaving the body vulnerable to infectious disease.
The therapeutic candidate combines anti-IL-21 antibody with the diabetes drug liraglutide. This two-pronged approach is based on research findings from the von Herrath Lab at LJI (von Herrath also serves as vice president and senior medical officer, Global Chief Medical Office, at Novo Nordisk).
“This is the first large trial for a combination therapy, and the data suggest it has value for patients,” says von Herrath. “The groundwork for choosing a combination therapy was laid through preclinical work at La Jolla Institute.”