Like many autoimmune diseases, Type 1 diabetes stems from effector T cells gone rogue. The immune cells launch an attack on the insulin-producing beta islet cells in the pancreas, leaving patients without the ability to process glucose. As a result, patients require lifelong insulin treatment.
With the advent of T-cell therapies, scientists have been looking to the body’s own defense against renegade T effector cells to see if they can prevent or even reverse Type 1 diabetes. In a study published Oct. 5 in Science Translational Medicine, researchers from Benaroya Research Institute and Seattle Children’s Research Institute described how they engineered regulatory T cells—or Tregs, cells that police the immune system if it begins attacking host tissues—that homed to the pancreas, where they successfully blocked diabetes development in mice.
“This study is an important step because it shows that by copying a natural process that protects the body, we might be able to stop [Type 1 diabetes] at the source,” Soo Jung Yang, Ph.D., first author, said in a press release.
The scientists were building on a decade of their own work genetically engineering Tregs to treat autoimmune disease, with a specific focus on Type 1 diabetes. Previously, they had developed a class of Tregs that expressed the FOXP3 gene, defects in which have been linked to their demise and, thus, inability to control effector T-cell activity. Their engineered Tregs had successfully suppressed effector T cells, but the scientists wanted to make them more specific to the pancreas’ beta islet cells—ideally sidestepping the potential problem of widespread immunosuppression, along with improving their efficacy.
To that end, the researchers combined two approaches to create engineered Tregs that were specific to an antigen on beta islet cells: the same platform they had developed to enhance FOXP3 gene expression in the Tregs, plus human T-cell receptor gene transfer. For the latter, they used seven different islet-specific T-cell receptors, all of which had been derived from effector T cells that were isolated from patients with Type 1 diabetes.
After confirming that the antigen-specific engineered Tregs would suppress effector T cells in the lab, the researchers moved to testing the cells in mice. They mixed the engineered Tregs with effector T cells and injected them into mouse models that would develop Type 1 diabetes upon administration of effector T cells, then observed their blood glucose levels over 49 days. The mice that received the engineered Tregs were almost completely diabetes-free by the end of the period, while those that were injected with a control solution all developed the condition between days 9 and 15.
Importantly, the engineered Tregs also needed to persist in the pancreatic tissue to have a long-term therapeutic benefit. In the mouse models, they had: The scientists found that by the end of the period, the antigen-specific engineered Tregs were as abundant in the treated mice as natural Tregs in healthy subjects.
While the scientists are well on their way to taking the research to the clinic, co-corresponding author and Benaroya Research Institute President Dr. Jane Buckner, MD, told Fierce in an email, there is a bit more work to be done. For one, while the engineered Tregs did indeed work, they had different levels of effector T-cell suppression depending on which of the T-cell receptors had been used to create them.
“What we found most surprising was the difference in the level of suppression seen with different TCRs, even those that were specific for the same peptide,” she said. “This suggests to us that better understanding the characteristics of TCRs that influence the function of engineered Tregs will be important to inform selection of TCRs for therapy.”
In addition, the scientists so far have developed their engineered Tregs specifically for patients who carry the HLA DR0401 allele, one of several HLA alleles associated with Type 1 diabetes. Going forward, they plan to identify and test T-cell receptors restricted to other HLA types, Dr. Buckner said.
In the meantime, companies are making progress on tackling Type 1 diabetes from other angles. Vertex made headlines last year with the first "functional cure” of the condition in a man who was infused with insulin-producing beta islet cells grown from stem cells. On another front, Provention Bio is looking to gain FDA approval next month for its drug teplizumab, a humanized anti-CD3 monoclonal antibody that’s designed to delay the onset of diabetes by a median of two years in high-risk children and adults.