X Cell–Derived Antibody Shows Potential to Reverse Type 1 Diabetes in Preclinical Models
核心洞察
Johns Hopkins researchers report that an antibody derived from the X cell, x-mAb (搜索), selectively targets and eliminates the islet-reactive T cells driving Type 1 diabetes (搜索) in preclinical models.
The therapy aims to protect insulin-producing beta cells while sparing the rest of the immune system, potentially correcting the underlying autoimmune dysfunction rather than only managing blood sugar.
Investigators note this is only the second therapy signaling an ability to reverse Type 1 diabetes (搜索), alongside the FDA-approved drug teplizumab, which broadly targets T cells.
Seven years after announcing the discovery of the X cell, a novel immune cell implicated in Type 1 diabetes (搜索), Johns Hopkins researchers are now exploring how this cell can be turned into an immune therapy that might one day reverse disease progression shortly after diagnosis. Their latest findings, published by the Journal of Immunology in April, show that an antibody developed from the X cell was able to target and eliminate immune cells involved in the autoimmune response in preclinical models.
"It's not just managing blood sugar, but potentially correcting the immune dysfunction caused by the disease. This discovery opens a new direction for thinking about treatment," said Rafid Al-Hallaf, a research fellow in the Hamad Laboratory at the Johns Hopkins School of Medicine (搜索).
A Precision Approach to the Autoimmune Attack
The therapy under study, known as x-mAb (搜索), is a monoclonal antibody produced by X cells in people with Type 1 diabetes (搜索). The goal, according to principal investigator Abdel-Rahim A. Hamad, a professor of pathology at the Johns Hopkins University School of Medicine, is to selectively target and remove the roughly 2% of islet-reactive T cells that attack insulin-producing beta cells while leaving the rest of the immune system intact.
"Based on animal studies, we think we can precisely go and grab these cells using x-mAb (搜索) to prevent them from residing in the pancreas," Hamad said.
The approach follows evolutionary patterns observed in humans and mice by using a natural antibody to selectively target and stop the destruction of insulin-producing beta cells in the pancreas. Hamad's team says its efforts to harness and refine the natural properties of x-mAb (搜索) aim to protect insulin-producing cells while also preserving T cells that support normal immune function.
The Disease Burden and Unmet Need
More than 9.5 million people worldwide, including an estimated 2.1 million in the U.S., live with Type 1 diabetes (搜索), which results when the immune system mistakenly attacks insulin-producing cells in the pancreas. As a result of this chronic autoimmune condition, the pancreas progressively fails to make enough insulin to regulate blood sugar.
Treatments have relied on the daily, lifelong use of replacement insulin delivered with needles, pens, patches, pumps, and inhalable powders. Other options, which bypass the need for insulin, include pancreas transplants or transplants of donated pancreatic islet cells, yet these curative treatments require lifelong immunosuppressive medications. Patients face an increased risk of dangerously low blood sugar levels and ketoacidosis, while long-term risks of uncontrolled diabetes include damage to the kidneys, eyes, nerves, and limbs, and an increased risk for heart attacks and strokes.
"This is a challenging disease for both patients and their care team to manage," said Thomas W. Donner, director of the Johns Hopkins Comprehensive Diabetes Center.
A Serendipitous Discovery
"The discovery was serendipitous," Hamad said. He identified the X cell while studying immune features of cancer cells, finding a previously undefined immune cell with properties of both B and T cells. Investigators still are not sure why this cell exists, Donner explained, but they believe it may serve to alleviate autoimmune attacks in conditions like Type 1 diabetes (搜索).
Al-Hallaf noted that while more than 200 studies in mice have been shown to prevent Type 1 diabetes (搜索), this is only the second therapy that signals the ability to reverse it. The other is the FDA-approved drug teplizumab, which is now used for prolonging the onset of Type 1 diabetes by about two years and preserving the function of insulin-producing cells once symptoms start.
In the U.S., teplizumab is given intravenously to children and adults throughout a two-week period, administered when a person with increased risk starts to show biological signs and markers of the disease but before reaching diabetes-range blood sugar levels. The therapy has been shown to delay onset for a median of two years and is also now available at the immediate onset of Type 1 diabetes (搜索) in children, where it helps preserve insulin-producing cells.
Hamad noted that while that landmark therapy represents progress, it broadly targets T cells rather than selectively eliminating disease-causing cells, which raises concerns about adverse effects from immune suppression. "These limitations underscore the urgent need for novel immunotherapies that selectively target diabetogenic T cells, which could offer a long-sought precision medicine approach for Type 1 diabetes (搜索)," he added.
Next Steps and Broader Implications
Next steps, the researchers say, include further studying the safety and effectiveness of their treatment through additional studies in the lab and other preclinical models. Pending those results, the research may advance to clinical research trials with people.
Al-Hallaf noted that the work with X cells could also provide additional insight into how to treat other autoimmune conditions, such as Graves' disease and multiple sclerosis, because these disorders share similar autoimmune characteristics. "Because our approach specifically targets those harmful immune cells, we believe it could be applied beyond diabetes," he said.
The research was supported by the W. M. Keck Foundation, the Normal Raab Foundation, the Breakthrough T1D Innovative Award, the Maryland Innovation Initiative, and the National Institutes of Health (R01 AI099027, T32HD044355).