Seven years ago, Johns Hopkins researchers and their collaborators announced they had found the X cell, a novel immune cell that plays a key role in the development of Type 1 diabetes.
Today the team is taking its research further, leveraging years of federally supported discovery to explore how the X cell can be turned into an immune therapy that might one day reverse the progression of Type 1 diabetes shortly after diagnosis.
Their latest findings, published by the Journal of Immunology in April, show that an antibody developed based on the X cell was able to target and eliminate immune cells involved in the autoimmune response. The work, while still in preclinical models, represents longstanding research partially supported by the National Institutes of Health.
"These are novel concepts," says Abdel-Rahim A. Hamad, the principal investigator of the Hamad Laboratory and a professor of pathology at the Johns Hopkins University School of Medicine. The therapy they are studying 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.
"It's not just managing blood sugar, but potentially correcting the immune dysfunction caused by the disease," says Rafid Al-Hallaf, a research fellow in the Hamad Laboratory. "This discovery opens a new direction for thinking about treatment."
The body relies on a variety of hormones, including insulin, to convert fuel into energy. Most people don't have to think twice about this process. However, more than 9.5 million people worldwide, including an estimated 2.1 million in the U.S., live with Type 1 diabetes, 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 the body's use of blood sugar, or glucose.
Treatments for Type 1 diabetes 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, where insulin is produced. Yet these curative treatments require the lifelong need to take immunosuppressive medications. Managing Type 1 diabetes can be challenging while leaving patients at increased risk of having potentially dangerously low blood sugar levels and ketoacidosis, a serious and potentially life-threatening condition that occurs when the body begins to break down fat as fuel, resulting in a buildup of acid in the blood. The long-term risks of uncontrolled diabetes include damage to their kidneys, eyes, nerves, and limbs, and an increased risk for heart attacks and strokes.
As a result, researchers have long sought better therapies and continue to study ways to address the underlying autoimmune cause of the disease. The goal is to eliminate complications, prevent the disease, and preserve the insulin-producing cells a person has after their diagnosis—which makes blood sugar levels easier to control.
"This is a challenging disease for both patients and their care team to manage," says Thomas W. Donner, director of the Johns Hopkins Comprehensive Diabetes Center.
Image caption: From left, Rafid Al-Hallaf, Abdel-Rahim A. Hamad, and Thomas W. Donner
Image credit: Will Kirk / Johns Hopkins University
An estimated 15% of cases have a close family member with Type 1 diabetes, but Donner notes that the majority of those newly diagnosed do not. The trigger for the disease remains unknown. Environmental exposures, including viruses, are likely involved and actively being studied, he says.
In a bid to expand treatment options, the Hopkins scientists, including Donner, have focused on the X cell.
"The discovery was serendipitous," Hamad says. He identified the X cell as he was studying immune features of cancer cells. This is when he found a previously undefined immune cell that had properties of both B and T cells, the well-known workhorses of the immune system's white blood cells that recognize and respond to outside threats, such as bacteria or viruses.
Hamad has since collaborated with researchers inside and outside of Johns Hopkins to understand the function of the X cell and to see how it could be used to develop an immune therapy for type 1 diabetes that could help prevent autoimmune damage. Investigators still aren't sure why this cell exists, Donner explains, but they believe it may be to alleviate autoimmune attacks in conditions like Type 1 diabetes.
In their latest experiments, they are studying how a therapy based on the X monoclonal antibody (x-mAb), an antibody produced by X cells in people with Type 1 diabetes, could help the body respond to autoimmune attacks.
The goal of the therapy, explains Hamad, is to selectively target and remove the 2% of islet-reactive T cells that attack insulin-producing beta cells in Type 1 diabetes and leave the rest of the immune system intact. "Based on animal studies, we think we can precisely go and grab these cells using x-mAb to prevent them from residing in the pancreas," he says.
Al-Hallaf notes that what's unique about this ongoing research is that while more than 200 studies in mice have been shown to prevent Type 1 diabetes, 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. It's administered when a person with an increased risk for Type 1 diabetes starts to show biological signs and markers of the disease, but before they reach diabetes-range blood sugar levels. The therapy has been shown to delay the onset of Type 1 diabetes for a median of two years. It is also now available at the immediate onset of Type 1 diabetes in children in whom it helps preserve insulin-producing cells.
Hamad notes 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," he adds.
In summary, Hamad's team says its efforts to harness and refine the natural properties of x-mAb by selectively targeting the T cells driving the autoimmune attack aims to protect insulin-producing cells while also preserving T cells that support normal immune function.
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 notes 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 says.
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).
