The new study also suggests that new drugs could stop the immune system from damaging beta cells and stop the onset of type 1 diabetes in vulnerable or early-onset patients.
When trying to figure out what causes type 1 diabetes, researchers often look at the autoimmune response, in which the immune system destroys the insulin-making islet beta cells in the pancreas.
Instead, a new study by researchers at the University of Chicago looks at how the beta cells themselves cause autoimmune disease. The research also raises the possibility that new drugs could stop the immune system from destroying beta cells and stop people at risk or with early-onset type 1 diabetes from getting the disease.
The study, which was just published in Cell Reports, details how the researchers utilized genetic tools to delete or knock out the Alox15 gene in mice with a genetic predisposition to type 1 diabetes.
An enzyme known as 12/15-Lipoxygenase, which is produced by this gene, is known to be involved in mechanisms that cause inflammation in beta cells. In these animals, deleting Alox15 conserved the quantity of beta cells, decreased the number of immune T cells entering the islet milieu, and stopped the development of type 1 diabetes in both males and females.
Additionally, these mice displayed increased expression of the gene that produces the PD-L1 protein, which inhibits autoimmunity.
“The immune system doesn’t just decide one day that it’s going to attack your beta cells,” explains senior author Raghavendra Mirmira , “our thinking was that the beta cell itself has somehow fundamentally altered itself to invite that immunity.”
“When we got rid of this gene, the beta cells no longer signaled to the immune system and the immune onslaught was completely suppressed, even though we didn’t touch the immune system,” he adds.
“That tells us that there is a complex dialogue between beta cells and immune cells, and if you intervene in that dialogue, you can prevent diabetes.”
The study is the result of a long-term partnership between Mirmira and several members of his lab, which started when they were all at Indiana University.
The role of the 12/15-Lipoxygenase enzyme was found by Jerry Nadler, MD, Dean of the School of Medicine and Professor of Medicine and Pharmacology at New York Medical College. Maureen Gannon, PhD, Professor of Medicine, Cell and Developmental Biology, and Molecular Physiology and Biophysics at Vanderbilt University, provided a strain of mice used in the study that allowed the drug tamoxifen to knock out the Alox15 gene.
Research Associate Professor at UChicago and co-senior author of the current study Sarah Tersey, PhD, was among the first to indicate that the beta-cell might be a crucial participant in the development of type 1 diabetes in 2012.
“This allows us to understand the underlying mechanisms leading to the development of type 1 diabetes,” Tersey adds. “This has been a huge, changing part of the field where we focus more on the role of beta cells and not just autoimmunity.”
The study’s findings have intriguing implications for cancer therapies that use the immune system to attack malignancies.
In order to weaken the immune system and get around the body’s defenses, cancer cells frequently express the PD-L1 protein. Inhibiting or disabling the PD-L1 “checkpoint” with new medications known as checkpoint inhibitors frees the immune system to target malignancies. Increased PD-L1 in the knockout mice in the new study achieves its desired result by blocking the immune system from attacking the beta cells, as shown by the results.
In the latest investigation, the scientists also put human beta cells through tests with a medication that blocks the action of the 12/15-lipoxygenase enzyme.
They discovered that the medication, ML355, raises PD-L1 levels, indicating that it might stop the autoimmune response and stop the onset of diabetes.
It should ideally be administered to people who are at high risk due to a family history of the disease and exhibit early indicators of type 1 diabetes, or soon after diagnosis, before the pancreas has sustained too much damage.
Clinical trials to assess a potential treatment employing ML355 are currently being initiated by Mirmira and his colleagues.
According to this study, blocking the enzyme in humans can raise levels of PD-L1, which is very encouraging, says Mirmira.
“With beta cell targeted therapeutics, we believe that as long as the disease hasn’t progressed to the point that there’s massive destruction of beta cells, you can catch an individual before that process starts and prevent the disease progression altogether.”
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