Research into type 1 diabetes tends to focus on the autoimmune reaction, which is where the immune system destroys beta cells of pancreatic islets that produce insulin. Researchers at the University of Chicago have now examined the role of beta cells in triggering autoimmunity. The researchers also suggest that new medications may be developed to prevent type 1 diabetes in those at risk of developing it.
The study was published today in Cell ReportsThis article explains how researchers used genetic tools for knocking out or deleting a gene called Alox15Type 1 diabetes can be caused by mice who are genetically predisposed. This gene produces an enzyme called 12/15Lipoxygenase that is involved in the production of beta cell inflammation. Eliminating Alox15 These mice retained their beta cells, decreased the number of immune cells infiltrating into the islet environment, and prevented the development of type-1 diabetes in both males as well as females. These mice also had higher levels of PD-L1 (a protein that suppresses autoimmunity) expression.
“The immune system doesn’t decide one day whether it’s going to attack your beta cell.” Our thought was that the beta cells had somehow fundamentally altered themselves to invite that immunity,” stated Raghavendra Mirmira MD, Ph.D., senior author and Professor of Medicine at UChicago.
He said that the beta cells stopped signaling to the immune system after we removed this gene. The immune onslaught was also completely suppressed even though we didn’t touch the immune system. “This shows us that beta cells and the immune system have a complex dialogue and that you can stop diabetes by intervening in that dialogue.
The long-term collaboration between Mirmira and his lab at Indiana University led to the creation of this study. Jerry Nadler, MD, is the Dean of the School of Medicine and Professor of Medicine and Pharmacology, at New York Medical College. Maureen Gannon, Ph.D. is Professor of Medicine, Cell and Developmental Biology and Molecular Physiology and Biophysics, Vanderbilt University. They provided a strain of mice for the study that allowed for the knockout of the enzyme. Alox15 gene when the drug tamoxifen is given to you.
Sarah Tersey, Ph.D. Research Associate Professor at UChicago, and co-senior writer of the new study, was published in 2012. led a projectThis was one of the first to suggest that type 1 diabetes could be linked to beta cells.
Tersey stated, “This allows us understand the underlying mechanisms that lead to the development type 1 diabetes.” “This has been an important, changing area of the field. We now focus more on the role beta cells and less on autoimmunity.”
This study also provides interesting connections to cancer treatments that harness immune system to fight off tumors. Cancer cells often express PD-L1 proteins to suppress the immune response and evade body defenses. Checkpoint inhibitors, which are new drugs that target this protein, either inhibit or remove the PD-L1 “checkpoint”, and allow the immune system to attack cancers. The new study found that the immune system is unable to attack beta cells when there is an increase in PD-L1.
The researchers also tested a drug that inhibits 12/15-Lipoxygenase enzyme in human beta cells. The drug, ML355, raised levels of PD-1. It could therefore prevent diabetes development by interfering with the autoimmune response. It would be ideal to give it to patients who are at risk for developing type 1 diabetes due to their family history, or soon after diagnosis to prevent further damage to the pancreas. Mirmira and his team have begun clinical trials to evaluate a possible treatment using the ML355.
Mirmira stated, “This study suggests that inhibiting PD-L1 can increase levels in humans.” “With beta-cell targeted therapeutics, we believe you can catch a person before they get to that stage and prevent them from getting worse.”
The study is titled “Proinflammatory Signaling in Islet β Cells Propagates Invasion of Pathogenic Immune Cells in Autoimmune Diabetes.”
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Raghavendra G. Murmira, Proinflammatory Signaling In Islet beta Cells Causes Invasion Of Pathogenic Immune cells in Autoimmune Diabetes Cell Reports (2022). DOI: 10.1016/j.celrep.2022.111011. www.cell.com/cell-reports/full … 2211-1247(22)00800-2
To prevent type 1 diabetes (2022, 26 June 28), it is important to focus on beta cells rather than the immune system.
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