A new study conducted by a group of experts showed that the reasons of type 1 diabetes are primarily focused on the autoimmune response, in which the immune system kills pancreatic islet beta cells, which help the body create insulin.
The researchers at the University of Chicago investigated the significance of beta cells in the initiation of autoimmunity. The study also found that new drugs might prevent the immune system from killing beta cells, hence preventing type 1 diabetes in at-risk or early-onset individuals. The study’s findings were reported in Cell Reports.
The researchers employed genetic techniques to knock off or remove a gene called Alox15 in mice that are genetically susceptible to developing type 1 diabetes. This gene encodes an enzyme known as 12/15-Lipoxygenase, which is implicated in mechanisms that cause inflammation in beta cells. Deleting Alox15 in these mice conserved their beta cell count, decreased the number of immunological T cells entering the islet milieu, and avoided the development of type 1 diabetes in both males and females. These mice also had higher levels of expression of the gene producing PD-L1, a protein that reduces autoimmune.
“The immune system does not spontaneously decide to assault your beta cells one day. Our hypothesis was that the beta cell has fundamentally transformed itself to encourage that immunity “Raghavendra Mirmira, MD, PhD, Professor of Medicine and Director of the Diabetes Translational Research Center at UChicago, is the senior author.
“When we removed this gene, the beta cells no longer communicated to the immune system, and the immunological onslaught was entirely repressed, despite the fact that we didn’t touch the immune system,” he explained. “This demonstrates that there is a sophisticated dialogue going on between beta cells and immune cells, and that if you interfere in that discussion, you can avoid diabetes.”
The research is the outcome of a long-term partnership that began while Mirmira and members of his team were at Indiana University. The role of the 12/15-Lipoxygenase enzyme was discovered by Jerry Nadler, MD, Dean of the School of Medicine and Professor of Medicine and Pharmacology at New York Medical College, and 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, which allowed for the knockout of the Alox15 gene when given the drug tamoxifen.
Sarah Tersey, PhD, Research Associate Professor at UChicago and co-senior author of the new study, led an experiment in 2012 that was among the first to show that the beta cell might play a role in the development of type 1 diabetes.
Tersey explained, “This helps us to understand the fundamental pathways that contribute to the development of type 1 diabetes.” “This has been a big, altering component of the research where we are focusing more on the role of beta cells rather than merely autoimmunity.”
The research also has intriguing links to cancer therapies that use the immune system to combat malignancies. Cancer cells frequently produce the PD-L1 protein in order to inhibit the immune system and avoid detection by the body’s defences.
Checkpoint inhibitors are new medications that target this protein, blocking or eliminating the PD-L1 “checkpoint” and allowing the immune system to assault malignancies. The enhanced PD-L1 in the mutant mice accomplishes its intended effect in the new study by blocking the immune system from targeting the beta cells.
The researchers also tried a medication that suppresses the 12/15-Lipoxygenase enzyme on human beta cells in the latest study. They discovered that the medicine, ML355, raises PD-L1 levels, implying that it might stop the autoimmune response and prevent diabetes from developing.
It would ideally be administered to people who are at high risk due to family history and exhibit early indications of developing type 1 diabetes, or quickly after diagnosis, before too much damage to the pancreas has been done. Mirmira and his colleagues are starting clinical studies to explore a potential therapy utilising ML355.
“This work shows that blocking the enzyme in people can boost levels of PD-L1, which is really promising,” Mirmira added. “With beta cell targeted treatments, we believe that as long as the illness hasn’t advanced to the point of significant beta cell death, you can catch an individual before that process begins and halt disease development entirely.”
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The National Institutes of Health and the Department of Veterans Affairs funded the study, “Proinflammatory Signaling in Islet b Cells Promotes Invasion of Pathogenic Immune Cells in Autoimmune Diabetes.” Annie Pineros, Hongyu Gao, Kara Orr, Yunlong Liu, Farooq Syed, Wenting Wu, and Carmella Evans-Molina from Indiana University; Abhishek Kulkarni, Fei Huang, and Cara M Anderson from the University of Chicago; Lindsey Glenn and Margaret Morris from Eastern Virginia Medical School; and Marcia McDuffie from the University of Virginia are among the other authors.
