The results of the study have been published in Cell Reports.
The study describes how researchers used genetic tools to knock out or delete a gene called Alox15 in mice genetically predisposed to developing type 1 diabetes. This gene produces an enzyme called 12/15-lipoxygenase, which is known to be involved in the processes that produce inflammation in beta cells. Deleting Alox15 in these mice preserved their amount of beta cells, reduced the number of immune T cells infiltrating the islet environment, and prevented the development of type 1 diabetes in both males and females. These mice also showed increased expression of the gene encoding a protein called PD-L1 that suppresses autoimmunity.
“The immune system doesn’t ever decide it’s going to attack your beta cells. Our thought was that the beta cell itself has somehow fundamentally changed to invite that immunity,” said lead author Raghavendra Mirmira. , MD, PhD, professor. of Medicine and Director of the Diabetes Translational Research Center at UChicago.
“When we got rid of that gene, the beta cells no longer signaled to the immune system and the immune attack was completely suppressed, even though we didn’t hit the immune system,” he said. . “This tells us that there is a complex dialogue between beta cells and immune cells, and if you intervene in this dialogue, you can prevent diabetes.”
The study is the result of a long-term collaboration that began when Mirmira and several members of her lab were at Indiana University. Jerry Nadler, MD, Dean of the School of Medicine and Professor of Medicine and Pharmacology at New York Medical College discovered the role of the enzyme 12/15-lipoxygenase, and Maureen Gannon, PhD, Professor of Medicine, Cell Biology and Developmental, and Molecular Physiology and Biophysics at Vanderbilt University provided a strain of mice that was used in the study, which allowed inactivation of the Alox15 gene when given the drug tamoxifen. In 2012, Sarah Tersey, PhD, associate research professor at UChicago and co-senior author of the new study, led a project among the first to suggest that the beta cell may play a central role in the development of type 1 diabetes. .
“This allows us to understand the underlying mechanisms leading to the development of type 1 diabetes,” Tersey said. “It’s been a huge and changing part of the field where we’re focusing more on the role of beta cells and not just autoimmunity.”
In the new study, the researchers also tested a drug that inhibits the enzyme 12/15-lipoxygenase on human beta cells. They saw that the drug, called ML355, increases PD-L1 levels, suggesting it could interrupt the autoimmune response and prevent the development of diabetes. Ideally, it would be given to patients at high risk due to a family history and showing early signs of developing type 1 diabetes, or soon after diagnosis before too much damage is done to the pancreas. Mirmira and her team are taking the first steps to start clinical trials to test a possible treatment using ML355.
“This study certainly suggests that inhibiting the enzyme in humans can increase PD-L1 levels, which is very promising,” Mirmira said. “With beta cell targeted therapies, we believe that as long as the disease has not progressed to the point where there is massive destruction of beta cells, you can catch an individual before this process begins and completely prevent progression. of disease.”
The study, “Pro-inflammatory signaling in islet b cells propagates pathogenic immune cell invasion in autoimmune diabetes,” was supported by the National Institutes of Health and the Department of Veterans Affairs. Other authors include Annie Pineros, Hongyu Gao, Kara Orr, Yunlong Liu, Farooq Syed, Wenting Wu, and Carmella Evans-Molina of Indiana University; Abhishek Kulkarni, Fei Huang and Cara M Anderson from the University of Chicago; Lindsey Glenn and Margaret Morris of Eastern Virginia Medical School; and Marcia McDuffie of the University of Virginia.
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