Studies investigating the causes of type 1 diabetes frequently tend to focus on the autoimmune response, in which the immune system destroys insulin-producing pancreatic islet beta cells. New research developed by scientists at the University of Chicago instead examines the role of beta cells themselves in triggering autoimmunity. The research is also interested in the possibility that new drugs could prevent the immune system from destroying beta cells and prevent the development of type 1 diabetes in at-risk or early-onset patients.
The results of the study have been published in the scientific journal Cell Reports.
Focusing on beta cells to prevent type 1 diabetes – here’s what the research says
The research described how the researchers harnessed genetic tools to eliminate 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. The elimination of Alox15 in these mice it 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 that codes for a protein called PD-L1 that suppresses autoimmunity.
“The immune system doesn’t just decide one day that it will attack our beta cells. Our thought was that the beta cell itself had somehow radically changed to invite that immunitySaid the senior author Raghavendra MirmiraProfessor of Medicine and Director of the Diabetes Translational Research Center in Chicago: “When we got rid of this gene, the beta cells no longer signaled the immune system and the immune assault was completely suppressed, even if we didn’t touch 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 that 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, Dean of the School of Medicine and Professor of Medicine and Pharmacology al New York Medical College discovered the role of the enzyme 12/15-lipoxygenase e Maureen GannonProfessor of Medicine, Cells and Development The biology and molecular physiology and biophysics of Vanderbilt University they provided a strain of mice that was used in the study, which allowed for gene knockout Alox15 when the drug was given tamoxifen.
In 2012, Sarah TerseyResearch Associate Professor at UChicago and senior co-author of the new study, he coordinated a project that was among the first to suggest that the beta cell could be a central player in the development of type 1 diabetes: “This allows us to understand the underlying mechanisms that lead to the development of type 1 diabetes“, Said Tersey:”This has been a huge and changing part of the field where we focus more on the role of beta cells and not just autoimmunity.“.
The research has also produced interesting connections with cancer treatments that use the immune system to fight cancer. Cancer cells often express the PD-L1 protein to suppress the immune system and evade the body’s defenses.
New drugs called checkpoint inhibitors target this protein, inhibiting or removing the PD-L1 “checkpoint” and freeing the immune system to attack tumors. In the new research, the increase in PD-L1 in konckout mice served its intended purpose of preventing the immune system from attacking beta cells.
In the new research, the team of scientists also tested a drug that inhibits the enzyme 12/15-lipoxygenase on human beta cells.. The researchers found that the drug, called ML355, increases PD-L1 levels, suggesting it could disrupt the autoimmune response and prevent the development of diabetes.
Ideally, it should be given to people who are at high risk due to family history and who show early signs of developing type 1 diabetes, or shortly after diagnosis before too much damage has been done to the pancreas. Mirmira and her team are taking the first steps to produce useful clinical studies to test a possible treatment using ML355.
“This study certainly suggests that inhibition of the enzyme in humans can increase PD-L1 levels, which is very promising “explained Mirmira: “With beta cell therapies, we believe that as long as the disease has not progressed to the point where there is massive destruction of beta cells, it is possible to detect a subject before that process begins and prevent disease progression altogether.“, Concluded the scientist.
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