Posted on Dec 10, 2020, 6 p.m.
The immune system mistakenly attacks insulin-making beta cells in the pancreas in type 1 diabetes, and those living with the disease require lifelong insulin injections. A study published in the Journal of Experimental Medicine from scientists at the University of Utah School of Medicine believe that they have found a way to tackle this autoimmune response by targeting a protein, OCA-B, essential for T-cell activation.
This proof of concept study shows promise for OCA-B as a promising new possible target for treating type 1 diabetes as it deals with the underlying cause of the disease and it could be used as the basis for further drug development, according to the paper authors.
The report describes how mice that were genetically modified to lack in OCA-B protein were protected from type 1 diabetes, and how a small peptide inhibitor of OCA-B helped to ward off the disease in newly diabetic animals. B cell-specific Oct1/2 coactivator/OCA-B binds to and regulates about 150 genes involved in a process whereby T cells are reactivated upon reencountering antigens that they had previously recognized and memorized.
“Repeated antigen exposure is a common property of autoimmune responses,” explained Dean Tantin, the study’s senior author. “We, therefore, hypothesized that targeting OCA-B would inhibit autoreactive, diabetogenic T cell responses.”
Scientists removed T-cell-specific OCA-B in some small animals and observed the onset of type 1 diabetes in mice that are prone to developing the disease; 60% of the animals showed spontaneous diabetes by 24 weeks of age while no OCA-B deficient animals became diabetic according to the study authors.
Pancreatic lymph nodes of the modified mice were examined which revealed autoantigen-specific CD8+ cytotoxic T-cells that could potentially trigger an autoimmune attack to directly kill pancreatic beta cells, but few actually entered the pancreatic islets that contain hormone-producing cells; and the team also showed a reduced ability to become activated in the lymph nodes.
Autoreactive CD4+ helper T-cells which can potentially recruit other immune cells to induce an inflammatory response were found to accumulate in the pancreas, but these cells appeared to remain in a mostly dormant anergy state.
Based on the observed immune cells profile the team suggests there may be a possibility of a “‘therapeutic window’ in which targeting OCA-B pharmacologically would blunt autoimmunity while minimally affecting baseline immune function.” With this in mind, the team designed a peptide capable of inhibiting the interaction of OCA-B with Jmjd1a enzymes that are critical for OCA-B to regulate the activity of T-cells.
According to the team, the peptide inhibitor blocked the reactivation of T-cells in lab dishes, and in mice with early signs of type 1 diabetes, reduced pro-inflammatory cytokine production, reduced CD8+ T-cell autoreactivity and prevented blood glucose levels from increasing. The team is hopeful that their findings could offer a potential way to inhibit autoreactivity in type 1 diabetes while preserving normal immune function.
“While the peptide is unlikely to be used in a clinical setting, it offers a proof-of-principle for OCA-B as a therapeutic target for Type 1 diabetes, and can be used as a tool for the further development of therapeutics,” said Tantin.
In other research published in Science Translational Medicine, a team from Icahn School of Medicine at Mount Sinai have found that combining DYRK1A inhibitors with GLP-1 receptor agonists induced human pancreatic islets to start proliferating, generating new beta cells in mice.
Additionally, in a study published in Nature, a team for the University of Geneva showed that increasing expression of PDX1 and MafA transcription factors could turn both alpha and gamma cells to adopt a beta-like function to produce insulin.
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