Preventing Type 1 diabetes by targeting a T-cell protein

Diabetes blood sugar testing
Scientists at the University of Utah School of Medicine have identified the protein OCA-B as a potential new therapeutic target to treat patients with Type 1 diabetes and offered proof-of-concept evidence in mice. (Pixabay / stevepb)

In Type 1 diabetes, the body’s immune system mistakenly attacks insulin-making beta cells in the pancreas. Scientists at the University of Utah School of Medicine said they've found a way to rein in that autoimmune response by targeting a protein that’s essential for T-cell activation.

The protein is called OCA-B. Mice that were genetically modified to lack the protein were protected from Type 1 diabetes, and a small peptide inhibitor of OCA-B also fended off the disease in newly diabetic animals, according to results published in the Journal of Experimental Medicine.

The study offers a proof-of-concept for OCA-B as a promising new target for treating Type 1 diabetes because it gets at the disease’s underlying cause and can be used as the basis for further drug development, the researchers argued in the paper.

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OCA-B, or B cell-specific Oct1/2 coactivator, binds to and regulates about 150 genes involved in a process whereby T cells are reactivated upon reencountering antigens they have previously recognized and memorized.

“Repeated antigen exposure is a common property of autoimmune responses,” Dean Tantin, the study’s senior author, explained in a statement. “We therefore hypothesized that targeting OCA-B would inhibit autoreactive, diabetogenic T cell responses.”

In mice that are prone to developing Type 1 diabetes, the scientists removed T cell-specific OCA-B in some animals and observed the onset of Type 1 diabetes. About 60% of control mice showed spontaneous diabetes by 24 weeks of age, while no OCA-B-deficient animals became diabetic, the team reported.

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The researchers studied the pancreatic lymph nodes of the OCA-B-modified mice and discovered autoantigen-specific CD8+ cytotoxic T cells, which could potentially launch an autoimmune attack to directly kill pancreatic beta cells. But few actually entered the pancreatic islets that contained the hormone-producing cells. They also showed a reduced ability to become activated in the lymph nodes.

Potentially autoreactive CD4+ helper T cells—which can recruit other immune cells to induce an inflammatory response—did accumulate in the pancreas. But they appeared to remain in a mostly dormant state called anergy, the scientists found.

The immune cell profile the researchers observed suggested the possibility of a “‘therapeutic window’ in which targeting OCA-B pharmacologically would blunt autoimmunity while minimally affecting baseline immune function,” they said. So they designed a peptide capable of inhibiting OCA-B’s interaction with an enzyme called Jmjd1a, which is critical for OCA-B’s regulation of the activity of T cell genes.

The peptide inhibitor blocked the reactivation of T cells in lab dishes. In mice with early signs of Type 1 diabetes, the therapy reduced pro-inflammatory cytokine production, reduced CD8+ T cell autoreactivity and prevented blood glucose levels from rising.

RELATED: Reprogramming pancreatic cells into insulin makers to treat diabetes

Type 1 diabetes patients require life-long insulin injections. Scientists have been looking for ways to tackle the underlying cause of the disease, and much of that research has focused on regenerating beta cells.

A team at the Icahn School of Medicine at Mount Sinai recently found that combining DYRK1A inhibitors with GLP-1 receptor agonists could induce human pancreatic islets to start proliferating, generating new beta cells in mice. Researchers at the University of Geneva previously showed that increasing the expression of two transcription factors, PDX1 and MafA, could turn alpha and gamma cells to adopt a beta cell-like function to produce insulin.

The University of Utah researchers believe their findings offer a potential way to inhibit autoreactivity in Type 1 diabetes while still 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,” Tantin said in the statement.