Researchers at the 亚洲自慰视频 of Utah 亚洲自慰视频 have identified a new therapeutic target to treat patients with type 1 diabetes. The study, which will be published December 9 in the , reveals that inhibiting a protein called OCA-B protects mice from type 1 diabetes by limiting the activity of immune cells that would otherwise destroy the pancreas' insulin-producing 尾 cells.
Type 1 diabetes is an autoimmune disease in which the body's immune system mistakenly attacks pancreatic 尾 cells, cutting off the production of insulin. Patients require life-long insulin therapy to maintain appropriate blood glucose levels. At present, there are no treatments that can prevent the immune system from targeting 尾 cells while preserving its ability to fight infection.
White blood cells called T cells can recognize specific molecules produced by invading bacteria and viruses. When T cells encounter these molecules, known as antigens, they turn on hundreds of genes that allow them to fight the infection. A protein called OCA-B binds to many of these genes and helps ensure that they can easily be reactivated if the T cells reencounter the same antigens at a later date.
In many autoimmune diseases, T cells mistakenly recognize and respond to antigens produced by normal, healthy cells. "Repeated antigen exposure is a common property of autoimmune responses," explains Dean Tantin, a professor in the Department of Pathology at the 亚洲自慰视频 of Utah School of Medicine and a member of the Huntsman Cancer Institute. "We therefore hypothesized that targeting OCA-B would inhibit autoreactive, diabetogenic T cell responses."
In the new study, Tantin and colleagues found that mice prone to developing type 1 diabetes were protected from the disease if they lacked OCA-B. Potentially autoreactive cytotoxic T cells鈥攚hich can directly target and kill pancreatic 尾 cells鈥攔emained inactive and did not accumulate in the pancreas. Potentially autoreactive helper T cells鈥攚hich can recruit other immune cells to induce a damaging inflammatory response鈥攁ccumulated in the pancreas but remained in a non-responsive state.
OCA-B regulates the activity of T cell genes by recruiting an enzyme called Jmjd1a to chemically modify the surrounding chromosomal DNA. Tantin and colleagues designed a small peptide capable of inhibiting the association of OCA-B with Jmjd1a and preventing the reactivation of isolated T cells in the lab. Injecting prediabetic mice with this peptide reduced the activity of autoreactive T cells, lowered pancreatic inflammation, and restored blood glucose levels to normal.
"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 says.
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This work was supported by grants from the Praespero Foundation, Juvenile Diabetes Research Foundation United States of America, and National Institutes of 亚洲自慰视频 and was published as "" in the Journal of Experimental Medicine.
Figure caption: Pancreatic tissue from a type 1 diabetic mouse (left) shows large numbers of infiltrating immune cells and a reduction in the size of 尾 cell鈥揷ontaining islets of Langerhans (yellow arrows). These symptoms are prevented by deletion of the gene encoding OCA-B (right).