Potential Cause of Immune Response in Diabetes Found

Genetically engineered mice lacking a specific protein developed diabetes at a faster rate.

Inhibiting the protein c-Rel may accelerate disease progression, and even lead to earlier onset of type 1 diabetes, despite prior findings.

Previous studies have identified inhibiting c-Rel as a way to protect against autoimmunity in diseases such as arthritis; however, in a study published in Diabetes, the opposite was found to be true, and this approach can lead to the early onset of certain diseases.

The c-Rel protein is necessary for the function of 2 types of T-lymphocytes that have opposing functions, according to researchers. One type of T cell is responsible for carrying out immune responses, and can become overactive and end up attacking health tissues.

The other T-cell suppresses its activity, and regulates the appropriate immune responses.

“c-Rel is critical in regulating both overlapping and distinct sets of genes in these T-cell types,” said lead study author Parameswaran Ramakrishnan, PhD.

To investigate the protein’s role in diabetes, researchers used genetically engineered diabetic mice that lacked c-Rel, checking to make sure the genetic alterations had no impact on other proteins. After measuring T-cell numbers, researchers found that the mice who lacked c-Rel had a 75% to 80% reduction in T regulatory cells, which are needed to suppress autoimmunity.

Researchers then collected T cells from the pancreases of c-Rel deficient mice, and found the T cells responsible for carrying out immune responses had enhanced proliferation within the pancreas, suggesting the over-activity in the absence of a sufficient number of T regulatory cells. The findings indicate that c-Rel is necessary to turn down autoimmune responses, and to maintain protective T cell populations.

In mice with no c-Rel, researchers found they were unhealthy, and that the pancreases were infiltrated with immune cells that were ready to attack. By 17 weeks of age, all of the mice without c-Rel became diabetic, compared with 80% of the controlled mice by 25 weeks of age.

Although researchers were unable to prevent diabetes in the mice completely, they could reverse the accelerated diabetes by giving the genetically engineered mice supplemental T regulatory cells containing c-Rel.

“We were expecting that the absence of c-Rel will prevent spontaneous diabetes development in non-obese diabetic mice,” Ramakrishnan said. “But to our surprise, we found an opposite effect, where 100% of the c-Rel deficient animals developed the disease at twice faster rate.”

Authors noted that future plans will include their newly created animal model to further research c-Rel regulation in type 1 diabetes. Furthermore, they plan to develop more genetically engineered mice with unique forms of c-Rel.