Houston Methodist Researchers Identify Key Protein to Halt Autoimmune Diseases and Allergies

The paper titled “Apex1 safeguards genomic stability to ensure a cytopathic T cell fate in autoimmune disease models,” appeared recently in the Journal of Clinical Investigation.Xian C. Li, M.D., Ph.D., director of the Immunobiology & Transplant Science Center in the Houston Methodist Research Institute, is co-corresponding author on the paper with Zhiqiang Zhang, Ph.D.

In this study, the researchers discovered that a protein called Apex1 protects the DNA of multiplying immune cells so they can become “killer” T cells.^[1] They have the potential to attack the body by mistake, which is what happens in autoimmune diseases and allergies. By demonstrating how indispensable this Apex1 protein is to the destructive autoimmune process, the researchers proved if they therapeutically target the protein with chemical inhibitors to either turn it off or remove it completely, then this could be a highly effective way to block immune-mediated diseases.

“We were surprised by the potency of suppressing multiple autoimmune diseases – not only in prevention, but also in treatment once the diseases were already established – upon blocking that single Apex1 molecule,” Li said. “Another unexpected finding was the extensive death of harmful T cells upon Apex1 inhibition.”

The research team studied various disease models but found the lupus and multiple sclerosis models to be efficacious. They deleted the Apex1 gene in murine models prone to a lupus-like disease – a condition where the immune system attacks the body’s own tissues. The models with the Apex1 gene deleted did not develop lupus symptoms, such as having protein in their urine, kidney damage or immune cell buildup in their kidneys, or produce harmful autoantibodies, thus resulting in long, healthy lifespans.

For those suffering from diseases like lupus, multiple sclerosis or allergies, where destructive T cells are involved, approaches to inhibit Apex1 may be the best way to cure the diseases, as those harmful T cells are eliminated through cell death,” Li said. “We provided proof of concept evidence in the paper using chemical inhibitors of Apex1.”Li said their findings are different from earlier approaches, because they show targeting Apex1 only affects T cells that are actively multiplying after being switched on by a trigger, making this potential treatment highly precise and having the capability to minimize unwanted side effects compared to other therapies".

“Our goal in the next stage of studies is to test Apex1 inhibitors and Apex1 gene knockout in organ transplant models, where graft rejection is strictly T cell-dependent,” Li said. “We will try to develop new protocols and better therapies for transplant patients to ensure long-lasting transplant survival in the long term.”

References:

1. Apex1 safeguards genomic stability to ensure a cytopathic T cell fate in autoimmune disease models,” appeared recently in the Journal of Clinical Investigation. Xian C. Li, M.D., Ph.D., Houston Methodist Research Institute.

(Newswise/CD)