Study finds potential target for stopping immune system attacks in autoimmune diseases

Houston Methodist researchers have identified a key protein as a potential therapeutic target for stopping the body's immune system from mistakenly attacking itself, offering new hope for treating 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., associate professor of transplant immunology in surgery.

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. 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. When the absence of Apex1 is achieved, it would render T cells incapable of causing the damage typically seen in autoimmune diseases and allergic reactions.

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. Another unexpected finding was the extensive death of harmful T cells upon Apex1 inhibition."

Xian C. Li, M.D., Ph.D., Director, Immunobiology & Transplant Science Center, Houston Methodist Research Institute

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. The control group, which exhibited these lupus symptoms, died by 24 weeks. The absence of the Apex1 gene seemed to prevent the lupus-like disease by controlling harmful immune cells, suggesting that Apex1 is important in how immune cells function and might be a key target for lupus and other autoimmune disease treatments.

"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, such as what happens in autoimmune diseases like lupus, after these immune cells see specific antigens they perceive as a threat. He said this demonstrates tremendous specificity, making this potential treatment highly precise and having the capability to minimize unwanted side effects compared to other therapies.

The researchers say their next steps to move these discoveries forward will require rational design of chemical compounds to selectively target Apex1 and additional testing in subsequent models and clinical trials.

"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."

Li and Zhang's collaborators on this study were co-first authors Xiang Xiao and Yong Du, Si Sun, Xiaojun Su, Junji Xing, Guangchuan Wang, Steven M. Elzein, Dawei Zou, Laurie J. Minze, Zhuyun Mao, Rafik M. Ghobrial, Ashton A. Connor and Wenhao Chen.

This project was supported, in part, by grants from the National Institutes of Health awarded to Li (R01AI129906 and R01AI106200), Chen (R01AI132492) and Zhang (R01AI155488), as well as funded by the Max and Lillie Frosch Centennial Chair in Transplant Research at Houston Methodist Hospital through Li.