Researchers at Cincinnati Children’s Hospital Medical Center (CCHMC) have developed a new experimental method to specifically target unwanted activation of the immune system without the toxicity of current immunoregulatory drugs.
According to the study “Manipulating DNA damage-response signaling for the treatment of immune-mediated diseases,” published in the journal Proceeding of the National Academy of Science, selectively targeting an Achilles heel of activated immune cells offers the potential of treating multiple sclerosis (MS) and other immune-mediated illnesses.
When immune cells are activated, they divide rapidly, dramatically increasing cellular stress and DNA damage. Under normal conditions, immune cells can overcome this potentially deadly event by repairing DNA and expanding as necessary. The new method, which the authors call “p53 potentiation with checkpoint abrogation,” or PPCA, takes advantage of this damage-repair balance. They found that inhibiting the repair process during cell division selectively killed activated cells, preventing the burst of immune cells that characterize many autoimmune diseases.
“Because T cells are always in a race with different viruses and bacteria, they have learned how to adapt and divide rapidly to respond, but this stress on their DNA means they also are living right on the edge of death,” CCHMC researcher Michael B. Jordan, the study’s senior author, said in a press release. “In our experiments, we selectively interrupted DNA damage repair in rapidly expanding T cells, and we threw them off-balance and into a chasm of death.”
The PPCA specifically targets two major mechanisms that regulate the DNA damage-repair balance. One is based on activating a protein called p53, also known as the “guardian of the genome.” The second inhibits proteins involved in cell cycle checkpoints, which forces cells to lose control over the cell division process. This double-targeting method prevents immune cells from pausing the cell division process and repairing their damaged DNA. This leads to catastrophic abnormal events that prompt the cells to die.
Researchers tested this method in experimental animal models of MS and hemophagocytic lymphohistiocytosis — a life-threatening condition characterized by overactive immune cells in the body. They found that PPCA killed the immune cells that were expanding, which impaired autoimmune processes, reversing or preventing the animals from becoming paralyzed. These findings supported the therapeutic potential of PPCA against autoimmune conditions.
More studies are still required to confirm whether these findings can be applied to clinical treatment in humans. The research team — funded by the National Institutes of Health and a research grant from CCHMC — plans to further test the PPCA in animal models of other autoimmune disorders to confirm and expand its potential use.