Selective inhibition of DNA damage repair has been achieved in activated T cells as part of an experimental combination treatment for immune diseases in mouse models. In this image, activated mouse T cells are shown with markers (pink) indicating DNA damage repair signaling. [Cincinnati Children's Hospital Medical Center]
Selective inhibition of DNA damage repair has been achieved in activated T cells as part of an experimental combination treatment for immune diseases in mouse models. In this image, activated mouse T cells are shown with markers (pink) indicating DNA damage repair signaling. [Cincinnati Children’s Hospital Medical Center]

T cells, like other mass-produced machines, may be subjected to destructive testing to determine how they fail in different circumstances, such as poor maintenance. In the case of T cells, the equivalent of racing around a track without a proper cooling or lubrication would be repeated rounds of division—rapid expansion—in the absence of DNA repair. Ultimately, the poorly maintained T cells would have a genomic breakdown and grind to a halt.

Genomic breakdowns in T cells could be desirable, such as when the immune system is so overheated that it attacks healthy tissues. The trick, however, is to push only activated T cells past the breaking point, and not anything else that may be essential to health. If that trick could be achieved, we could be on the way to developing new treatments to resolve conditions such as multiple sclerosis (MS) and hemophagocytic lymphohistiocytosis (HLH).

Progress toward selectively stressing already stressed T cells has been reported by scientists based at Cincinnati Children’s Hospital Medical Center. They report that a treatment modality called PPCA—p53 potentiation with checkpoint abrogation—takes advantage of DNA damage in rapidly expanding T cells, which they show was therapeutically beneficial in mouse models of MS and HLH. And for the most part, PPCA appears to exert the desired effect without harming other immune system components needed to protect the body from infection.

Details appeared May 22 in the Proceedings of the National Academy of Sciences, in an article entitled “Manipulating DNA Damage-Response Signaling for the Treatment of Immune-Mediated Diseases.” The article describes a unique strategy for therapeutic immune suppression, relying on targeted manipulation of DNA damage-response (DDR) signaling, that exploits unique aspects of lymphocyte biology.

“We found that potentiation of p53 (via inhibition of MDM2) or impairment of cell cycle checkpoints (via inhibition of CHK1/2 or WEE1) led to the selective elimination of activated, pathological T cells in vivo,” wrote the article’s authors. “The combination of these strategies…displayed therapeutic benefits in preclinical disease models of hemophagocytic lymphohistiocytosis and multiple sclerosis, which are driven by foreign antigens or self-antigens, respectively.”

PPCA was conceived during experiments on mouse and donated human immune cells called lymphocytes, which include the aggressively effective germ killers T cells and B cells. Researchers hypothesized that along with the highly adaptable and proliferative abilities of T cells came an abundance of genomic stress. They observed T cells used DNA damage response pathways to survive while adapting and gearing up to attack lymphocytic choriomeningitis virus (LCMV) as it tried to infect cells and animal models.

“We found that when T cells activate and go through extraordinarily rapid cell division during initial immune responses, it leads to an unusual level of genomic stress in the cells,” explained Michael B. Jordan, M.D., the article’s lead author.

“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,” Jordan says. “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.”

A gene and its protein called p53 (also called the “guardian of the genome”) helps initiate DNA damage repair—the primary reason researchers decided to target it in T cells. They also leveraged a concept developed for the treatment of cancer called cell cycle checkpoint inhibition or abrogation—in which cells are forced to lose normal control over the mitotic cell division cycle.

In selective instances of rapid T-cell expansion in mouse models of HLH and experimental autoimmune encephalomyelitis (experimental mouse MS), the researchers used a small molecule called Nutlin to alter the activities of p53. They also inhibited cell cycle checkpoint proteins known as CHK1/2 or WEE1. This prevented the T cells from pausing and repairing their DNA damage, which prompted them to die off.

In mouse models of HLH—mainly a childhood disease where the immune system overheats, attacks healthy tissues, damages organs, and causes early death—PPCA reduced disease in the animals and allowed them to survive long-term.

The researchers also tested PPCA treatment in mice with experimental autoimmune encephalomyelitis (EAE) used to model MS. In MS, autoimmune-driven inflammation damages a protective insulating sheath on nerves called myelin. This causes disruptions in the central nervous system that disrupt signals between the brain and extremities, which can lead to paralysis and other symptoms.

In EAE mouse models of MS, PPCA treatment killed off aggressively expanding T cells, tempered autoimmune processes, and either reversed or prevented paralysis in the animals, the authors report in their study.

“PPCA therapy targeted pathological T cells but did not compromise naive, regulatory, or quiescent memory T-cell pools, and had a modest nonimmune toxicity profile,” the article continued. “Thus, PPCA is a therapeutic modality for selective, antigen-specific immune modulation with significant translational potential for diverse immune-mediated diseases.”

Dr. Jordan and his colleagues caution that their experimental results are early. Years of additional research are needed before knowing whether the current findings will eventually apply to clinical treatment in humans. Dr. Jordan’s team now plans to test PPCA in laboratory models of other autoimmune disorders to see how widely applicable it might be.

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