Manipulating DNA repair response is a promising therapeutic strategy for immune diseases


Therapeutic immune suppression is an important treatment strategy for many immune conditions, such as autoimmune disorders, immunoregulatory disorders, and in transplantation. Since immune pathways typically have essential functions in the body, broadly acting drugs and pathway-specific agents may cause severe problems. Thus, antigen-specific immune suppression might be a better option.

Now investigators at Cincinnati Children's Medical Center have developed a new approach for therapeutic immune suppression. The approach, called PPCA, relies on targeted manipulation of DNA damage in rapidly expanding T cells and allows for highly selective suppression of these cells.

Some immune diseases involve prolonged inflammation and subsequent tissue destruction. For this work, the investigators looked at multiple sclerosis (MS) and hemophagocytic lymphohistiocytosis (HLH). MS is an autoimmune disease that occurs when the immune system attacks the myelinated sheaths of neurons, and it is characterized by inflammation in the central nervous system thought to be mediated by autoreactive T cells. HLH is an uncommon but life-threatening syndrome of severe inflammation caused by uncontrolled proliferation of hyperactivated macrophages and lymphocytes. More effective immunosuppressive therapies are needed to improve the prognosis of patients with MS and HLH.

The investigators found that activated mouse and human T cells displayed a pronounced DNA damage-response when they divided rapidly during initial immune responses. According to study leader Michael Jordana, T cells have adapted to rapid division because they are part of the body's defenses against diverse pathogens, but this leads to unusual genomic stress in these cells. The investigators observed that T cells used DNA damage-response pathways to survive. These data suggest that selectively interrupting DNA damage repair in rapidly expanding T cells might be a way to inhibit T cell proliferation.

It is well established that the protein p53 helps initiate DNA damage repair. So the investigators decided to target it in T cells. Using preclinical disease models of MS and HLH, they found that potentiation of p53 and impairment of cell cycle checkpoints led to the selective elimination of activated, pathological T cells. This approach, which was named as PPCA (p53 potentiation with checkpoint abrogation), is a therapeutic modality for selective, antigen-specific immune modulation that could have implications for the treatment of immune diseases. The study is published in the  Proceedings of the National Academy of Sciences.
 
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