To treat autoimmune diseases like multiple sclerosis (MS) and hemophagocytic lymphohistiocytosis (HLH), it’s important to sacrifice as few healthy immune cells as possible. While the autoimmune reaction is indeed damaging to the body, the immune system is still needed for protection against regular exposure to agents like viruses and bacteria. A new approach seems to find the right balance, from scientists at Cincinnati Children's Hospital Medical Center.
In mouse models of both MS and HLH, researchers saw that genomic stress results in DNA damage in rapidly expanding T cells. "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," described lead author Michael B. Jordan, MD.
Jordan’s study involved inhibiting the normal process of DNA damage repair in MS and HLH mouse model cells. They used nutlin molecules to alter p53 activity, a protein responsible for regulating DNA damage repair. Additionally, CHK1/2 and WEE1 cell cycle checkpoint proteins were inhibited. “We threw them off balance and into a chasm of death,” Jordan explained
After manipulating the cells to inhibit DNA repair, researchers applied their new treatment approach, “p53 potentiation with checkpoint abrogation,” or PPCA. Abrogation describes a method of treating cancer where cell cycle checkpoints are inhibited.
In HLH mouse models, researchers saw PPCA reducing disease and improving long-term survival. In mouse models of MS, the treatment eliminated “aggressively expanding” T cells and “either reversed or prevented paralysis. While the present findings are promising, the study researchers stress that much research still needed to illustrate how PPCA could one day be applied to human cases of immune diseases like MS and HLH.
MS is characterized by an autoimmune attack on the central nervous system, specifically the protective layer of myelin sheath that coats and insulates nerves. Because of this attack, MS results in muscle weakness, numbness, or loss of coordination.
HLH is a disease caused by too many activated immune cells, either an acquired condition through viral or bacterial infections or an inherited condition through genetic mutations.
HLH can cause a variety of symptoms, including fever, enlarged liver or spleen, cytopenia, and neurological abnormalities. Treatment options vary depending on the source of disease: antibiotics and antivirals are used to treat the infections that triggered HLH and allogeneic hematopoietic cell transplantation, chemotherapy, and immunotherapy are options to replace or destroy excess immune cells in cases of inherited HLH.
The present study was published in the journal PNAS Early Edition.