December 14, 2020
In a recent study published in the Journal of Immunology, LRA-funded researcher Dr. John Zhang at Medical University of South Carolina found that a protein called Fli-1 causes immune cells to produce a molecule that causes inflammation. When Fli-1 was hindered by the chemotherapeutic drug camptothecin, immune cells produced fewer inflammatory molecules. These results suggest that an existing cancer drug could lower inflammation caused by immune cells in lupus.
Increased Fli-1 within immune cells correlates with active disease in lupus patients and with kidney problems in laboratory mice similar to lupus nephritis in humans. Lupus nephritis, inflammation of the kidneys, is one of the most common and dangerous complications from lupus. Fli-1 contributes to lupus by triggering immune cells to produce extra proteins called cytokines that promote inflammation. Normally, cytokines regulate the immune system like a thermostat, balancing inflammation with tissue repair. In lupus patients, Fli-1 upsets the body’s balance between inflammation and repair, causing lupus flares and complications like lupus nephritis. Although scientists know several cytokines that are produced in response to Fli-1, more may exist. In this study, Dr. Zhang investigated whether Fli-1 helps immune cells produce GM-CSF, a cytokine that contributes to rheumatoid arthritis and may also contribute to lupus.
To find out if Fli-1 helps create GM-CSF in immune cells, Dr. Zhang and his colleagues took cells from normal mice and from mice that were engineered to lack the genetic material to produce Fli-1. By growing the cells in the lab, he and his team measured the impact of Fli-1 on GM-CSF production. They discovered that immune cells lacking Fli-1 had decreased GM-CSF compared to cells from normal mice. To see if this was also true in humans, he treated human immune cells with camptothecin, a chemotherapy drug that interferes with Fli-1. Using this drug, Dr. Zhang and his colleagues successfully decreased GM-CSF production in human cells.
Dr. Zhang’s findings suggest that existing drugs against Fli-1 are effective in reducing GM-CSF produced by immune cells. If GM-CSF turns out to be important during lupus, researchers can conduct clinical trials to test camptothecin for this use. Since four camptothecin analogues have been approved and are used in cancer, the time necessary to test it as a treatment for lupus would likely be reduced.