New Approach May Better Treat SLE

Findings in a recent study conducted at Vanderbilt University Medical Center suggest that targeting iron metabolism in immune system cells may offer a new approach for treating systemic lupus erythematosus (SLE) — the most common form of the chronic autoimmune disease lupus. Specifically, blocking an iron uptake receptor reduces disease pathology and promotes the activity of anti-inflammatory regulatory T cells in a mouse model of SLE.

The study was conducted based on postdoctoral fellow Kelsey Voss, PhD, who found iron appeared to be a “common denominator in many of the problems in T cells.” To explore T cell iron metabolism in lupus, Dr. Voss and Jeffrey Rathmell, PhD, professor of pathology, microbiology and immunology and Cornelius Vanderbilt chair in immunobiology, used a CRISPR genome editing screen to evaluate iron-handling genes in T cells. They identified the transferrin receptor, which imports iron into cells, as critical for inflammatory T cells and inhibitory for anti-inflammatory regulatory T cells. They also found that the transferrin receptor was more highly expressed on T cells from SLE-prone mice and T cells from patients with SLE, which caused the cells to accumulate too much iron.

According to Dr. Voss, an antibody that blocks the transferrin receptor reduced intracellular iron levels, inhibited inflammatory T cell activity and enhanced regulatory T cell activity. Treatment of SLE-prone mice with the antibody reduced kidney and liver pathology and increased production of the anti-inflammatory factor, IL-10.

“It was really surprising and exciting to find different effects of the transferrin receptor in different types of T cells,” Dr. Voss said. “If you’re trying to target an autoimmune disease by affecting T cell function, you want to inhibit inflammatory T cells but not harm regulatory T cells. That’s exactly what targeting the transferrin receptor did.”

In T cells from patients with lupus, expression of the transferrin receptor correlated with disease severity, and blocking the receptor in vitro enhanced production of IL-10. The researchers are interested in developing transferrin receptor antibodies that bind specifically to T cells to avoid any potential off-target effects (the transferrin receptor mediates iron uptake in many cell types). They are also interested in studying the details of their unexpected discovery that blocking the transferrin receptor enhances regulatory T cell activity.