Study identifies potential new approach to treating lupus – Zoo House News
Targeting iron metabolism in cells of the immune system could offer a new approach to treating systemic lupus erythematosus (SLE) – the most common form of the chronic autoimmune disease lupus.
A multidisciplinary team of researchers at Vanderbilt University Medical Center has discovered that blocking an iron uptake receptor reduces disease pathology and promotes anti-inflammatory regulatory T cell activity in a mouse model of SLE. The results were published Jan. 13 in the journal Science Immunology.
Lupus, including SLE, occurs when the immune system attacks a person’s own healthy tissues, causing pain, inflammation, and tissue damage. Lupus most commonly affects the skin, joints, brain, lungs, kidneys, and blood vessels. According to the Lupus Foundation of America, approximately 1.5 million Americans and 5 million people worldwide have some form of lupus.
Treatments for lupus aim to control symptoms, reduce immune system attacks on tissues, and protect organs from damage. Only one targeted biologic was approved for the treatment of SLE in 2011, belimumab.
“It has been a real challenge to develop new therapies for lupus,” said Jeffrey Rathmell, PhD, professor of pathology, microbiology and immunology and the Cornelius Vanderbilt Chair in Immunobiology. “The patient population and the disease are heterogeneous, which makes designing and conducting clinical trials difficult.”
Rathmell’s group has long been interested in lupus as part of broader efforts to understand the mechanisms of autoimmunity.
When postdoctoral researcher Kelsey Voss, PhD, began studying T-cell metabolism in lupus, she noticed that iron seemed to be a “common denominator in many problems in T-cells,” she said. She was also intrigued by the finding that T cells from patients with lupus have high levels of iron, even though the patients are often anemic.
“It wasn’t clear why the T cells had high iron levels or what that meant,” said Voss, first author of the Science Immunology article.
To explore T-cell iron metabolism in lupus, Voss and Rathmell drew on the expertise of other researchers at the VUMC:
Eric Skaar, PhD, and his team are experienced in the study of iron and other metals;
Amy Major, PhD, and her group provided a mouse model of SLE; and
Michelle Ormseth, MD, MSCI, and her team recruited patients with SLE to provide blood samples.
First, Voss used a CRISPR genome editing screen to evaluate genes involved in handling iron in T cells. She identified the transferrin receptor, which imports iron into cells, as critical for inflammatory T cells and inhibitory for anti-inflammatory regulatory T cells.
The researchers found that the transferrin receptor was more highly expressed on T cells from SLE-prone mice and T cells from patients with SLE, causing the cells to accumulate too much iron.
“We see a lot of complications that result from this — the mitochondria don’t function properly and other signaling pathways are altered,” Voss said.
An antibody that blocks the transferrin receptor decreased intracellular iron levels, inhibited inflammatory T cell activity and enhanced regulatory T cell activity. Treating 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,” said Voss. “If you’re trying to fight an autoimmune disease by affecting T-cell function, you want to inhibit inflammatory T-cells but not damage regulatory T-cells. That is exactly what the attack on the transferrin receptor did.”
In T cells from patients with lupus, transferrin receptor expression correlated with disease severity and receptor blockade enhanced IL-10 production in vitro.
Researchers are interested in developing transferrin receptor antibodies that specifically bind to T cells to avoid 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 T cell regulatory activity.
Skaar is the Ernest W. Goodpasture Professor of Pathology and Director of the Vanderbilt Institute for Infection, Immunology, and Inflammation. Major, Associate Professor of Medicine, and Ormseth, Assistant Professor of Medicine, are faculty members in the Department of Rheumatology and Immunology. Rathmell is director of the Vanderbilt Center for Immunobiology.
Other authors of the study are Allison Sewell, Evan Krystofiak, PhD, Katherine Gibson-Corley, DVM, PhD, Arissa Young, MD, Jacob Basham, MD, Ayaka Sugiura, PhD, Emily Arner, PhD, William Beavers, PhD, Dillon Kunkle, PhD, Megan Dickson, Gabriel Needle, and W Kimryn Rathmell, MD, PhD.
The research was supported by the National Institutes of Health (grant DK105550, AI153167, DK101003, AI150701, CA253718) and the Lupus Research Alliance’s William Paul Distinguished Innovator Award to Jeffrey Rathmell.