lupus researchers iron out details of ‘exciting’ new approach to therapy
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an analysis of t cells from lupus patients revealed that expression of the transferrin receptor correlated with disease severity. getty
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a team of researchers has moved tantalizingly close to a new therapy for lupus by targeting the way in which t cells metabolize iron.
the research, published in the journal science immunology, found that blocking an iron uptake receptor not only reduced the pathology of systemic lupus erythematosus (sle) in mice models, it promoted the activity of anti-inflammatory regulatory t cells.
it is estimated that between 15,000 and 50,000 canadians are currently living with lupus, a baffling chronic disease in which the immune system mistakenly attacks healthy tissue instead of actual threats to the body. according to lupus canada, these attacks can target any tissue or organ — including the skin, muscles, joints, blood, heart, lungs and brain — causing pain, inflammation and tissue damage.
treatments for the disease, which focus on controlling symptoms and protecting organs from the immune system, have been hard to come by, with only one drug (belimumab) currently approved for use against sle, the most common form of the disease.
“it has been a real challenge to come up with new therapies for lupus,” said jeffrey rathmell, professor of pathology, microbiology and immunology at vanderbilt university medical center in tennessee. “the patient population and the disease are heterogeneous, which makes it difficult to design and conduct clinical trials.”
“it has been a real challenge to come up with new therapies for lupus,” said jeffrey rathmell, professor of pathology, microbiology and immunology at vanderbilt university medical center in tennessee. “the patient population and the disease are heterogeneous, which makes it difficult to design and conduct clinical trials.”
this may have changed when one of rathmell’s postdoctoral fellows observed that iron seemed to be a “common denominator in many of the problems in t cells.” she was equally intrigued by the finding that, despite a tendency to be anemic, patients with lupus had t cells with high iron levels. “it was not clear why the t cells were high in iron, or what that meant,” said voss, first author of the paper.
to explore these peculiar findings, voss used a crispr genome editing tool to evaluate iron-handling genes in t cells. this led to the discovery that the transferrin receptor, a carrier protein that imports iron into cells, was critical to inflammatory t cells and inhibitory to anti-inflammatory regulatory t cells. this receptor, which was more highly expressed in t cells found in sle-prone mice and human lupus patients, caused cells to accumulate too much iron.
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“we see a lot of complications coming from that — the mitochondria don’t function properly, and other signaling pathways are altered,” voss said. “when the team used an antibody to block the transferrin receptor, they found it reduced the level of iron within t cells, inhibited inflammatory t cell activity and enhanced regulatory t cell activity. treating sle-prone mice with this antibody reduced kidney and liver pathology and resulted in elevated levels of an anti-inflammatory factor known as il-10.
“it was really surprising and exciting to find different effects of the transferrin receptor in different types of t cells,” 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.”
an analysis of t cells from lupus patients revealed that expression of the transferrin receptor correlated with disease severity. blocking the receptor in vitro was found to promote the production of il-10. spurred by these findings, the team hopes to develop transferrin receptor antibodies that are capable of binding directly to t cells to prevent any off-target effects of future therapy. they also plan to explore why blocking this particular receptor had the unexpected effect of enhancing regulatory t cell activity.
dave yasvinski is a toronto-based writer.
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