Fifty percent—that’s the percentage of patients with inflammatory bowel disease (IBD) who experience long-term benefits from anti-inflammatory drugs commonly prescribed to manage the debilitating condition. These treatments block an inflammatory cytokine called tumor necrosis factor-alpha, or TNF-alpha, from latching on to its receptors on intestinal tissues, thereby setting off uncontrolled inflammation and tissue destruction.
However, only a subset of patients sees a long-term improvement from taking these TNF-alpha-blocking therapies, driving researchers at the University of California-Riverside to look for more targeted approaches against IBD.
An estimated 3 million adults in the U.S. received an IBD diagnosis in 2015, with the disease more likely to affect older adults. Patients with IBD also have an elevated risk of developing other conditions, including cancer, liver disease, and cardiovascular disease.
A team led by David D. Lo used an animal model of IBD to investigate some of the molecular mechanisms involved in the disease’s pathology. According to the authors, TNF-alpha is known to target two distinct receptors, TNFR1 and TNFR2. Clinically-available biologic therapies for IBD typically ‘switch off’ both receptors as a means of controlling TNF-alpha’s pro-inflammatory effects.
However, Lo’s team found that TNF-alpha’s involvement in IBD pathology is more complex than once thought. While the cytokine promotes inflammation by binding to TNFR1, it has the opposite effect when TNF-alpha binds to TNRF2, and here, it activates healing and anti-inflammatory pathways.
“If you block both the receptors, you block the destructive effects and the recovery,” said Lo. “To circumvent this, in our work we opted to do selective targeting of TNFR1.”
The scientists used a molecule that selectively inhibited TNFR1 to treat animals in a mouse model of IBD to test their hypothesis. They found that mice had better healing outcomes when TNFR1 cell signaling pathways were blocked.
TNF-alpha is also involved in other disease pathways, including rheumatoid arthritis and multiple sclerosis, so insights from this study may also offer alternative strategies for managing these conditions. “It’s about continuously finding better cutting-edge drugs and better targets to treat diseases,” concluded Lo.