Defensin hBD2 Treats Colitis as Effectively as Anti-TNF and Steroids in Three Mouse Models

Systemically administered recombinant hBD2 showed therapeutic efficacy in three distinct colitis models: DSS-induced mucosal injury, TNBS-induced loss of mucosal tolerance, and T-cell transfer colitis. In all three models, hBD2 reduced inflammation, improved disease activity index, and prevented colitis-induced weight loss.

The effectiveness matched anti-TNF-alpha treatment and steroids, which are current standard-of-care therapies for inflammatory bowel disease.

Mechanistically, hBD2 targeted dendritic cells through the CCR2 receptor. It decreased NF-kB phosphorylation (the main inflammatory switch) and increased CREB phosphorylation in these cells, effectively reprogramming them from pro-inflammatory to anti-inflammatory. This is the first study showing in vivo efficacy of a systemically administered defensin.

Inflammatory bowel disease (IBD) affects millions of people, and current treatments like anti-TNF drugs have significant side effects and stop working over time. A naturally occurring defensin peptide that matches their effectiveness could represent an entirely new class of IBD therapy.

The fact that hBD2 worked across three different colitis models, each representing a different disease mechanism, suggests it could be broadly effective rather than limited to one type of IBD.

These were mouse models of colitis, which do not perfectly replicate human IBD. The optimal dosing, frequency, and route of administration for humans are unknown.

Long-term safety of systemic defensin administration was not assessed. As a peptide, hBD2 would likely need injection rather than oral administration.