Siva Kumar Kolluri, Ph.D., Nancy Kerkvliet, Ph.D.
Oregon State University
NIEHS Grants R01ES016651, P30ES000210
NIEHS grantees have discovered a compound that could be a safer alternative for treating autoimmune diseases. The compound works differently than currently used drugs, and the researchers think that it will likely have fewer side effects.
In previous work, the researchers had discovered that the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppressed the immune system by targeting the aryl hydrocarbon receptor (AhR) in T cells. The researchers used this knowledge to screen for compounds that activated AhR without harming cells and identified 10-chloro-7H-benzimidazo[2,1-a]benzo[de]Iso-quinolin-7-one (10-Cl-BBQ) as a candidate. Further analysis showed that 10-Cl-BBQ binds to AhR inside T cells and changes the cells into regulatory T cells, which suppress the immune response.
The researchers tested 10-Cl-BBQ in mice with graft-versus-host disease, a condition in which the immune system tries to eliminate foreign cells. Daily injections of 10-Cl-BBQ completely suppressed the disease. The compound was rapidly metabolized and excreted and was not toxic at the dosage used, making it a potential candidate for drug development.
Citation: Punj S, Kopparapu P, Jang HS, Phillips JL, Pennington J, Rohlman D, O’Donnell E, Iversen PL, Kolluri SK, Kerkvliet NI. 2014. Benzimidazoisoquinolines: a new class of rapidly metabolized aryl hydrocarbon receptor (AhR) ligands that induce AhR-dependent Tregs and prevent murine graft-versus-host disease. PLoS One 9(2):e88726.