Santucci L et al. (2007) GITR modulates innate and adaptive mucosal immunity during the development of experimental colitis in mice. Gut 56: 52–60

The mechanism underlying mucosal damage in IBD could involve a dysregulated, extreme T-cell response to normal enteric bacteria, and inhibition of this immune response could potentially be an effective treatment for IBD. Santucci and colleagues investigated the role of tumor necrosis factor receptor superfamily member 18 (Tnfrsf18, formerly Gitr) in two mouse models of colitis. Tnfrsf18 is highly expressed on regulatory T cells and cells of the mucosal immune system, while its ligand is expressed on antigen-presenting cells. Interaction between Tnfrsf18 and its ligand coactivates effector T cells and reverses the suppressor function of regulatory T cells, both of which upregulate T-cell activation.

Tnfrsf18−/− mice were protected against colitis induced by intrarectal instillation of 2,4,6-trinitrobenzene sulphonic acid, because Tnfrsf18−/− mice had reduced innate and adaptive immune responses (the authors attributed the subnormal T-cell response observed in Tnfrsf18−/− mice to low levels of interleukin 12 released from mucosal antigen-presenting cells). T cells from Tnfrsf18−/− mice were less effective than T cells from wild-type mice in transferring colitis to immunodeficient mice. Blockade of the Tnfrsf18 ligand (by administration of a soluble Tnfrsf18–Fc fusion protein) prevented chemically-induced colitis in wild-type mice, and also prevented T-cell-mediated transfer of colitis to immunodeficient mice.

The authors conclude that Tnfrsf18 has a crucial role in regulation of both innate and acquired immune responses in mice, and suggest that TNFRSF18 or its ligand could be a valid target for IBD therapy in humans.