Targeting the human βc receptor inhibits contact dermatitis in a transgenic mouse model.

Allergic contact dermatitis (ACD) is a prevalent and poorly controlled inflammatory disease caused by skin infiltration of T cells and granulocytes. The βc cytokines GM-CSF, IL-3 and IL-5 are powerful regulators of granulocyte function that signal through their common receptor subunit βc, a property that has made βc an attractive target to simultaneously inhibit these cytokines. However, the species specificity of βc has precluded testing of inhibitors of human βc in mouse models. To overcome this problem, we developed a human βc receptor transgenic (hβcTg) mouse strain with hematopoietic cell-specific expression of human βc instead of mouse βc. hβcTg cells responded to mouse GM-CSF and IL-5 but not IL-3 in vitro and developed tissue pathology and cellular inflammation comparable to wild-type mice in a model of ACD. Similarly, IL-3-/- mice developed ACD pathology comparable to wild-type mice. Importantly, the blocking anti-human βc antibody CSL311 strongly suppressed ear pinna thickening and histopathological changes typical of ACD and reduced accumulation of neutrophils, mast cells and eosinophils in the skin. These results show that GM-CSF and IL-5, but not IL-3 are major mediators of ACD and define the hβcTg mouse as a unique platform to test inhibitors of βcin vivo.