Targeting the Human β c 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 beta common (β _c ) cytokines GM-CSF, IL-3, and IL-5 are powerful regulators of granulocyte function that signal through their common receptor subunit β _c , a property that has made β _c an attractive target to simultaneously inhibit these cytokines. However, the species specificity of β _c has precluded testing of inhibitors of human β _c in mouse models. To overcome this problem, we developed a human β _c receptor transgenic mouse strain with a hematopoietic cell‒specific expression of human β _c instead of mouse β _c . Human β _c receptor transgenic cells responded to mouse GM-CSF and IL-5 but not to IL-3 in vitro and developed tissue pathology and cellular inflammation comparable with those in wild-type mice in a model of ACD. Similarly, Il3 ^-/- mice developed ACD pathology comparable with that of wild-type mice. Importantly, the blocking anti-human β _c 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 human β _c receptor transgenic mouse as a unique platform to test the inhibitors of β _c in vivo.
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